edqm pat proceedings, 2004

2000

COUNCILOF EUROPE

CONSEILDE L'EUROPE

Cannes, 3-4 May 2004

Process Analytical Technologies

PROCEEDINGS


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Proceedings of the International Symposium, Cannes, 3-4 May 2004 © Council of Europe

TABLE OF CONTENTS

WELCOME ADDRESS Prof. Dr H. G. Kristensen, Chair of the European Pharmacopoeia Commission ................................ 3 SESSION I: PROCESS ANALYTICAL TECHNOLOGIES: ROLE OF THE PHARMACOPOEIA Process analytical technologies in the manufacture of medicinal products: an overview Mr Silvano Lonardi, GlaxoSmithKline (I)........................................................................................... 9 Viewpoint of the regulators: How can the Pharmacopoeia contribute to regulatory assessment of PAT? Dr Jean-Louis Robert, Chair Joint CVMP/CPMP Quality Working Party, (QWP, EMEA)............. 15 The PAT Initiative: PAT and Pharmacopoeias Dr Ajaz Hussain, FDA (USA) ........................................................................................................... 21 A perspective and overview of Process Analytical Technology (PAT) Mr Gary Ritchie, United States Pharmacopeia (USP) (USA) ........................................................... 31 Process analytical technologies currently in use, or under development: What role for the Pharmacopoeias? Dr Alistair Swanson, Pfizer (UK) ...................................................................................................... 37 PAT experiences in the paper and pulp industries Dr Ralf Marbach, VTT (FIN) ............................................................................................................ 39 SESSION II: SPECIFIC TECHNOLOGIES/ TEST METHODS TO BE APPLIED The integration and use of vibrational spectroscopy sensors in PAT Technology Dr Mats Josefson, AstraZeneca (S) ................................................................................................... 45 Making sense of multivariate data Prof. Tom Fearn, University College, London (UK)......................................................................... 51 Acoustics Dr Ron Belchamber, Process Analysis & Automation Ltd. (UK) ..................................................... 55 Processability and functionality of excipients Mr Steve Hammond, Pfizer (UK) ...................................................................................................... 59 Implementation of PAT in automated tabletting Mr Ivor Pegington, MSD (UK).......................................................................................................... 63 Use of imaging to understand tablet performance Ms Fiona Clarke, Pfizer (UK)............................................................................................................ 67


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Applications of PAT in API manufacture Dr Chris Killen, GlaxoSmithKline (UK) .......................................................................................... 71 Rapid methods in microbiology in the PAT Process Dr Sylvie Guyomard- Devanlay, Aventis Pharma (F) ...................................................................... 77 Software validation Dr Ciro Cottini, GlaxoSmithKline (I) ................................................................................................ 89 Qualification of PAT instruments in contrast to conventional analytical systems Mr Steve Hammond, Pfizer (UK) ...................................................................................................... 95 Relationship of in-process specifications to expectations for the final product – Moving from the sample to the batch Dr Arne Torstensson, AstraZeneca (S) ............................................................................................ 101 Design and implementation of quality systems based on PAT. In-depth process understanding to improve quality Prof. Staffan Folestad, AstraZeneca (S)........................................................................................... 105 Continuous processes: New concepts compared to batch processes in philosophy Dr David Rudd, GSK (UK) ............................................................................................................. 107 SESSION III: PAT AND THE PHARMACOPOEIA FINAL ROUND TABLE DISCUSSION

- Impact of PAT on Pharmacopoeia standards - New general chapters - Expectations of users - International Harmonisation: - The need to prospectively harmonise pharmacopoeial monographs and methods With the participation of: Prof. H. G. Kristensen (Ph. Eur), Dr J.-L. Robert (QWP, EMEA), Mr G. Ritchie (USP), Dr A. Hussain (FDA), Prof. T. Moffat (RSPGB), Dr J. Berridge (EFPIA) and Dr C. Potter (EFPIA). ...................................................................................................................... 115 BIOGRAPHICAL NOTES ........................................................................................................... 129 FINAL LIST OF PARTICIPANTS ............................................................................................. 135


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WELCOME ADDRESS

Prof. Dr Henning G. Kristensen, Chair of the European Pharmacopoeia Commission On behalf of the European Pharmacopoeia Commission and the EDQM I am pleased to welcome all of you to this symposium on Process Analytical Technologies (PAT). The symposium has attracted approximately 135 participants coming from 25 different countries. I will in particular welcome the invited speakers. Your contributions to our discussion on the role of the Pharmacopoeia in the development and regulatory assessment of PAT are highly appreciated. The program for the symposium is organised by a Programme Committee counting members from the EDQM, the European Pharmacopoeia Commission, national authorities and European pharmaceutical companies. I will thank each of you for your assistance in developing an interesting programme. The Process Analytical Technology initiative launched by the Food and Drug Administration (FDA) in 2002 encourages the concepts of quality by design, process- and product monitoring methods through advanced instrumentation and data collection and evaluation. Thus, PAT focuses on the principles of building quality into the product during the manufacturing process. The idea of building quality into the product instead of ensuring quality by testing is not new. It has been practised for years in the field of sterilisation processes, in Europe under the name ‘parametric release’. The reference materials distributed to participants contain the Note for guidance on parametric release and a copy of Annex 17 to the European Union (EU) Good Manufacturing Practices (GMP) guide. The PAT concept develops very fast. To day we have available a range of advanced analytical methods including methods for data processing, which allow the monitoring of manufacturing processes of solid dosage forms as well as other dosage forms. In the field of food processing, for example, implementation of process analytical chemistry seems well advanced. The idea to organise a conference on the impact of PAT on the Pharmacopoeia came up one year ago, when EDQM organised a meeting on microbiological methods. During the discussions at that meeting it became clear that there are obstacles to the introduction of rapid microbiological methods in the production of pharmaceuticals, in particular with regard to validation of modern methods against the traditional pharmacopoeia methods. You can see it as a kind of conflict between the performance tests presented in the Pharmacopoeia and the use of alternative testing methods. The Pharmacopoeia presents in general monographs and specific monographs requirements on the quality of pharmaceuticals that have to be met in their lifetime. It has been said that the PAT initiative is incompatible with pharmacopoeia quality standards. I do not see it this way. General Notices of the European Pharmacopoeia states in its Chapter 1.1 that an article must comply with all the requirements stated in the monograph, but this does not imply that performance of all the tests is necessary for assessing compliance with the Pharmacopoeia before release of the product. It is stated further, that the manufacturer may obtain assurance that a product is of pharmacopoeia quality from data derived, for example, from validation studies of the manufacturing process and from in-process controls. Parametric release in circumstances deemed appropriate by the competent authority is thus not precluded by the need to comply with the Pharmacopoeia.


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The quotations from General Notices show that there is room for PAT systems in the European Pharmacopoeia. In the case of modern microbiological methods (MMM), the Pharmacopoeia Commission decided June 2003 to establish a Working Party to elaborate a general chapter for information on the validation of alternative microbiological methods. I have already seen the first draft from the Working Party and hope it can be published for public inquiry late this year. The Pharmacopoeia cannot and shall not address all thinkable aspects of PAT. For the purpose of this meeting and for the purpose of pharmacopoeia progresses it will be appropriate to consider the tool box by which I mean the range of analytical techniques, but not the way there are used in specific processes. Questions to be discussed at this symposium and to be concluded upon so proposals can be handed over to the European Pharmacopoeia Commission are first of all how the Pharmacopoeia can assist in the regulatory acceptance of PAT systems. Do we need new general methods in the Pharmacopoeia, and do we need to adapt existing general methods and general chapters to take account of PAT? Many efforts have been made in the last few years by the Pharmacopoeia Commission to meet the needs by manufacturers and regulators in ensuring the marketing of safe and effective drug products. Consider, for example, the introduction of functionality-related characteristics in standards on excipient materials. The aim of that work is to provide suppliers and users of excipients with a common language and, thereby, facilitate the setting of appropriate specifications, and also to provide regulators with data obtained by analytical methods that have been independently assessed. A parallel can be drawn to the PAT initiative. Standards or general texts on instrument qualification, data treatment, statistical methods etc. should facilitate the introduction of PAT systems. I do not know whether the current Pharmacopoeia specifications for raw materials and finished products represent difficulties with regard to PAT systems. I can imagine that the traditional way of expressing quality in terms of a sample plan together with acceptance criteria is a crucial point. For example, specifications for dose uniformity based on a certain sample size may give rise to concern when a PAT system is to be validated against the Pharmacopoeia’s specification. Pharmacopoeia specifications are generally not designed for batch release, rather for use by the so-called ‘independent controller’, who has no knowledge about the manufacturers specification and release tests. Possibly, we are at the stage where Pharmacopoeia quality specifications for finished products should be expressed in a manner making the connection to batch release more transparent. New initiatives within the European Pharmacopoeia are not taken without reporting to the Pharmacopoeial Discussion Group, the PDG, with a view to possible harmonisation among the three major pharmacopoeias. The outcome of this symposium in the form of recommendations will be reported to and discussed by the PDG. The programme for the symposium is divided into three Sessions. Session I, this morning, is devoted to role of the Pharmacopoeia. Session II stating in the afternoon and continuing to morrow morning concerns specific technologies. Finally, tomorrow after lunch a final round table discussion will take part. I will invite all participants to take part in the discussions following each presentation and to contribute to the round table discussion. The outcome of the discussions will be presented to the European Pharmacopoeia Commission as a report, hopefully containing recommendations on initiatives to be taken by the Commission.


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Once again, I will welcome you to the symposium. I do hope you will take part in the discussions so we in the end can identify the role of pharmacopoeias in the PAT initiative and recommend actions to be taken by the European Pharmacopoeia as well as the Japanese and the United States Pharmacopoeia.


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SESSION I: PROCESS ANALYTICAL TECHNOLOGIES: ROLE OF THE PHARMACOPOEIA

Process analytical technologies in the manufacture of medicinal products: an overview Mr Silvano Lonardi, GlaxoSmithKline (I) Viewpoint of the regulators: How can the Pharmacopoeia contribute to regulatory assessment of PAT? Dr Jean-Louis Robert, Chair Joint CVMP/CPMP Quality Working Party, (QWP, EMEA) The PAT Initiative: PAT and Pharmacopoeias Dr Ajaz Hussain, FDA (USA) A perspective and overview of Process Analytical Technology (PAT) Mr Gary Ritchie, United States Pharmacopeia (USP) (USA) Process analytical technologies currently in use, or under development: What role for the Pharmacopoeias? Dr Alistair Swanson, Pfizer (UK) PAT experiences in the paper and pulp industries Dr Ralf Marbach, VTT (FIN)


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PAT in the Manufacture of Medicinal Products: an overview

Silvano Lonardi, Glaxosmithkline, Italy

Abstract: The PAT initiative aims to achieve higher quality medicines by transferring quality control from the product to the manufacturing process through a wider use of in-line and on-line measurement systems. The application of the PAT philosophy thus involves process design and the methodologies used for measuring output to deliver consistent product quality and a consistent product Prof.ile over time to the consumer. A part of this could be to extend the process signatures considered to the physical and mechanical domains as well as the chemical domain. The successful widespread application of PAT may require a culture shift in pharmaceutical companies, which a recent survey has shown still tend to place a higher value on product specifications rather than process understanding and related skills. Dr S. Lonardi’s slides are available on page 2 of the PAT-SessionI.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2

Drivers

Average human life expectancy has increased significantly since the beginning of the last century. A child born in the early 1900s could expect to live to the age of 55, which in today’s developed countries is considered middle age. Yet although the average European can now confidently expect to enjoy at least fifteen-to-twenty years of retirement, there is no shortage of challenges for those working in sectors where the aim is to help people increase their life span and quality of life. Today, one in five residents of the European Union, which enjoys the highest levels of healthcare in the world, still die prematurely, and World Health Organisation (WHO) statistics show there is still no effective cure for three-quarters of the 30,000 diseases known worldwide.

Companies in every industrial sector are constantly striving to meet customer needs more effectively by improving quality and reducing costs through increasingly efficient processes. This objective is arguably of even more crucial importance in the healthcare industry where improvements have a direct impact on the customer’s ability to enjoy the technological advances made in other areas. As part of its social role, the pharmaceutical industry must be able to guarantee consistent medicine quality, security of supply and reasonable prices while simultaneously striving to make improvements in all these areas.

It would be understandable for a lay person to assume that quality and choice are constantly rising despite the above statistics, given the plethora of products on the market and the multitude of related regulations and standards, not to mention the guidance offered by experts and official organisations such as the FDA and the European Medicines Agency (EMEA). And yet a careful analysis of the facts shows otherwise. The United States of America pharmaceutical industry saw an increase in manufacturing-related problems between 1998 and 2002, when the number of batch recalls doubled, resulting in potential essential drug supply problems, the disruption of manufacturing activities and an increase in unsuccessful drug approval applications that led to further cost increases.


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The PAT initiative aims to render manufacturing processes leaner and more cost effective through the use of in-line and on-line instrumentation. This means building quality control into the manufacturing process, an approach that was first adopted by Toyota many years ago, as has been well documented. Rather than periodically taking samples for analysis outside the production area, and incurring the resultant costs in terms of both time and money, manufacturers use real-time or near-real-time techniques to monitor and control their processes closely. As a result they know whether a critical value, such as the composition of a component, is out of range almost immediately and can promptly rectify the variance automatically, saving both time and materials. PAT builds on this with a wider use of multivariate statistics and chemometric rather than univariate analysis techniques, with benefits that include a reduction in production cycle times, rejects and waste.

Leaving aside the social costs of not improving the drug approval and supply processes, an appraisal of the costs involved in bringing a medicine to the patient underlines the importance of streamlining processes wherever possible. The average cost of a prescription in Europe was €10 in 2001, while the average weekly cost of a stay in hospital is 1,800 euros. Intensive care treatment weighs in at 720 euros a night, while the cost of researching and developing a single new medicine has been put at between 500 million Euros and 600 million Euros. At the same time, the 1% of gross domestic product that the average European country spends on medicines is set to double in the next few years.

The pharmaceutical industry is in general agreement regarding the scale of the improvements that need to be made. The demanding targets it has set itself include raising the average Stock Turn (ST) from between 3 and 5 to 14, increasing On Time In Full (OTIF) delivery from between 60% and 80% to 97.4%, and Right First Time (RFT) from between 85% and 95% to 96%. Cpk (capability index), a statistical process control measure of the variability of the product, is a further area for improvement. Other challenging objectives include more than doubling overall equipment effectiveness and bringing cycle times to around 10% of the total currently required. Last but not least, the industry aims to achieve a 50% reduction in the index for accidents at work.

At the same time, we need to ask ourselves how much we can improve our current processes and ways of measuring output when it comes to delivering consistent product quality to the consumer, and indeed a consistent product Profile to the consumer over time and across national boundaries. Good Manufacturing Practices have gone some way to supporting the interests of all stakeholders in the healthcare supply chain but have largely been based on ensuring that products meet their registered specifications rather than on building quality. Another limitation has been that product quality testing has so far been largely inferential, that is to say based on the assumption that if a small proportion of the total product output meets the required specifications, then the remainder is also likely to do so. This would be tantamount to carrying out a daily computer virus check that only looks for a limited number of virus activity signs in the programme functions, rather than designing and installing an all-encompassing updated antivirus system. The expression ‘all-encompassing’ is used intentionally since lab tests currently focus mainly on the chemical Profile of the product. Indeed, Pharmacopoeias and GMP were mainly created to provide chemical Profile guarantees.

Domains

To succeed fully in building quality into our products the output of manufacturing processes must be necessarily of the highest, most consistent quality, it is therefore first necessary to decide which


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processes need to be built and what they need to be built to ensure. Different examples of the same product output may well have a near identical process signature if tests are limited to its chemical domain, but vastly different process signatures if its physical or mechanical domains are taken into account, as can be seen in Figure 1.

Figure 1: Chemical and physical domain of 20 different manufacturing batches of the same drug product.

While the product's chemical formula may remain the same, one batch of tablets could have a different dissolution Prof.ile for example. Differences in production location and atmosphere or minor plant set-up variations can all result in variances in the properties of the finished product depending on the plant where it is produced, despite the same processes being applied and the same ingredients being used, as anyone who has ever tried to make a Pizza in England will know.

Tests carried out on a number of intermediate products showed little variance between the Prof.iles of batches produced in a European plant and those produced in a Far Eastern plant. Evaluation of the chemical domain did not reveal any differences. When the physical domain was tested, however, a variance was found between the two plants. Moreover, the mechanical domain still showed differences in the spectroscopic response even after the granules had been milled in an attempt to remove these physical differences. In other words, the resultant process signature showed that the batches had significantly different Prof.iles.

When applying the PAT philosophy, it will therefore be necessary to evaluate all the fields of activity over which we have control and to apply this philosophy in such a way to build quality into drug product or by the design of these processes. These areas will unquestionably include the product, chemical, physical and mechanical domains as well as the microbiological domain, measurement technologies, risk assessment techniques and the related skills required.

At present, 75% of products tested are non-sterile products and the remaining 25% sterile. Of the non-sterile products, 65% are solid and 35% semi-solid. These products/processes drive the selection of the different available measurement technologies. Current laboratory test practices enable the chemical domain to be tested but do not provide sufficient information on the other aspects of the product Profile. It is expected that the use of on-line Near-Infrared (NIR) technology will increase in the coming years to cover approximately 60% of process technologies in order to


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perform tests that provide a wider range of useful information, greater accuracy and an improved ability to process understanding.

Microbiological testing concerns only sterile products and are only laboratory based. When we look back on how sterility tests are performed today, we are likely to consider they were a rather hit-and-miss affair. One need simply consider, for example, that every time a batch of 100,000 units is produced, only 20 samples are taken for microbiological tests, in accordance with Pharmacopoeia requirements, to demonstrate that there has been no microbiological contamination. Whilst there is little probability of any existing contamination being detected (see Figure 2), the tests are at the same time also very time-consuming both in preparation and analysis. Additionally only around one-third of existing microorganisms grow in the culturable media currently used for performing these tests; therefore a different approach is not only desirable but also essential.

Figure 2: Risk analysis of current sterility test

Conclusions

Higher levels of test accuracy can be built into the processes we design using the PAT philosophy, as, indeed, can lower requirements for post-production testing. Quality can be built into the medicines by designing production process and utilising appropriate advanced software, ergonometrically-designed plant and other technological innovations. The aim for the future is therefore to transfer control from the product to the process, building a real-time quality control system into our production processes.

A recent survey on the importance of various skills and coursework when evaluating new employee candidates produced some interesting results. Whereas the more formal, regulatory requirements such as GMP attained high ratings, relatively little weight was given to areas relating to the process itself. Areas such as statistical process control and validation were not rated very highly as key employee competencies. It may therefore be necessary to engineer a cultural shift regarding how

0.5 1.0 1.5 2.0

010

2030

40

Contamination %

Sam

ple

size

Probability Curves

Batch size = 100.000 pieces


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skill bases are viewed, and to align them more closely to the requisites for improvement in total quality control in order to begin adopting the PAT philosophy and exploiting its full potential.

DISCUSSION Question from the floor: The axes on your figure risk analysis of actual stability test – what would the axes be? Dr S. Lonardi: It is .005 is the probability curve in percentage. It is the percentage of the products at the point of manufacture that are delivered right first time with no defects. Any recycling, blending or other adjustments are excluded from the right first time. Mr G. Ritchie: I have an interest in the spectroscopy, the part that you showed where you attempted to remove the physical effect of the offset of the spectroscopy by milling. One of the purposes of using the technology is to be able to come to a quicker conclusion of root cause analysis. Have you been able to solve that? Do you know why that off set still exists, even after milling? Dr S. Lonardi: We look at 2 different processes, the Far East and the European, just because there wasn’t a need to build another one and basically the performance of the Far East process was better than the European one. It has not been possible to determine exactly the reason why one plant was working better than the other. It was probably a series of combinations. Basically the accurate set up of Far East plant, rather than a European plant was the explanation of this.


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Viewpoint of the regulators: How can the European Pharmacopoeia

contribute to regulatory assessment of PAT?

Dr Jean-Louis Robert, Chair Joint CVMP/CPMP Quality Working Party, (QWP, EMEA)

Dr J-L. Robert’s slides are available on page 11 of the PAT-SessionI.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 Introduction Last Thursday we had a meeting of our Committee for Proprietary Medicinal Products (CPMP) PAT team and I will make this presentation on behalf of it. The composition of this European Union PAT team is 3 assessors, plus the Chair of the Quality Working Party, 3 inspectors plus the Chair of the Inspector’s Working Party and the European Directorate for the Quality of Medicines (EDQM) as an observer. More details about this team can be found on the EMEA internet site. PAT: setting the scene My presentation addresses general considerations on PAT, the challenge and claimed benefit for industry, the challenge for the regulators, the current PAT activities within the QWP/GMP-WP and I will end with some conclusions. The first point I want to address here, is the definition for Process Analytical Technologies and sometimes I wonder if we really use the correct terminology. If you take it as a very narrow definition you could say that it is analytical technology, which is used during process control. This starts with temperature measuring, HPLC, etc. Of course it’s also, and this is probably what we’ll talk about more today, NIRS, Raman, Acoustics, Laser-Induced Fluorescent Imaging Technology and so on. Our team likes very much the FDA definition for PAT. As you know this is defined in their PAT Guidance for Industry where PAT is considered to be a system for designing and controlling manufacturing under timely measurements during processing of critical quality and performance attributes for raw and in-process materials and processes with the goal of ensuring final product quality. What we like in this definition is that you have elements of pharmaceutical development and this is a very important point. In general I can say that the EU PAT team is very much in agreement with the framework of this document. Basically, we can say that the quality or specification of a medicinal product is essentially influenced by the characteristics/properties of the starting materials and the manufacturing process. Of course under characteristics/properties of the starting materials we include the active substances and the excipients, their chemical-physical characteristics, but also the chemical stability, the physical stability of these starting materials and of course the manufacturing process. I want also remind you the statement, which we will probably hear more often today, "Quality cannot be tested into products, but quality has to be built-in by design". Therefore PAT can be, and is, a high performant tool to design quality into the product, not only due to the possibility of real-time testing, but mainly by improving process understanding and this


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is a very important point. Often it is thought that you apply PAT or you apply advanced technology into your process and automatically it will be of some value. It is very important to apply it properly. That’s why I put this provocative sentence, ‘can be a high performance tool’; what is important here is really to identify what are the critical parameters, to identify what are the critical steps of the manufacturing process and then you have to choose the appropriate tool to control these critical steps in order to improve your process understanding. Again here, we are back to pharmaceutical development. This can of course equally apply to the drug substance and the drug product. We are very much talking about the drug product, but it’s the same philosophy, the same concept which can also be applied to the drug substance. Therefore PAT is one element of a broader process, which has received some dynamic with the FDA GMP initiative for the 21st century and continues within the ICH process. If initially the FDA GMP initiative was very much GMP driven, I think with time it became evident that it is not only GMP alone. It starts very much at an early step during pharmaceutical development and that’s why we have agreed to continue this process within ICH, having 2 expert groups working on 2 different guidelines – Q8 which is pharmaceutical development and Q9 which is risk-management. Of course these two topics are very much linked with each other and I think the challenge for the ICH expert working groups will be to mix appropriately between pharmaceutical development and risk-management. Q8 - Pharmaceutical development Just to give you the current definition for pharmaceutical development as it is proposed for the moment, because it can always change: the aim of the pharmaceutical development is to design a quality product and the manufacturing process, to deliver the product in a reproducible manner. It is a basis for risk-mitigation. Risk mitigation is also linked to PAT, because the better you control your process, the better you can assure risk mitigation. Q9 – Risk management The current wording in the proposed draft for risk management: the focus should be to identify hazards that have the potential for patient impact, that have the potential to affect product quality, safety and efficiency. PAT or advanced technology cannot only be used during a manufacturing process, but also sometimes to test the final drug product or substance. We have already received many submissions in Europe, where NIR spectroscopy is now used on a routine basis for the identification or assay of the final product. What is the claimed benefit for industry? We often hear that PAT will enable industry to have a better understanding of their process. It will give them the possibility of introducing

- real time release versus release testing, which is a better tool to ensure product quality, - reduction of cycle times, - less batch failure, - better management of changed controls and regulatory relief or more regulatory flexibility.

But where there is a benefit, there is also a challenge. I think the amount or level of information to be presented to the regulators will be important to be discussed further; chemometrics, statistics, to


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which we will be faced as regulators, a black tool or a black box? We were told data are not important, knowledge is important. Knowledge is based on data, so it is really a challenge for us as to how we will deal with this in the future. Also the correlation between measurements during the process and release testing specifications, which is still the basis for release of the batch will need to be discussed further. Challenge for regulators I think we have great experience in Europe with the concept of pharmaceutical development and also with the concept of risk based approach, even if we had not specifically mentioned the terminology risk based approach; I think in the CVMP/CPMP pharmaceutical development guideline, the idea of a concept of risk based approach is already included. We have also drafted a guideline on NIR spectroscopy. I know industry is not so happy with it, because it is going too much into details, it doesn’t give enough flexibility. On the other hand, you should know that all of our guidelines are recommendations, they are not mandatory. Will PAT become a standard requirement? I formulated the question slightly differently in my initial slides, but the PAT team told me that I should not be so provocative. The answer is no. It will not become a standard requirement in Europe. We have already seen this in the Q8 current draft, that we will have 2 approaches for pharmaceutical development, but being aware that we do not want to have differences in standards in Europe. So one of the approaches will be the minimum approach, which is currently requested for pharmaceutical development in the European Union anyhow. Then you can have an additional option which is the PAT concept if you like. This is very much the company strategic choice, which model he will choose in the future. Under additional option we understand better process understanding. This can be the basis for future regulatory relief. To illustrate this approach: this is a slide, which has been prepared by Dr J. Berridge after discussion, which we had in March 2004 at our expert working group. It shows you the variations in a manufacturing process. It should illustrate to you the difference between the traditional process with narrow operating parameters, and a more flexible approach based on more knowledge or understanding of the process. For these batches you will not be forced for each change in a process to submit a new variation, when these changes are within a well defined frame. So this is a concept, which we have for the moment, but as I said it already earlier it is a concept and we will have to work very much on how we will implement it in practice.

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ICH Q8: Discussion on Regulatory Flexibility

Var X

Var Y

Traditional process – limited knowledge – 3 batches, any change needs new data and new approval

New paradigm: influence of factors explored creating knowledge. Risk analysis of impact of change possible. Approval to move within defined area post-approval could give flexibility for continuous improvement without need for further approval


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The challenge for the regulators is that we will have to change our review process. There will be an enhanced collaboration necessary between assessors and inspectors needed already at time of submission and during the life cycle of the product. Clarification of respective responsibility, a new definition for the specification might be needed, for instance uniformity of dosage units depending if you perform real time release testing or release testing. Batch releasing from third countries, if a company which manufactures in a third country, which is outside the EU and which does not have a mutual recognition agreement: can we accept the PAT concept despite the fact that we are bound by the directive, which says that you have to test, (re-test) the product when it enters the European Union, last but not least the training aspects. Current PAT activities within QWP/GMP-WP The mandate of the PAT team is the following: to make proposals on the definition of PAT. We will have to review legal and procedural implications, review and assessment of mock submissions. I think that mock submissions are a very important tool because it will help us to better understand the information that needs to be submitted at time of submissions. We will review documents produced by other organisations, for instance the FDA Guideline. We have to install or set up a procedure for assessment of PAT related applications and to look at the interaction between assessors and inspectors. Potential contribution from the European Pharmacopoeia There was a lively debate with our team about the potential contribution from the European Pharmacopoeia. Is there a need for a contribution at all? I have to ask the question just like this. The fact is that the PAT concept is a very fast moving field: what is true today might be wrong already tomorrow, or at least out of date tomorrow. It is important to maintain flexibility in this field. I think the outcome of Q8 and Q9 should be awaited to better understand the future evolution. This is also one of the reasons why the EU or CPMP will not come up with an own guideline on PAT, because we really want to wait the outcome of Q8 and Q9, what will be addressed in these two guidelines and one of the topics which we will need to discuss in Q8 is this Process Analytical Technology concept. On the other hand, we have also to see that there are already elements of the PAT concept in the European Pharmacopoeia. Compliance with the Pharmacopoeia: the manufacturer may obtain assurance that the product is of pharmacopoeial quality from data derived for example from validation studies of the manufacturing process and from in-process controls, further we have the concepts of alternative methods of analysis or parametric release for the method of preparation of sterile products. This was also mentioned both by Prof.. H. G. Kristensen and Dr S. Lonardi. So we have already now in the European Pharmacopoeia elements of this PAT concept. Conclusion In conclusion, are regulations a barrier to PAT implementation? The answer very clearly is NO. Why can industry not introduce PAT into the manufacturing process on it’s own initiative already now? We think that the system is already in place to deal with it. What might be a problem or a barrier is probably the uncertainty of regulatory consequences: relief flexibility or whatever you want to call it; but if you never try, you will never know the answer. If industry is honest with the topic, I think you have on one side in your companies, the scientific people and you have the regulators. The scientists, as they are working in the manufacturing process or development, they are interested in science, they want to go forward to put science to the licensing authorities. On the other hand, the


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regulators in your companies are more interested in getting a marketing authorisation, they are not so much interested in science. Maybe the main barrier is a challenge in your own company. So PAT is already possible today, that’s our message. However, there are some challenges for both regulators and industry and we will have to work together on it. How will it be assessed. The balance between information in the dossier and on site, what is the adequate level of information, which has to be submitted to the licensing authorities. This is, I think, the challenge we will have in the future and we will have to work together and that’s why we are very keen to receive these mock submissions from industry. This will be of value both for regulators and industry to understand, what is the adequate level of information which needs to be submitted, because we are not interested in receiving a huge amount of data.

DISCUSSION Prof. Dr H. G. Kristensen: I think the most provocative slide you had was the question whether regulators represent a barrier to PAT and of course you say no. In a very fast, rapid changing environment you have to be very cautious, therefore I agree with you also and your comments whether the Pharmacopoeia should or could do anything now. We need to be very cautious because there is a need for flexibility. The point I made in my introduction is that in the future with a better understanding of PAT and PAT systems we can run into a situation where we need to express ourselves differently. You had a slide with the same viewpoint - Pharmacopoeia Specifications to be accepted by the regulators. If such a change should be made, we have to begin to think now because it will be a very long development. Question from the floor: I’m just interested to hear what kind of co-operation is with the FDA PAT team from this European PAT team you have now established. I have seen that a lot of work is going on in both places and as we are supplying our products to the whole world it would be beneficial if we work on the same track. I see from your presentation here that we are actually working on the same track, but could you elaborate about the co-operation and how you think the future will be between USA and Europe? Dr J–L. Robert: When we had our meeting last Thursday we had a teleconference with Dr A. Hussain and his FDA colleagues. So there is a collaboration with the FDA on this level. In Q8, the ICH process, we collaborate with the US and Japan and I think also there we will also address these PAT issues. This is one of the topics on our next agenda. In our first full meeting in March 2004 understanding but specifically the PAT issue will be discussed. So we have already in a certain sense a global collaboration here. The PAT team is of course dedicated to having an international collaboration. But of course we have also 25 member states since few days now and we have to make sure we also harmonise within the European Union, so it goes in two senses, regionally but also with Japan and the FDA together with industry of course.


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21



The PAT Initiative: PAT and Pharmacopoeias

Dr Ajaz Hussain, FDA (USA) Abstract: Process Analytical Technology is a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. The term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner. The PAT Initiative was designed as a directional vector for the broader FDA's CGMP Initiative that is also referred to as the Pharmaceutical Quality for the 21st Century Initiative. The PAT is an important directional vector intended to move the current regulatory system towards the desired state for pharmaceutical quality assessment in the 21st Century. This desired state includes application of regulatory policies tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability. Improving the FDA's ability to recognize scientific knowledge provides an opportunity for a industry sponsor to demonstrate that their product quality and performance were achieved and assured by design of effective and efficient manufacturing processes and that their proposed product specifications were based on mechanistic understanding of how formulation and process factors impact product performance. Sharing of this knowledge between FDA and industry sponsors provides an opportunity for risk based regulatory scrutiny that relates to: (1) level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance, and (2) the capability of process control strategies to prevent or mitigate risk of producing a poor quality product. A risk-based focus provides many public health benefits, for example improving the efficiency of the current process that delivers high quality drugs to the patients. Dr A. Hussain’s slides are available on page 19 of the PAT-SessionI.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 I was thinking about the title assigned to me, ’The FDA PAT Initiative?’ so I thought I would talk to you not only about the Process Analytical Technology initiative but also about PAT and the pharmacopoeias. The presentation outline is to share with you some thoughts on why we started the PAT initiative and how it is part of the Pharmaceutical Quality for the 21st Century Initiative and I completely agree with Dr J-L Robert, in the sense that this is not just about GMP but about the whole of quality. It is a review and inspections aspect of our work. I will talk to you about PAT and the USP, opportunities for the USP to support the PAT framework and what that might look like, what I would like to see it look like. In order to frame the presentation, I chose to use a change model to describe it. If you look at this bar, this is our new set of buildings – that’s my lab, that’s our research lab, that’s our review building and that’s our conference centre. We are moving to White Talk and that is a significant move, as it is the first time we actually will bring all of our CMC reviews together and you will see a new CMC process emerge when we move to this location in March 2005.


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Leading the change, I think that did have something influence on our direction but in order to change you have to articulate a shared need. You have to shape a shared vision. You have to mobilise commitment to go from what we think is the current state and opportunities to go to the desired state. You have to monitor progress. You never finish a job because everything is continuous improvement, you have to keep working at it. There’s nothing called finishing the job. How you anchor this in the culture is the framework of my talk. This slide (slide 3, PAT SessionI.pdf, EDQM internet site) has been shown already, but clearly one of the drivers was that quality standards are adequate and our quality is good, especially in reference to the US. There are many problems we are facing especially from a resource perspective at the FDA, but also that many major companies have warning letters. Many are under consent decree and this is not an ideal way of managing quality within the US. Think cost was also a driver. We have to realise that the cost of manufacturing can four times the cost of R&D. We talk about high R&D costs but the opportunity to improve efficiency was there. Actually if you improve efficiency by 50-60% you have a block-buster drug every year for a major company. Innovation and modernisation was slow. This was a high burden on FDA resources. Dr Woodcocke made this case at our FDA Science Board. When you look at some of the industry factors industry is reluctant to innovate and invest in manufacturing sectors. Some regard this sector as the poor step-child compared to R&D. Emphasis on getting products out discourages early work during development and we have to change after marketing. We have to deal with a number of supplements. The possible role of regulatory oversight might have caused unintended consequences. I think if you look at this from a regulatory perspective, 30 years ago FDA’s emphasis was on institution of basic procedures and record-keeping which evolved into GMPs. Currently, this is when we started this initiative two years ago, FDA’s attempting to drive innovation and investment in manufacturing sector with compliance and enforcement action and that model doesn’t work. We have literally half of the major companies in consent decree and in consent decree the judge and FDA essentially become the quality unit and that really doesn’t improve innovation. I think we felt very seriously that all we were doing was improving the quality of the paperwork and not of the manufacturing process. Therefore we have to think about a different approach to do this. An opportunity was Science, empirical methods are probably approaching their theoretical maximum effect in this. An empirical approach would be data driven decisions, which is the minimal requirement we have. New scientific understanding and new technology can provide a science-based approach and 2.5 years ago when we started this, we wanted to use PAT as a model and PAT was simply a seed crystal that led to the GMP initiative which led to the medical technology initiative and then we have a critical part initiative. So all initiatives started with PAT as a model. PAT is not a standard lone initiative anymore it is part of the strategic plan of the FDA. Again I will echo what Dr J-L Robert told before me. We have to think differently and this is a team approach. In order to shape a shared vision you have to think about a team approach to CMC review and CGMP inspection. The only reason I am showing you this slide is because it is the starting point for thinking about how you work as a team. The FDA – PAT team has a reviewers, assessors, inspectors and compliance officers working together. This team is trained together, certified together and we are managing the PAT steering committee policy and support team and training co-ordination. So training and certification was critical and team building was critical here and for example chemometrics, mathematical aspects were going to be a challenge and so we created a


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support team and hired experts to deal with that as a support consulting role for this team. Now the PAT initiative was a starting point for thinking broadly and this led to the 21st Century Initiative. I think we made the mistake of calling it GMPs for the 21st Century but subsequently every talk I have given, I have called it Pharmaceutical Quality for the 21st Century Initiative and because it covers GMP as well as CMC review. We defined 6 dimensions for that. Five dimensions are strong public health protection, integrated quality systems orientation and this is very important. You have to think about systems orientation rather than analytical chemistry process engineering and so forth. Science-based policies and standards, risk-based orientation and international co-operation. All of these things have been happening before, but the difference now is to actually think about the same challenges we have faced before, but in a more systems orientation way. We have been trying to build science-based policies for the last 30 years. What’s different now is a systems-orientation to all these activities that happened before. The 6th dimension, since we are working twice as hard, is that we still have our regular jobs, and we are still working on these initiatives, we said we couldn’t do this for a long period of time, so we said we will do if for two years and the dimension time is a 2 year period, but the dimension time is to identify all of the issues to be addressed, put them on the table and create a strategic plan for addressing all of those issues. All issues would not be solved in 2 years, but then we have a plan to solve them over the several years before. The opportunities that we are trying to build a shared vision on is the scientific. I think one of the challenges I faced was that I really could not understand the system. I have been at FDA for almost 10 years now and when I came to FDA, I came on the research side, I have been on the research side during most of my time at the FDA and I am looking at the CMC review process and said, “we don’t get a pharmaceutical development report like Europe. Why?” There were many reasons why. I think I like the European system from that perspective, on the European side is that the pharmaceutical development is there. I could see a lot of resistance from our CMC review staff to even move in that direction and I couldn’t understand that til it hit me that we don’t really have anyone who understands pharmaceutical development in our CMC review process. The challenge there was, that you have mostly biochemists and chemistry focus in our CMC review, so all focuses on the CMC part were being ignored. Hence I created this as a way forward, because pharmaceutical development manufacturing is evolving from an art to one that is not science and engineering based because a chemist looking at industrial pharmacy type submission and so forth looks at that as an art. No it’s not, you are ignoring 30 years of pharmaceutical sciences. So that was a way forward. Risk-mitigation and communication. Clearly we have been risk-based all of our lives, but we wanted to move from an acute and subjective approach to more quantitative approaches. Quality-systems thinking was the third opportunity. If you look at 1950’s sampling plants, zero defect movement, the European Quality Award, ISO, etc., these are all quality systems and there’s a lot of jargon associated with those quality systems, but they share a common-platform of systems thinking. If you look at those as milestones in quality they provide a way forward to bring a systems perspective to pharmaceutical quality assessment and assurance. So in order to bring that in a jargon free manner. In order to shape the vision we also had to have many public meetings and I have been travelling around the globe to do that and we had advisory committee discussions, FDA science-board


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discussions. We created a PAT sub-committee. Many of the members of that sub-committee are in this room. We had a very international committee in fact. There were a significant number of Europeans on that committee and that started because one of the first thought processes on the PAT status in Europe when discussed in the new technology forum and at that point that crystallized that thought and that thought was carried over because the Royal Pharmaceutical Society new technology forums, one of the meetings was a key point in that discussion. Now we are working on a manufacturing sub-committee. We had many conferences in Europe and Japan and US and led to the ICH meetings in Brussels, Japan and London and we look forward to that in Washington now. I think the key aspect of our desired state is to define a desired state. We think product quality and performance should be achieved and assured by design of effective and efficient manufacturing processes. This is key. Product specifications are based on mechanistic understanding of how formulation and process factors impact product performance – another important aspect - continuous real-time assurance of quality. All of these aspects do a better job in guaranteeing quality than from the current testing to document quality. But to make that happen our regulatory policies are tailored to recognise the level of scientific knowledge supporting product applications, process validation and process capability. In the US we were struggling with this because process validation to a large degree, we believe, has become a paper chase. It’s all documentation focused and this is not science and risk-based and so creates a lot of volume of material, which is not very useful. So we felt that every product on the US market is validated but many are not capable. So what does the process validation really mean? We are using process capability as a means to signify a change in process validation thinking in the US. Risk-based regulatory scrutiny would relate to level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance. This is a key, because to a large degree many companies are doing a lot more science. A lot more technology innovation and so forth, but that information is not shared with the regulators and again I recall what Dr J-L Robert said, the divide between information sharing, you have the scientists, you have the regulatory department and then you have the regulators. So, you have a filtering department ,which keeps the science away and I think that creates many of the challenges we have today. The capability of process control strategies is to prevent or mitigate risk of producing poor quality products. Clearly this focuses on entire CMC, but in a more science-based perspective. If you imagine this is an initiative with many dimensions, the key dimensions I talked to you about was science, risk and systems and integration approaches. Think of this as a multi dimensional plot we have PAT, but equally important is ICH, Q8 and Q9, but another thing we have done is more compatibility protocol to work on aseptic guidance. Our CFR Part 11 had to be addressed to support innovation. I think we went in the wrong direction in the original approach to how we tell with Part 11 what had to be addressed. Product specialists, our reviewers, our inspection process focusing on a pharmaceutical inspectorate, inspectors that only focus on pharmaceuticals and a high level of training and certification for them, were also in a large organisation. You need to have dispute resolution processes, a more clear and open dispute resolution process and we felt this was important because companies in the US would look at a 483 observation or a warning letter in another company in the district and then adopt all of that and say we don’t want to avoid a warning letter, whether that makes scientific sense or not, and that was the wrong practice. We felt that companies really didn’t bring scientific issues as a dispute resolution process. We’re moving towards an inspection process, which will be focused on risk and one of the elements of risk would be the level of process understanding. We hope to have by next year a quantative model that we will assign a number, a weighted number for each facility based on risk and the level of


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process understanding at that site and how effective the quality system is. Our inspection resources will be directed in that manner. One of the elements of the Pharmaceutical Quality for the 21st Century is PAT. PAT becomes part of that. Our Draft Guidance was also part of that commitment to support innovation and the Draft Guidance was a framework for innovative pharmaceutical manufacturing and quality assurance. The concepts expressed in this guidance are not new, many are 16 – 30 years old. What we have done is simply bring those concepts in a pharmaceutical context and that’s the contribution of this guidance to bring those concepts in a pharmaceutical context and create a path forward. The draft guidance is a commitment to support innovation because industry was saying that regulatory uncertainty is a major challenge and we believe that the regulatory system is flexible enough and provides all the flexibility, but hesitance is because of lack of knowledge sharing and training and so forth. The regulatory system need not be a stumbling block or a challenge. It’s a framework approach to PAT, not a How-To Guidance. It is applicable to any new technology. Now to support this, we have a team approach to review and inspection with supportive training, certification, expert consultant and research support to this team. A systems approach to provide flexibility and validation of new technology for it’s intended application and a very flexible regulatory process by taking advantage of our team approach addresses area of regulatory uncertainty and fear. So the ball is now in industry’s court. If they don’t innovate they shouldn’t blame the regulators and I think they have a tendency to do that anyway. It’s important to think about PAT. A lot of people, and you’ll hear some presentations, PAT is only about census. Census is 1/4 part of the whole PAT system, it’s not PAT. I keep reminding people that if it was just census you don’t need a PAT Guidance. For PAT as a system, for designing, analysing and controlling manufacturing to timely measurements of critical quality and performance attributes of raw and influences materials and processes. Analytical is more about analytical thinking and I think we should probably change that meaning. Process Assessment Technology would keep the PAT acronym. Chemical, physical, microbiological, mathematical and risk-analysis conducted in an indicated manner. The key is process understanding. We believe that process understanding would be inversely proportional to risk and we are moving forward in that direction. Process understanding is the way to support innovation because it provides a range of options to qualify and justify new technology and to achieve real-time release. Less burdensome processes for validating new technology for the intended use. In the absence of process knowledge we test to test comparison between on-line process analyser and a conventional test method on a collected samples, may be the only available option. So if you are approaching that way you don’t need PAT Guidance. That’s one reason you have to think about process understanding as a means to qualify new technologies, not a test-to-test comparison. A test-to-test comparison would simply mean that the brand uniformity test or the qualifier test is goal standard. Some of the new technologies are far superior to those technologies. Process Analytical Technologies, our tool box, consists of multi-variate data acquisition and analysis, modern process analyser or process analyser chemistry tools. So when people talk about PAT, they just talk about this part. They forget about all other aspects. Process and end point monitoring and controls, continuous improvement in knowledge management tools. This is the tool box for PAT.


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The key focus is also to justify real-time release – this is an efficiency driver, but is also a process understanding driver because you only achieve real-time release if you have a very high level of process understanding. Otherwise you don’t achieve that. Another aspect I do have to mention is that we distinguished slightly real-time release from parametric release. Parametric release, although approved for terminally sterilised preparations, is, since we approved this in 1985, not practiced in the US well, because they fear the legal departments will allow you to do that and said you still need to do that test. The real-time release focuses more on material attributes so that you have, if you do real-time dissolution, you actually have a predicted value for dissolution for every batch. That’s the distinction we have tried to draw – to make real-time release more practical and realistic. Parametric release has baggage associated with the terminology at least in the US. Again it is focused on process understanding. You’ll see a definition of process validation changing in the US and one of the key aspects is with PAT you control a process using validated controls, the focus is on controls and validation is focused on controlling the controls themselves. We believe that process understanding can provide a high assurance of quality on every batch and provide alternative affective mechanisms to achieve validation. Process validation in the PAT world could be summarised in one sentence. You control a process using validating controls. We are moving forward. We have formed an ASTM committee, international committee on pharmaceutical applications of PAT because we believe this is moving so rapidly, the regulators of the pharmacopoeias are not really capable of meeting the challenges of standard practices and guides to come to. So industry really needs to move forward there and this ASTM committee provides that way forward. We are working on research. We have an agreement with the National Science Foundation. We are hoping to create a national centre for pharmaceutical engineering. We have a collaborative research and development agreement with Pfizer, several academics and we are for communicating and co-operating with regulatory agencies. Health Canada are going to join with us and so are the Japanese. We are communicating amongst ourselves. Anchoring change is important. All that we need to ensure is that the change is anchored in our culture. ICH Q8 and Q9 are important parts of that anchor and so are the other things that we are talking about. Innovation in medical technology and critical part initiatives are a continuation of the thought process. I think the key aspect is, since this session is focused on opportunities for pharmacopoeias, I’m going to focus on the USP because that’s the thing I understand best. Again similar to Jean-Louis (Robert), the concepts of PAT are very much supported. In fact the USP recognises that assuring quality by design may provide greater assurance than testing to document quality. You have that in the General Notices already. PAT if you really look at the language in the general notices, is consistent with that, because pharmacopoeial standards are pharmacopoeial market standards and they have to remain that way, because there’s a need to have market standards available. So this is again consistent with that. I would like to share in some detail how the PAT framework supports that further.


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The PAT framework provides an opportunity to utilise novel, modern process analysers along with other tools to improve process understanding and to improve confidence in process validation. PAT framework ensures a proper control of all relevant critical quality attributes on in-process materials; for example using process end points to allow the process to manage the inherent variability in physical attributes of pharmacopoeial materials, that can impact their processability. This is the key because it is easy for us to say we will create functionality tests for excipients,we will create this for excipients and so forth. That has limited value because functionality, the physical attributes are difficult to manage in a standard setting way. How do you define the shape, particle size similarity between different lots and so forth? Physics is difficult to address in a public setting way. If you start increasing requirements on your excipients supplier, at least in the US what we have learnt is, the excipients suppliers of the pharmaceutical industry is a very small proportion of this thing. They’ll simply say that they don’t want to sell you the material – take it or leave it. The PAT process says that you must understand your variability but design your process to manage that variability – that’s the focus. Physics is difficult to manage in a standard-setting way but can be managed by design of your process. So you improve manufacturing efficiency and provide a means for greater assurance of quality. Some believe that the PAT framework is not compatible with the USP compliance. This is totally incorrect. The USP can help remove this misperception. For example USP compliance uncertainty comes from the fact that PAT framework provides for a high level of materials scrutiny. This suggests that in some cases, every batch is a specification, from a market standard perspective. This unfortunately is perceived as increasing the risk as a large number of batches may be judged to be non-compliant with certain USP monographs such as content uniformity. Content uniformity is fine, but the same is with dissolution tests also. On this slide the key point is that we allow for certain variability and what that means is that if you increase the sample size you will find some units outside the 75 - 125 range for example and the myth of zero tolerance is a mythical concept. No unit is outside of 75-125 because that truly is not practical. You have to think about that from a more scientific perspective of defining specifications. The USP Compliance Uncertainty and how can USP support PAT framework. The Pharmacopoeias established market place legal standards, which help to assure practitioners and patients that products need quality requirements. The market place standard must be met regardless of how products are produced. From compounding to PAT business manufacturing, the pharmacopoeias directly do not dictate or define how to achieve the established market standards. Any attempt to do so by pharmacopoeias or a regulatory authority will impede innovation and continuous improvement. USP can support the PAT framework for providing clear communication on issues identified as compendial uncertainty, that PAT is compatible with the pharmacopoeia. Anything other than that, will be difficult to manage at this time. To summarise, PAT is defined as a system based on a set of principles and a toolbox for process design. The FDA’s draft guidance is a framework that provides a flexible approach for innovation, it is by design, not a how-to guidance. We will not be ready to write a how-to guidance for some time to come. The PAT framework is a directional vector in a broader FDA’s 21st Century Initiative. USP can support PAT, by providing clear communication that PAT based quality control and quality assurance is an acceptable alternative approach. That’s all we think pharmacopoeias should


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do at this time – clear communication and ensure the understanding is clear about market place standards from release standards.

DISCUSSION Question from the floor: Just a question concerning where you the think the USP is at this point in time. Are there any movements that the expansion of the acceptance criteria to a more statistical based approach is going to happen in the near future, for example for continuity conformity or even more importantly for dissolution? Dr A. Hussain: I think this question should be asked to the USP speaker after me, but Dr Woodcock made a presentation to our FDA science board. We are not waiting for the USP to make the changes, we will be making those changes ourselves, in terms of how we enforce and how we interpret these things. We are moving very quickly towards the approaches to manage that. Again we have a clear distinction of what is a market standard and what is a release standard. We are focused on the release standards and any other specifications from that will be addressing it from that perspecive. Question from the floor: What is your interpretation of the legal impact of such as dual standard situation? Dr A. Hussain: I think it’s not a dual standard per say. It is a standard which is a minimal standard, because I think that PAT from a process understanding and design perspective, the minimal standard is the least of your worries. You’ll achieve a higher quality standard and legal standards, which are enforceable when you take somebody to court, you really have to, from a science perspective, violate that legal standard, which is a minimal standard. Prof. Dr H. G. Kristensen: In slide number 4 you showed drug code of high quality but the second point is high burden on FDA resources. You didn’t comment on that point, but one can get the impression from the slide that you think there is a high burden on the FDA resources today and PAT could diminish them. Is that your opinion? Dr A. Hussain: PAT will diminish the need for our resources, yes. That is the point in a sense, because of a lack of sharing of knowledge and the focus on testing to document quality. Unfortunately I think the challenge is from a validation and release perspective if we do minimal testing. So the FDA approach has been as if everything is suspect, you have to scrutinise every step and with the increasing number of products and the increasing number of companies, our resources do not matter at that level. The PAT process is, if there is more sharing of knowledge, more science-based approaches and PAT focused process understanding, then these companies, which achieve a higher standard would be recognised from a risk-based perspective and our FDA resources would not have to be spent on those companies and so from an inspection perspective, a review perspective. We want to shift our limited resources to high-risk areas. So companies that have understood the processes would be at lower risk and those that’s have that information with us would be lower risk. Dr J. Berridge: You mention a number of times standards and the ability of companies to reach higher standards. You also talked about the FDA developing a quantitative tool to enable risk assessment of presumably firms or firms and products or products. Would you like to comment on how you think these standards will actually be developed and agreed and how industry and regulators might agree that they are appropriate standards and how they would be applied? How


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will we get to an understanding basically of what those standards are? Who will own those? Do you envisage the pharmacopoeias might own some of those standards? I don’t have a very crisp picture in my mind of how I would recognise a standard if I bumped into it. Dr A. Hussain: Standards could mean a couple of things. From an FDA perspective for example, a practice standard could be a guidance. It could be a document, which says these are the best practices, from one perspective. Or a general chapter could be a practice standard. It all depends on what is the source of that standard material. For example our efforts of ASTM are to help to provide a framework, a gain or a platform for industry to identify best practice standards and borrow from other industries to create their standards. On the drug side we have not utilised that to a large degree. However, our Centre for Devices recognises ASTM to a very high degree, so if you practice the standards under ASTM you don’t have to submit all that information in submission. We say you are practising, we can inspect on that basis. So that’s one way of looking at standards. The other one would be reference standards and so forth. In the PAT world a lot of this would be, in my opinion, specific to a given process, to a given company, to a given product. These standards to a large degree would be owned by the companies themselves. They will conform to a set of broad principles. So the standards we are talking about in the ASTM would be broader principles which you will follow and then we will share that information with the agency for an assessment by the regulatory authority. So, that’s the view of standards in a broader way. The role of the pharmacopoeia will evolve over time. At this point the work load on pharmacopoeias is quite significant. At least from the USP perspective, the way we struggle, we still don’t have reference standards for many of the materials and monographs already in the pharmacopoeias. Pharmacopoeias have a big task ahead of them to meet their responsibilities right now and as PAT evolves over time there may be a role there. At this time, however, I do not see that role.

Prof. Dr H. G. Kristensen: I think that the question raised by John Berridge is very essential for this meeting and I will make sure we take it up again when we come to the round table discussion.


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31



A Perspective and Overview of Process Analytical Technology (PAT)

Dr Gary Ritchie, USP (USA)

Abstract: Process Analytical Technology (PAT) first appeared in the Fifth Supplement to USP 23-NF 18 in 1997 in the form of General Chapters ‘643’ Total Organic Carbon, and ‘645’ Water Conductivity. Since then, numerous advancements have been made in the field of process analytical technology for measuring pharmaceutical processes in real or near real time to control the process and/or drug product attribute. Currently in-process or product release attributes are measured to assure the progress of a process, so that the intended product’s quality attributes provided in the dossier are met before the product is released into commerce. In most cases, when a process is executed as intended y the product dossier, these attributes are, in fact, met. However, in those cases where these attributes are not met, the pharmaceutical industry pays a high price to investigate and climate the source of these failures. There can be numerous reasons for a failure; however, when they are not identified in a timely manner, it may be concluded that critical design qualities that were validated as specified in the product dossier may not be valid for subsequent production batches. This phenomenon may be attributed to variability in some desired quality that was not accounted for in the raw materials that are necessary to achieve the desired product quality attribute by the pharmaceutical manufacturing process. Given that this may be the case, regulatory authorities in the US and abroad are working to provide timely and appropriate approaches to address this problem. PAT is one approach that may be applies to minimizing and, in some cases, completely eliminating process failures that result in missed product quality targets. In addition to the issue of adopting and implementing PAT approaches for mitigating process failures it will be necessary to establish process standards for ensuring that these processes remain well inside of their intended targets. Process standards include the specification (tests, procedures, and acceptance criteria) that are used to assess the equipment, the process and the final result of an applied process. What is not clear, however, is what the regulatory authorities, the industry and the Pharmaceutical bodies worldwide may agree on in terms of what, how, when and why these standard might be applicable. This paper will present a perspective on current approaches to and an overview of the issues confronting all parties as we move into the PAT era of the 21st Century. Mr G. Ritchie’s slides are available on page 32 of the PAT-SessionI.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 Good morning Prof. Dr H. G Kristensen, members of the European Pharmacopoeia Commission and honoured guests. On behalf of my colleagues at the United States Pharmacopoeia (USP), I thank you for inviting me to participate in this very important symposium on Process Analytical Technology (PAT) today with you and to present my views on this subject, something that I have been involved in for only a very short time, compared to some of you, who have spent a lifetime in the process field. However, I feel very strongly about the emerging PAT activity as it may be


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applied to the pharmaceutical industry and the potential changes it brings with it. PAT will impact not only the pharmaceutical industry but also the regulatory authorities; pharmacopoeial bodies worldwide, and last, but not least, the patients. The United States Pharmacopeia actually is credited with having the first pharmaceutical process analytical method in 1997 with the publication in the Fifth Supplement to the USP 23-NF 18 of General Chapters ‘643’ Total Organic Carbon, and ‘645’ Water Conductivity. More recently, in 2002, the proposed general chapter in PF 28(1) Pharmacopoeial Previews, general chapter ‘1223’ Validation of Alternative Microbiological Methods, has received considerable attention as rapid methods for microbiological identification, enumeration, and speciation appear to take their place along side of more traditional microbiological assessment approaches for pharmaceutical products. In June 2003, the USP held an open conference on analytical methods and general USP topics. I will discuss the outcome of this meeting with respect to PAT on USP later on in this presentation. In that same year, I joined the USP as a Scientific Fellow for Process Analytical Technology; USP has been very active ever since, preparing to responsibly move forward. I have participated in various symposia and conferences and subsequently joined the ASTM E55 Committee on Pharmaceutical Application of Process Analytical Technology in the fall of 2003. I also chair the ASTM subcommittee E13.11 on Chemometrics, and this may be useful for the E55 at some future time. The E13.11 subcommittee on Chemometrics stands ready to fully assist E55. Finally, I stand before you today, representing the USP, as it, along with the distinguished body of the European Pharmacopoeia Commission, participates in this symposium organised by the European Directorate for the Quality of Medicines (EDQM), Council of Europe. Working together with participants from various industrial concerns, as well as the regulatory authorities, we will question, deliberate, and finally come to some consensus on the best course to follow to utilize this technology to its fullest potential in the pharmaceutical manufacturing area. USP is often asked to define its position on PAT. Based on careful and thoughtful deliberation, the USP’s strategy is designed to facilitate and compliment the FDA framework for improving product quality in pharmaceutical manufacturing. USP will accomplish this by creating general chapters for breakthrough technologies as they evolve in order to strengthen the scientific understanding and application of these technologies. The USP has formed a Project Team, PT18, on PAT that is composed of twenty-one individuals who provide a broad range of process knowledge both within industry as well as regulatory experience in pharmaceutical process manufacturing. Not only do they bring a vast reserve of knowledge within their respective fields from biostatistics to process X-ray technology, but they also bring a synergy that will serve the USP and its expert committees well in determining the best course of action to take concerning future standard setting activity on process centered pharmaceutical manufacturing practices. The PT-148 is chaired by Dr Walter Dziki from Abbott Laboratories. The PT has identified their role and the role of the organization with respect to advancing the utilization of PAT. The Project Team’s mission: is to “Expand and clarify the use of PAT in the USP General Chapters.” USP projects teams are advisory to the Expert Committees most suited to consider the recommendations; e.g, information concerning calibrators is referred to the Biopharmaceutics Expert Committee, information on process equipment is referred to the Expert Committees possessing the particular expertise to evaluate that technique. To date, the PAT project team has met


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three times and is considering its current objective, which is to recommend that the USP Biostatistics Expert Committee study the meaning and implications of process specifications, out of specification (OOS) in process measurements, and out of trend (OOT) in-process measurements. Process Specifications may be defined as the tests, procedures, and acceptance criteria used to accurately verify validated measurements. For instance, the use of an on-line Near-Infrared (NIR) measurement for a particular process would be the test, the procedure would describe how the measurement is carried out and the acceptance criteria would be the rationale used to determine, in real or near-real-time, if the specific requirements of the process have, in fact, been met. Process validation in the spirit of PAT would no longer focus on the careful examination of the first three production batches to demonstrate that the manufacturing process is under control. Process Validation in the PAT era would mean that that focus of validity would be on the ability of the manufacturer to produce a reliable quality product that would be based, in part, on repeatable, stable, robust and rugged measurements; these measurements could be taken as often as twenty-four hours a day, seven days a week and three hundred and sixty five days a year. Another significant issue relevant to PAT is the use of rapid microbiological methods. The USP General Chapter ‘1223’ Validation of Alternative Microbiological Methods, while not specifically targeted for emerging technologies aimed at reducing the overall time to determine the microbiological activity of raw materials, in-process, or finished product goods, nevertheless can be utilized during the implementation of rapid methods. The purpose of this chapter is to provide guidance for validating methods for use as alternatives to the official compendial microbiological methods. For example, while the concept of ‘detection limit’ has merit in quantitative microbiological assays, the critical question is whether or not alternative methods will yield data equal to, or surpassing in quality, to the data generated by conventional methods. ‘1223’ covers three major areas, quantitative, qualitative, and identification of microbes. The next three slides cover the very familiar validation parameters for microbiological methods. The USP held an open conference on analytical methods and general USP topics in June 2003. One of the topics discussed was PAT and how and what its impact would be, not just on the USP, but on the pharmaceutical industry on the whole. Now I would like to give you an overview of some highlights of that meeting related to the role that the USP and other pharmacopoeial bodies can play in the adoption, development, and eventual implementation of PAT. The pharmacopoeias could facilitate the use of PAT as an option or an alternative, if you will, to current manufacturing approaches. For example, USP-NF could be utilized to present general information that would lower the barrier of understanding between industry and regulators by Stimuli articles in PF that increase awareness of PAT; general information chapter(s) on the particular elements of PAT, such as multivariate statistics or statistical process control (SPC) theory; and/or general chapters on techniques. The pharmacopeial bodies may choose to utilize their respective web sites as a way to provide information to the community. Obviously, workshop participation, such as this initial European meeting on PAT hosted by the EDQM, will continue to play a major role in educating, advancing and promoting PAT across the industry. Other approaches that might be taken by the USP include indicating PAT as optional in USP-NF General Notices, providing a list of PAT literature references, including relevant PAT elements, where applicable, into existing chapters (e.g., use of multivariate techniques to predict content uniformity, or perhaps even creating a separate section for PAT-containing monographs in the compendia. Finally, harmonization efforts may ensue. Whatever the approach or routes taken, to be


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sure, meetings such as this with the industry and the regulatory authorities, are a must, so that the overall approach chosen will always be seen as fruitful and never as an impediment. In closing, I leave you with some parting thoughts regarding areas where we may focus over the course of this and subsequent meetings. Will the regulatory authorities, the industry and the Pharmacopoeial bodies worldwide agree on what, how, when and why these standards might be applicable? One thing is for sure, the primary laboratory methodologies, and the corresponding standards, for now, will be required for product release, building PAT models, measuring finished product stability, post-production market support, and perhaps parallel testing. To summarize, pharmacopoeias should consider supporting the current PAT activities in as much as they can, or allowed to, facilitate and complement the PAT initiative, and actively work with each other, industry and regulatory agencies. The United States Pharmacopeia, and all other Pharmacopoeias for that matter, should continue to provide primary standards for helping to ensure product quality. These standards serve as a means of demonstrating compliance, or non-compliance, with legally recognized compendial requirements. The use of manufacturing controls for the same purposes has not yet matured domestically or globally in any significant way that suggests the status quo is going to be challenged. However, as manufacturer controls gain greater usage and become more acceptable, they too may become suitable for use for ensuring product quality over time. One of the roles of Pharmacopoeias is to provide standards to serve as the final arbiter of product quality; the choice of how to do this is purely arbitrary as they should provide standards for laboratory controls or standards for manufacturing controls. Looked at another way, if manufacturing controls had evolved first rather than laboratory controls, they might have been the de facto legal standards, and laboratory standards might be vying for a place in the compendium. Both approaches can and should be maintained by Pharmacopoeais worldwide. Manufacturing controls certainly can be included in compendia. It is the responsibility of these Pharmacopoeias to accurately record, provide, and maintain suitable means to establish the validity of manufacturer’s claims about the quality of drug products around the world. Indeed, it is one way that we can help to ensure the safety of the public that we are given to protect.

DISCUSSION

Prof. Dr H. G. Kristensen: It seems that the USP is thinking along the same lines as I outlined in my opening. There is a basis for international harmonisation in this field. Dr J. Kincaid: USP traditionally has really stayed away from getting involved in new technology. It’s something that we’ve been told over and over again, that they really want to look at things when they are well developed, well understood and well in place in industry. So, why is the USP trying to push forward now in this area when there’s so much going on within the regulatory bodies and within industry, instead of taking a step back and waiting and seeing what happens and looking to see what your role would be? Mr G. Ritchie: I think the leadership that the USP has in trying to orchestrate a well balanced approach and dealing with, as Dr A. Hussain alluded to, some of the past issues which are still outstanding with respect to standard setting activities, but in looking forward the perception now is


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that we want to reflect the needs of both the regulatory agencies and the industries positions. Given that this is the case, while there might be emerging technologies that may not be perceived as not readily available or not ready to be used in it’s fullest way, for PAT approaches if the need arises for providing information from other resources that currently don’t exist, if people want the knowledge in order to proceed I think that’s one way the USP can facilitate the process without impeding research and development of those tools. Primarily as an information resource I think that’s the take-home message that came out of the open conference. We can do those (general chapters) without being prescriptive. Dr. C. Potter: Could you perhaps explain to us how you are hoping to work with the FDA? Given that Dr Ajaz Hussain explained to us that the FDA was proposing to work with the ASTM, if I understood correctly? Mr G. Ritchie: I think the avenues that have been open for the USP and other pharmacopoieal bodies to be responsible in carrying out its main mandate, to protect the public health. When you look at the necessary definition that has been given in order to facilitate the development of PAT, one comes away with a sense of improving the public health, through improving the quality of the products - the two are one and the same, they are inseparable. I think it shouldn’t be considered whether one standard setting body has the ability because of an outright sanction versus another standard setting body. I think that to facilitate the best science available for the industry to get it right, to improve the quality. The more places the appropriate information can be found, can only be seen as good and not harmful. For instance, I think one of my project team meetings, one of my senior people who has been doing this for quite some time, said that they don’t only have one medical college or one set of medical text books to teach your physicians. Now, there’s many resources and many authors and I think in this sense you can provide information, and again when I refer to the use of the General Chapters, I point out that they’re being used at a level of one thousand and above, which means that they are there for information and for teaching and learning. There’s no regulatory impact for that. So, if the need is there for people to submit a technology that they need to use and they want to see it reflected in the current status with the state of the art, then I think it’s ok and I think the senior management at USP also believe that it’s ok. So, again, it does no harm. If we don’t see it as a harmful way to putting barriers then it should not matter how many standard setting bodies are involved in this activity. As long as we get it right. Dr C. Potter : In the USA there are three groups potentially working on the same standard. I think you all have mentioned the uniformity of content issue. What assurance to we get, that we get one standard and not three standards? Mr G. Ritchie: That’s an interesting question. I think that’s an assumption that’s being made, that you are getting the same standard. In fact I’m in receipt of three technologies and I also know that the ASTM committees are also looking at the same three. They are not the same. So the assumption that we are working on the same standard is being misstated. There’s a difference between information that’s being imparted, that relays the “what” of a technology, the physics of a technology, the current state of the art of that technology, without relaying or relying on how to implement that technology and more importantly how to marry it to a standard setting activity. I’ll repeat again, I think the approach that the USP is following is to implement the technologies that are relevant to the current status of alternative manufacturing approaches, without impacting how they should be implemented or how those standards should be evolving. I think it’s been pointed out to me and I’ve got the message clearly and I’m trying to relay that message to the senior people


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at USP. When you deal with alternative manufacturing processes it should be left up to the user and developer on what’s the appropriate standard. So I’ve been trying to send that message home for as long as I have been in this position and I continue to send home the message that we can deal with the technologies without actually impeding or encroaching upon standard setting activity and I think what also needs to be said is, at a time when industry may feel it would be relevant to approach the pharmacopoeial bodies and suggest that a process standard could augment, sit alongside of a current product standard or even stand alone in a monograph. I think that’s appropriate. The two specifications don’t have anything to do with each other. The two standards are one end of the spectrum and the other. I think that they can co-exist without necessarily being an impediment or a barrier to each other. Dr J-L. Robert: I just want to make a statement and not necessarily ask a question. I think as I said in my presentation, we are in a very fast moving field and we have a lot to discuss between regulators and between the industry. At the end of the day it will be the licensing authorities who have to give an authorisation for marking an application and I don’t know if we are a little confused about what has been said now. We have one standard, two standards, three standards. I think what is clear is that we should have one standard, not only one standard for each region but also probably one standard globally. At the moment, we are working in the ICH process on Q8,Q9 and so on. We know the difficulties that we have to look at the specification when we apply real time release and when we apply release testing. These are things, which as far as I understand, are on our agenda for one of our next meetings. I would not like that parallel to this process we have other processes running. Then suddenly we end up with different approaches or different standards. This is something I would not like to have. At the end of the day when we have finalised our discussion and we come out a 4 step 2 document, then we might have of course to go further and identify and who are the other partners we are involved with, because they are also affected by this guideline. For the moment I would warn that we have different approaches and parallel working groups.


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What role for the Pharmacopoeias?

Dr Alistair Swanson, Pfizer (UK)

Abstract : Quality by Design is a major, on-going theme for the pharmaceutical industry. Increasingly, the focus is on understanding the sources of variability in processes (for both API and drug products), and using this to increase process robustness and reduce risk. PAT is a key enabler of Quality by Design since it can provide a direct way to get information about a process, and to identify and characterise Critical To Quality factors. It is clear that the application of PAT as part of a Quality by Design philosophy is of growing importance for companies, regulators and pharmacopoeias, however the area is still evolving rapidly, expectations are changing and there are many areas where there is as yet no consensus. This presentation will provide an overview of the range of PAT technologies and their applications in the pharmaceutical industry, and will set the scene for many of the more detailed technical presentations to follow. Possible ways in which the pharmacopoeias could facilitate the use of PAT by industry will be discussed. Dr A. Swansons’s slides are available on page 49 of the PAT-SessionI.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2

DISCUSSION

Dr A. Hussain: I think the key aspect is when it comes to an assessment and regulatory approval, unless you look at PAT as a system, you will actually be doing extra work for nothing and I think that’s the reason why it’s very important to look at PAT as a system for assessment because all regulatory decisions depend on the intended use. The focus becomes the intended use and regulatory flexibility comes from that. No matter how you look at PAT it boils down in the end as a system and not just tool. Dr A. Swanson: I think this is a terminology thing. The part of the pyramid I call quality by design and process understanding gives that system framework. It’s surely just a case of deciding whether we’re going to call all of that PAT or just the bottom bit of it. Dr S. L. Ali : On one of your slides I saw the different PAT technologies you put together with the P agent at PLC, NIR and FT-IR, etc.. Do you think that colour is also an important aspect and a characteristic? Is it a new PAT candidate to instrumentally monitor the colour of your product, Active Pharmaceutical Ingredient (API) or an excipient? Dr A. Swanson: I think if you can show that there is some link between colour during a process and the quality attributes that you care about in the product down stream or the process ability further down stream, then yes. That’s why we deliberately created a very broad definition there of process measures that lead to understanding. Now if it’s the case that colour is incidental on the way through, then in that particular case no it wouldn’t be.


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PAT experiences in the paper and pulp industries.

Dr Ralf Marbach, VTT (FIN)

Abstract : The paper & pulp industries (PPI) are very advanced in the application of leading edge techniques of on-line process control measurements and analysis. Technologies have been proven in PPI e.g., imaging spectroscopy for very high sampling rates, or today's possibilities for efficient prototyping of complicated opto-mechanical assemblies which have a strong potential to be applied to the pharmaceutical industry. Various instruments based on NIR, IR, and Raman spectroscopy, and relevant techniques for customizing these instruments for demanding on-line environments, are described. Finally, it is attempted to place the proven advantages of adopting PAT techniques (process optimizing, improvements in process understanding, quality assurance and reliability, waste minimization, etc) in the context of the pharmaceutical industry. Dr R. Marbach’s slides are available on page 44 of the PAT-SessionI.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2

Summary of the presentation The paper & pulp industry (PPI) is different from the pharmaceutical industry in two important aspects. First, PPI is not subject to strict regulatory control and second, PPI uses continuous manufacturing processes. On the other hand, competitive pressure is very strong in PPI and utilization of state-of-the-art process analytical technologies is a must for survival. Over the years, therefore, PPI has gained a reputation as being the most advanced of all manufacturing industries in terms of PAT, both regarding its widespread deployment and its technical sophistication. The Optical Measurement group within VTT Electronics in Finland has over 20 years of history as an R&D Service Provider and Engineering Contractor in this field, developing both the methods and the optical instruments needed for on-line process control in various manufacturing industries. With over 30 staff in the field, we may well be the largest such contractor in the world. There are two reasons for this relatively large amount of expertise concentrated near the Arctic Circle. First, the large and sustained need of Scandinavia's PPI for improved PAT instruments. And second, VTT's rather unique position as an independent organization between the end-user companies, e.g. pharma, and the PAT supplier companies. (The latter being members of the so-called Measurement, Control and Automation industry – MC&A.) By not competing with companies on either side, i.e., by strictly specializing in the development of new instruments, VTT's contracting services are available to both the end-users and the instrument suppliers. Optical measurement techniques offer unique advantages for PAT compared to other measurement principles. The advantages of optical methods include:

• Non-contact, non-destructive • Fast (hundreds of samples per second) • Specificity of response • Measure "real thing" (no sampling errors) • Easy to install and suitable for process measurements


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• Robustness of process instruments => easy maintenance • NIR widely used in industrial process measurements

A very important, first step when starting a PAT development project is to select the right technology for the needs of the customer. VTT has broad experience in the mainly used NIR, IR, and Raman; spectroscopic hardware techniques and has developed commercialized instruments based on all of these. In order to give an overview and rough comparison of these mainly used technologies, we have done the comparison chart shown in slide 7, page3, PAT-SessionI.pdf, EDQM internet site.) The various technologies shown in slide 7, session I file, EDQM internet site were shortly discussed in the presentation and some of their practically important limitations were mentioned. Also, example PAT instruments used in PPI and based on several of these technologies were shown. Of particular interest to the pharmaceutical industry may be latest developments in the area of imaging spectroscopy, which can be utilized to realize very high sampling rates (by realizing 100 spectrographs in the size of one, so to speak). VTT was very actively involved in the development of the first commercial product based on this technology, which was launched to the paper industry in 2002 and which realized a very significant increase of approx. 5% in paper machine "runnability." Another potentially useful technique, wireless data transfer from "mobile" PAT units, was not mentioned in the talk but is a specialty of VTT Electronics. In every PAT development project there is a pattern of key issues or milestones, which tends to repeat regardless of the details of the application. These key issues come about whenever optical methods are applied to "real" on-line processes, and include:

1. Instrumentation 2. Process interface 3. Calibration 4. Closing the loop

(The list above assumes that the R&D-ish part of the project is completed and that the key specifications for the application are available.) Issue 1: Instrumentation concerns the core of the hardware of the instrument, i.e., the principle way of realizing the ‘spectroscopy.’ Issues here include: Cost; performance (SNR, spectral resolution, long-term stability of calibration, etc.; robustness (dirt, temperature, humidity,etc.); amount of required maintenance (cost of ownership); and availability of key components (number of component suppliers). Infrared detectors are typically among the critical components, both from a cost of direct material point of view and from an availability point of view. One important remark here is that as soon as some volume of units is involved, say, 100 units as a very rough rule of thumb, component suppliers tend to become interested in OEM supply and many of the availability problems can be solved in this way. Issue 2 Process Interface concerns the interfacing of the PAT instrument to the manufacturing process. Cost is critical again here. Another goal is to cause as little change to existing pieces of manufacturing equipment as possible. Last but not least, performance is also very important here, because the accuracy of a PAT instrument is usually not limited by electronic noise, but rather, by variations in the on-line sample and/or the sampling process. Design of the interface optics is therefore often far from trivial, and detailed understanding of the physical environment and the optical properties of the sample is desirable. The ability to perform relatively quick and relatively inexpensive feasibility studies on the "real" process is a key tool in the design of the interface. VTT


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has a number of dedicated, on-line capable spectrometers available for this purpose, which can be fitted with custom interface optics and deployed into manufacturing sites on a temporary basis. In order to reduce the cost and improve the performance of process interfaces, VTT has developed, and is now routinely utilizing, high-precision, 5-axis CNC machining for the realization of tailored process interfaces (Fig. 3 Slide 8, page 3, PAT-SessionI.pdf, EDQM internet site). By utilizing highly accurate optical testing methods and improving various aspects of the "normal" CNC process, machining accuracy could be improved to a point where optical-quality, free-form surfaces can be directly machined into metal parts. The optical surfaces and the mechanical features of the part can be machined in single chucking, so to speak. This technology offers a number of significant advantages, including:

• cost reduction (often dramatic) • new design possibilities leading to better customization to the process (for example, special

geometries of illumination and pickup spots on the sample are easily realized; or, insensitivity to variations in sample "fill-height" can be designed in, leading to less sampling noise and better performance)

• no chromatic aberration • minimizes the size of instrument • high optical throughput => more light back, higher SNR • good thermal and mechanical stability • reduces, or even completely eliminates, manual alignments, which results in significantly

reduced assembly time and increased ruggedness • fast prototyping (modern optical and mechanical design programs interface more or less

directly with each other and with the CNC machine) • availability is not an issue because local suppliers can be relatively easily trained

Issue 3 is calibration of the instrument. Whenever possible, VTT employs newly developed calibration methods based on multivariate measurement science, as opposed to multivariate statistics. These methods reduce the cost of calibration dramatically and they are also more transparent and reliable. Specificity of response can usually be guaranteed. Issue #4 is how to close the loop, i.e., how to actually use the output of the PAT analyzer for closed-loop process control or quality monitoring.

Conclusion The paper & pulp industries are advanced in the areas of PAT and on-line process control. Technologies have been proven in these industries, e.g., imaging spectroscopy for very high sampling rates, or today's possibilities for efficient manufacturing of complicated opto-mechanical assemblies, which have strong potential also in the pharmaceutical industry. In addition to paper & pulp, VTT has PAT experiences also in other manufacturing industries, including the chemical, food, and steel industries. The pharma industry seems to be a special case in the following sense. Ideally, the manufacturing industry should be able to buy all PAT related equipment and know-how from outside, i.e., from specialized companies of the Measurement, Control and Automation industry. This is indeed the case, e.g., in the paper industry. The pharma industry, on the other hand, at this point in time seems to get relatively little support from the instrument supplier companies. This situation is not completely unlike situations in other industries, in the presence and past.


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Every PAT project is a multidisciplinary undertaking and requires expertise in a number of different branches of applied science and engineering. The most important piece of knowledge, however, is application knowledge. By definition, so to speak, every new PAT application starts out with only the end-user having the necessary application knowledge to solve the problem. In these situations, the end-users must take initiative, i.e., pharmaceutical companies themselves must get involved in the development of the measurement methods, selection of appropriate technology, and development of first-generation instruments. Independent organizations like VTT can be contracted by pharma to help take this first hurdle. Depending on the experience gained and the volume of units involved, supplier companies (MC&A) can then make educated decisions whether or not to get involved. The final goal and ideal state from the point of view of the end-users is probably when pharma can buy all PAT related services from outside, not only spectrometers and other individual pieces of hardware, but complete process control systems providing complete measurement and process control solutions. VTT would feel honored to be involved in supporting pharma move closer towards this goal.

DISCUSSION Mr G. Ritchie: It seems like you a great advantage not being hand strapped by the regulatory burden of data collection. You must have a very direct path and know precisely what data to collect, what data to analyse, what data to discard (that word which we don’t like to say here.) Just data management in general, you must have a clear perception of that and it would be good to hear some of the insight. Dr R. Marbach: Actually I’m not the expert of that. Our prime customers are these MC&A companies that I just talked about. Although we also do a lot of one c two c types of instruments for end users. Prime customers are these MC&A companies and they actually close the loop. They are the ones who know best how to make use of the measured data and how to control the process very quickly. It is a close loop process control and things can happen as fast as on, say second time scale and they will set valves or change pressures or angles of roads downstream and they will wait for that to return to normality. These are the core competences that the MC&A companies have and with which they compete with one another. I would not be able to say much about that. Dr C. Potter: Excuse my ignorance of the paper industry, but how easy is it to get the measurement and control right first time and how much change is made when we get to manufacturing, both in the measurement and the production process? Dr R. Marbach: From our point of view as far as building the hardware, the hardware is actually tested on pilot plans. So the hardware that we built pretty much ends up in the final stage. As far how much time the MC&A companies spend in the pilot plan and what routines they go through, to simulate future expected events, I could not comment on that. All I can say is that the instruments, when we build them are ready for use, they are calibrated, they are ready for installation. How much work has been done on the application side to make sure that this instrument covers then everything, how much testing was done, I could not say. But the time frame is typically two years. Two years is a typical time to get ready before moving it out. These people also have a reputation they want to keep.


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SESSION II: SPECIFIC TECHNOLOGIES/ TEST METHODS TO BE

APPLIED The integration and use of vibrational spectroscopy sensors in PAT Technology Dr Mats Josefson, AstraZeneca (S) ....................................................................................................... Making sense of multivariate data Prof. Tom Fearn, University College, London (UK)............................................................................. Acoustics Dr Ron Belchamber, Process Analysis & Automation Ltd. (UK) ......................................................... Processability and functionality of excipients Mr Steve Hammond, Pfizer (UK) .......................................................................................................... Implementation of PAT in automated tabletting Mr Ivor Pegington, MSD (UK).............................................................................................................. Use of imaging to understand tablet performance Ms Fiona Clarke, Pfizer (UK)................................................................................................................ Applications of PAT in API manufacture Dr Chris Killen, GlaxoSmithKline (UK) .............................................................................................. Rapid methods in microbiology in the PAT Process Dr Sylvie Guyomard- Devanlay, Aventis Pharma (F) ......................................................................... . Software validation Dr Ciro Cottini, GlaxoSmithKline (I) .................................................................................................... Qualification of PAT instruments in contrast to conventional analytical systems Mr Steve Hammond, Pfizer (UK) .......................................................................................................... Relationship of in-process specifications to expectations for the final product – Moving from the sample to the batch Dr Arne Torstensson, AstraZeneca (S) .................................................................................................. Design and implementation of quality systems based on PAT. In-depth process understanding to improve quality Dr Staffan Folestad, AstraZeneca (S) .................................................................................................... Continuous processes: New concepts compared to batch processes in philosophy Dr David Rudd, GSK (UK) ...................................................................................................................


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SESSION II: SPECIFIC TECHNOLOGIES/ TEST METHODS TO BE APPLIED

The integration and use of vibrational spectroscopy sensors in PAT Technology

Dr Mats Josefson, AstraZeneca (S)

Abstract: Infrared (IR), Near Infrared (NIR) and Raman are three common vibrational spectroscopy techniques that are suitable to use for process analytical technology (PAT). They have their relative merits and drawbacks. IR is more sensitive than NIR for organic molecules but NIR has a better light penetration and thus often larger sampled volume. Raman and NIR are less sensitive to water or humidity interferences than IR. Raman is more useful for inorganic compounds. IR is most used in the attenuated total reflection mode often in production of bulk pharmaceuticals, while NIR is useful for identity and limit tests. NIR and IR instruments are available for process use. Raman seems to be less used in PAT applications today but is a strong companion in the future PAT toolbox. When vibrational spectroscopy is going to be used in PAT it is recommended that the application starts early during the development of the product. Then enough experience and detail knowledge will be available to support the understanding of formulated product properties in later steps of the development. Design of Experiments (DOE) is an important tool to use in conjunction with the measurements, to gain most information with the least number of trial formulations. Without DOE it will e.g. be difficult to set appropriate limits for the allowed variations in spectra from the formulation, i.e. there will be a lack of cases with borderline formulation functionality. Vibrational spectroscopy methods may be used in at-line, online or in-line. For at-line methods it will be possible to set standards while online/inline methods will need to be developed more on the basis “fit for purpose”. When PAT is going to be implemented for the first time, this will constitute a major cross-disciplinary effort for the organisation. The people who are going to maintain and develop the PAT system has to be educated to a level were they understand the PAT system enough to be able to estimate implications for the product and to update chemometric models. The needed instrumentation often has to be interfaced in a customised way and this may create a challenge for the existing process IS system at the operations site. The integration will be easier if a modular approach is used for both hardware and software. A vibrational spectrometer should have a similar role as a standard temperature sensor, although with more information output. Models from chemometrics softwares should be fitting behind the operator interface without conversions to minimise work and possible compromises with electronic records standards. Where well-defined procedures are present or emerging, they could be given the status of pharmacopoeial methods to facilitate the spread of PAT. Dr M. Josefson’s slides are available on page 2 of the PAT-SessionII.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 Infrared (IR), Near Infrared (NIR) and Raman are three common vibrational spectroscopy techniques that are suitable to use for process analytical technology (PAT). All the three techniques are useful for measurements directly on the solid phase. This means that physical and chemical interactions such as degree of compression in tablets, particle size, polymorphs in the formulation,


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and H2O content are possible to measure using one of the techniques. In contrast, analysis by liquid chromatography (LC) will not tell anything about the physical state of a solid formulation. Another factor is the speed of analysis, a spectral reading can be acquired quickly compared to a LC run, and thus spectroscopy is one of the methods of choice for PAT applications also for liquid formulations. The vibrational spectroscopy techniques have their relative merits and drawbacks. IR is more sensitive than NIR for organic molecules but NIR has a better light penetration and thus often larger sampled volume. Raman and NIR are less sensitive to water or humidity interferences than IR. Raman is more useful for polymorphs, salt/base state, and inorganic compounds. IR is mostly used in the attenuated total reflection (ATR) mode, often in production of bulk pharmaceuticals, while NIR is useful for identity and limit tests for the whole formulation. The amount of sample penetrated is quite different for these methods. The depth penetration is wavelength dependent. For NIR the depth penetration is in the order of 1-3 mm. A more detailed view is given in reference (1) where it is shown that NIR penetration is higher up to 1500 nm and will then be significantly lower at 1500-2500 nm. This gives a great advantage for NIR over IR in diffuse reflectance mode where the better NIR penetration creates the opportunity to make good quantitative calibrations for solid organic materials. A commonly used Raman laser wavelength for solids is 1050 nm. This means that Raman is a type of NIR method regarding the penetration. But this is not entirely true since the laser beam is much narrower than the NIR-halogen lamp. To compensate for this in quantitative Raman measurements on e.g. tablets it is necessary to in some way sample a larger area of the tablet e.g. by moving the tablet in front of the laser beam. In ATR applications of IR the depth penetration is in the order of a few nanometres. This is still very useful in bulk production when reaction liquids are fully mixed and may be an advantage for solids when analysing the surface separately. In diffuse reflectance NIR spectra from white powders and white or light tablets, the major spectral variation is due to physical effects such as particle size, and degree of compression. If these factors are critical for the product, a qualitative NIR is a good choice, but if the function of the product is minimally affected by these factors, the NIR method will still indicate variations of the same magnitude, but the majority of the variations will be inside the specification. The value of a qualitative NIR application for this type of step in the process may then be unrelated to the final quality of the product. NIR and IR instruments are available for process use. Raman seems to be less used in PAT applications today but is a strong companion in the future PAT toolbox. In the wider perspective, the vibrational spectroscopy techniques are options in a large toolbox of sensor technologies ranging from temperature measurements to e.g. low resolution NMR A product risk analysis should be the basis for decisions of what techniques to be used, how they are going to be used, and where the critical process steps are located in the process. This decision should be finalised at the R&D stage when the final composition for the formulation is known in order to be able to deliver a package of PAT methods together with the technology transfer of the production method from R&D. When vibrational spectroscopy is going to be used in PAT, it is recommended that the application starts early during the development of the product. Then enough experience and detail knowledge


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will be available to support the understanding of formulated product properties in later steps of the development. Design of Experiments (DoE) is an important tool to use in conjunction with the measurements, to gain most information with the least number of trial formulations (10). Without DoE it will e.g. be difficult to set appropriate limits for the allowed variations in spectra from the formulation, i.e. there will be a lack of cases with borderline formulation functionality. Vibrational spectroscopy methods may be used in at-line, online or in-line. For at-line methods it will be possible to set standards for the instrument operation while online/inline methods will need to be developed more on the basis “fit for purpose”.

0

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80 50 % less pellets, same coating speed

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thic

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m, f

rom

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Figure 1, Film coating process monitoring. Upper trace: thickness calculated from in-line NIR spectra, Lower trace: Magnitude of Partial Least Squares residual at calculation of thickness. See reference (6) for full details. The monitoring of a coating process using diffuse reflectance NIR is shown as an example in the lecture, detailed information regarding this application can be found in reference (6). Here a multivariate quantitative approach is taken to monitor the growth of the coating film thickness during the process. In addition to the film thickness, a spectral residual is obtained from the chemometric model. The size of this signal acts as a quality control indicator for the calculation of the film thickness at each time point taken during the process. In Figure 1 one example is shown where only half the amount of starting material is charged in the fluidised bed. The chemometric model correctly found the target thickness at a shorter process time. In this way we could go from a constant time process to a situation where we measure the maturity of the product in the process step and end the process at 100 % maturity. At initialisation of the process there is a section of high spectral residuals. This indicates that the measurement at this point is not reliable due to the start-up of the process. Nevertheless reliable measurements are obtained after the initialisation phase. Those indicate a process on track that yields a good quality product. When we run multivariate monitoring tools like this, we will encounter situations where we have to decide were in the process we want the most precise measurements. In this case it is technically hard to get those at initialisation. In other cases such as a


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drying process, a calibration should be most well tuned at the levels of humidity present in the product at the end of the drying, while a coarser calibration valid for a larger range may be employed at earlier stages. When PAT is going to be implemented for the first time, this will constitute a major cross-disciplinary effort for the organisation. The people who are going to maintain and develop the PAT system has to be educated to a level were they understand the PAT system enough to be able to estimate implications for the product and to update chemometric models. The needed instrumentation often has to be interfaced in a customised way and this may create a challenge for the existing process IS system at the operations site. The integration will be easier if a modular approach is used for both hardware and software. A vibrational spectrometer should have a similar role as a standard temperature sensor, although with more information output. Models from chemometrics softwares should be fitting behind the operator interface without conversions to minimise work and possible compromises with electronic records standards. Where well-defined procedures are present or emerging, they could be given the status of pharmacopoeial methods to facilitate the spread of PAT. At the same time it is very important to not create a quality climate where understanding and evaluation of new results is discouraged due to a strict rule based quality system that try to automate the human interaction to increase the repeatability of behaviour at the cost of innovation. As much as possible of the process variations should be explored using DoE in the early development and scale up. New product variations may nevertheless show up later, especially when we use the more sensitive PAT-tools. A PAT-based quality system should be adaptable enough to yield the same quality product even with slightly varying raw materials and process conditions. The product quality will benefit when e.g. the process conditions can be varied to counterbalance the variations e.g. in a raw material. References (all references are not indexed in the text) Sample penetration

1. Berntsson O,* Burger T, Folestad S, Danielsson L.-G., Kuhn J, and Fricke J; Effective Sample Size in Diffuse Reflectance Near-IR Spectrometry. Analytical Chemistry 1999; 71(3): 617-623.

Drying

2. Berntsson O, Zachrisson G, Östling G. J. Pharm. Biomed. 1997; Anal. 15: 895-900. Tabletting

3. Sparén A, Malm M, Josefson M, Folestad S, Johansson J., Applied Spectroscopy 2002 May; 56 (5): 586-592.

4. Gottfries J, Depui H., Fransson M, Jongeneelen M, Josefson M, Langkilde 5F.W, Witte D. T, Pharm. Biomed. 1996; 14: 1495-1503

5. Folestad S, Johansson J, European Pharmaceutical Review 2003; 8: 36-42. Coating process

6. Andersson M, Folestad S, Gottfries J, Johansson M.O, Josefson M, Wahlund K.G, Anal. Chem. 2000; 72: 2099-2108

7. Andersson M, Josefson M, Langkilde F.W, Wahlund. K.G. Journal of Pharmaceutical and Biomedical Analysis 1999; 20: 27-37


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8. Östling G., Quist P.O, J Pharm Biomed Anal. 2002; 28(6):1081-1089 9. Rost, M., Quist, P.O., J Pharm Biomed Anal. 2003; 31(6): 1129-1143

Design of Experiments for process

10. Bergman, R. et al. Chemom. Intell. Lab. Syst. 1998; 44: 271-286.

DISCUSSION Dr A. Swanson (Pfizer): I was interested in the model free approach where you were using chemometrics to look at the variants in the data. Can you say a bit more about that and when you might be able to apply an approach like that? The follow on to that is how would you show people that what you are actually measuring is meaningful? Dr M. Josefson: In the presentation I defined “model free” as a situation where you do not create a chemometric model before the individual process for one specific batch. A merit is that time is saved because no chemometric model has to be developed before the production of a batch. A drawback is that it is not possible to build in previous process knowledge in the chemometric model. This way of working is useful e.g. for early R&D batches when the formulation is developed and the conditions may change. Examples of “model free” methods are standard deviation, moving windows standard deviation, and Evolving Factor Analysis (EFA). If Design of Experiments (DoE) is applied, there will still be a DoE model on an upper level for the relations between batches in an experimental design, but each individual batch may be independently monitored with a chemometric tool on a lower level in the “model free” way. EFA can be applied by doing a principal components analysis when a few multivariate observations are available after the start of a batch process and then automatically calculate a new model for every acquired observation. The diagnostic information from the series of models may be used e.g. for homogeneity measurements at powder mixing or granulation. You will then see that e.g. the score plot variations are diminishing with time for a properly adjusted process. EFA used in this way is useful to gain understanding of what happens in single process runs in new situations, but is not the ultimate tool for comparison of variations between process runs. We have been using that in the R&D phase, it is a good tool because the operator and the experimenter can use it and look at the diagnostics without doing modelling work before the batch run. An answer to the follow on question: When DoE has been used to define the allowed variations inside the specification that still yields an approved product, it will be possible to judge if e.g. standard deviation is an important parameter to monitor. DoE then also makes it possible to set trend limits for the same standard deviation.


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Making sense of multivariate data

Prof. Tom Fearn, University College, London (UK)

Abstract: One of the challenges that PAT brings with it is that many of the measurement technologies involved rely on multivariate methods for their calibration. It is probably true to say that the widespread mistrust of these multivariate methods has been one of the major factors holding back the use of some types of instrumentation. This seems to have been particularly true in the pharmaceutical industry, for here it is not only necessary to convince oneself that multivariate calibration is not all smoke and mirrors, but it is necessary to convince a naturally sceptical regulator as well. In the presentation I shall explore some of the problems associated with multivariate calibration: the fact that few chemists have been trained in this methodology, its image as a black box, and the understandable concern that it is capable of being misused. I shall argue that these problems can be overcome, the first two by education, and the misuse problem by a strong emphasis on validation.

One of the challenges that PAT brings with it is that many of the measurement technologies involved rely on multivariate methods for their calibration. It is probably true to say that the widespread mistrust of these multivariate methods has been one of the major factors holding back the use of some types of instrumentation. This seems to have been particularly true in the pharmaceutical industry, for here it is not only necessary to convince oneself that multivariate calibration is not all smoke and mirrors, but it is necessary to convince a naturally sceptical regulator as well.

Prof. T. Fearn’s slides are available on page 9 of the PAT-SessionII.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 After some brief comments on multivariate methods in general, the paper explores some of the problems associated with multivariate calibration: the fact that few chemists have been trained in this methodology, its image as a black box, and the understandable concern that it is capable of being misused. It is argued that these problems can be overcome, the first two by education, and the misuse problem by a strong emphasis on validation. The author’s background is in statistics, food technology, and near infrared spectroscopy. This explains the choice of food examples below. It would of course have been nicer to use pharmaceutical examples, but it tends to be harder to get permission to publish these. Why multivariate methods? Perhaps the most important point to be made about multivariate data is that the information content of several variables considered together can be more than the sum of the information in the individual variables.


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Slide 5 (page 3, PAT-SessionII.pdf, EDQM internet site) an outlier that can be seen using two measurements in combination (Session II file, EDQM internet site) is a scatter plot showing 50 items, with two measurements on each item and one axis for each measurement. In this two-dimensional plot an outlier is clearly visible in the top left quadrant. This item would not stand out at all if either one of the two variables was considered singly. If these were batches of raw material a multivariate control chart1 would detect this as an odd batch. Two univariate charts would not. Although there are many possible applications for multivariate methods in the context of PAT, the one that stands out is the use of multivariate calibration methods by some measurement technologies, notably but not exclusively near infrared spectroscopy. This application is a difficult one because of the number of variables available from a spectrum. Two variables are an opportunity, one thousand variables are a challenge. It is however well worth rising to the challenge. The near infrared reflectance spectra in slide 7 NIR spectra of 40 biscuit dough pieces (page 3, PAT-SessionII file, EDQM internet site) have been used to enable rapid measurement of the composition of biscuit dough pieces with no sample preparation, a method that could be used for on-line process control2. This is a food industry example, but there are many similar opportunities in the pharmaceutical industry. How do the methods work? The workhorses in the multivariate calibration toolbox are principal components analysis (PCA) and partial least squares (PLS)3. Both of these work by constructing new variables from the original measurements. These new variables are linear combinations of the original ones, constructed in such a way that they capture, in only a few variables, most of the information in the data. They can be used to visualise the data. Slide 9:3-D scatter plot of three principal components of the biscuit spectra (page 3, PAT-SessionII.pdf, EDQM internet site) is a plot of three principal components of the spectral data in slide 7, with each of the 40 points corresponding to one dough piece. The 600 variables have been reduced to 3 whilst retaining much of the original information. One can think of this as a three-dimensional window into the 600-dimensional space in which the spectral data lie. These new variables may also be used to predict reference values, via an equation fitted to training data. The shading in Figure 3 indicates the fat content of the biscuit doughs. It is clear that there is information about fat content in the variables that have been constructed, and also that we need more than one of them to produce a good predictor. In fact we can use multiple regression3 to derive an excellent prediction equation. Some problems and some solutions The most obvious problem with multivariate calibration methods is that most people do not understand them. Remedying this requires an effort on two fronts. Firstly, there is a need to give both the industry and the regulators enough of an understanding of how the methods work to raise the overall comfort level. I believe that this is possible, because it is certainly possible to explain the basic ideas without covering blackboards with matrix algebra. Secondly, there is a desperate shortage of people with the skills needed to implement the methods. There are very few universities where it is possible to get training in chemometrics, and the situation seems to be getting worse rather than better. I do not have an easy answer to this problem, except to urge those of you with influence in university chemistry departments to use that influence to encourage them to expose their students to at least some chemometrics.


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Two specific concerns often voiced about these multivariate methods are that we should not trust ‘black box’ approaches that produce calibrations that work for ill-understood reasons, and that abuse of the methodology can result in calibrations that fit beautifully on training data but fail to predict unknowns. The answer to the first is that multivariate methods do not have to be black boxes. One of the best things about the growth of chemometrics is that there is now plenty of good software that not only enables but encourages the extensive use of graphical techniques to give insight into and understanding of why calibrations work. Figure 4 Calibration coefficients for fat ( Slide 12, page 4, PAT-SessionII.pdf, EDQM internet site) shows the coefficients of a calibration equation for fat content of biscuits derived from the spectra in slide 12 by PLS. There is one coefficient for each wavelength in the spectrum, and the fat prediction for a new sample is obtained by multiplying these coefficients by the spectrum of the sample and summing over wavelengths. The double peak around 1750nm in this coefficient plot is characteristic of the NIR spectrum of fat, and explains clearly how and why this calibration works The answer to the problem of abuse is to insist on validation on an independent test set. Slide 14 Validation of fat calibration (page 5, PAT-SessionII.pdf, EDQM internet site) shows a plot of measured versus NIR predicted fat values on a further set of biscuit dough samples not involved at all in the derivation of the calibration. This is pretty convincing. It is also very simple: there is one prediction and one reference value for each sample, so that, e.g., checks for linearity are easy to carry out. The more sophisticated the calibration methodology, the more important it is to challenge the resulting calibration with unseen samples in this way. Conclusions It is important not to be frightened off these multivariate methods by the apparently scary mathematics, especially if that means failing to exploit measurement technologies with exciting possibilities. It is not necessary to have a PhD in matrix algebra to understand what is going on, nor does multivariate analysis have to be a black box. It is important though to validate sophisticated calibration methods using independent test sets. References Massart, D. L., Vandeginste, B. G. M., Buydens, L. M. C., De Jong, S., Lewi, P. J. and Smeyers-Verbeke, J. (1997) Handbook of Chemometrics and Qualimetrics: Part A. Amsterdam: Elsevier, Chapter 20. Osborne, B. G., Fearn, T., Miller, A. R. and Douglas, S. (1984) Application of near infrared spectroscopy to compositional analysis of biscuits and biscuit doughs. J. Sci. Food Agric., 35, 99-105. Næs, T. Isaksson, T., Fearn, T. and Davies, T. (2002) A User-Friendy Guide ot Multivariate Calibration and Classification. Chichester: NIR Publications.

DISCUSSION

Mr G. Ritchie: Here’s what I would suggest. You have been involved for a period of time now writing a very good series of columns in NIR News and I think there’s enough information in there


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to begin with. I guess the only way I could compare it, Jim Brown and Jerry Workman a couple of years ago for the ASTM standard, wrote out a series of steps on how to build a model, validate it, calibrate it, select examples, so forth and so on. You’ve gone much further into looking into some of the trouble-shooting areas and things to avoid. It would be nice to formalise that outside of the NIR News, so that it could be useful for this group of people. What do you think about that? Prof. T. Fearn: Some of it clearly has been formalised in that there’s a book around that’s based on some of those articles, which you could buy a copy of. The problem with writing in NIR News is that the only people who read that are people who are actively involved in using NIR. I think there is scope for trying to find out what Prof.essional magazines the regulators and the managers in the pharmaceutical industry read and to try to put things in there that will explain some of these methods in fairly simple terms. Mr G. Ritchie: Maybe to you it might seem like you are going back and re-visiting some of those issues, but for some of the people here, to re-do some of that work with you let’s say and have you discuss the specifics of the type of samples and the type of problems that will deal with the whole scope of chemometrics and perhaps refer to the use of DOE. You wrote a significant amount of articles dealing with DoE and things we should be avoiding. For this group there is room for collaboration to re-do it. Prof.. T. Fearn: I think the problem is to find exactly the right vehicle and exactly the right level, but I would be happy to talk to you about this. Prof. T. Moffat: Getting into chemometrics is sometimes quite difficult and as I think what we’ve just heard from Gary - getting a textbook, reading NIR News. But if you were going to suggest a chemometrics package that people can buy, is there one that’s relatively easy to get into? We have bought several and you just get a great tome and that’s pretty scary stuff and you just daren’t open the book or run the chemometrics until you are quite happy with it. Is there a suite of chemometrics packages that you would advocate for first time users? Prof. T. Fearn: If I answer that I’ll make one friend and a lot of enemies! What I would advocate, though, is going on some sort of training course. It’s the initial hurdle that’s the problem. So you should buy one and as long as it’s one of the good ones, and there are several good ones, then I don’t think it matters terribly which one. It ought to be one where there are some training courses associated with it, so that you can get over the initial hurdle and start using it.


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Acoustics

Dr Ron Belchamber, Process Analysis & Automation Ltd. (UK)

Abstract: Many processes produce natural acoustic emission. Analysis of these signals can often reveal detailed information about the process e.g. how fast is it proceeding, is it producing consistent product, has it reached an end point, has an upset occurred etc.

Acoustic emission measurements are performed non-invasively, provide real time information and are highly sensitivity. This combination of factors makes acoustic emission an attractive process analytical tool.

We have focussed our attention on solids processing and have applied acoustic emission monitoring to a number of important processes in the pharmaceutical industry. These include the product fluid bed drying and high-shear granulation. In these processes the characteristics of the particles change with the degree of processing. This in turn affects the nature of the acoustic emission signal in a very direct way. Qualitative pattern recognition techniques (e.g. SIMCA) enable the process state to be inferred from the acoustic emission signals by comparing them with those obtained under known conditions. Using this approach we have developed a number of successful applications.

High-shear granulation and fluid bed granulation are used to produce material for tablet making. The granules produced must have the right properties of particle size, flow and density to produce high quality tablets. Acoustic emission provides a means of monitoring the material quality and identifying when the process end point has been reached, enabling the process to be stopped at the optimal time. Dr R. Belchamber’s slides are available on page 14 of the PAT-SessionII.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 One of the first observed occurrences of acoustic emission form particulates was of booming sand. This occurs in many deserts of the world where sand dunes are set into motion by the wind or by people walking on them. These strange sounds are caused by the shear of sand particles. The first observation of this phenomenon was by Marco Polo in Marco Polo in 1295 who described evil desert spirits ‘at times filled the air with the sounds of all types of musical instruments and also of drums and the clash of arms’.

Acoustic emission monitoring is an attractive process analytical technology. It is:

• rich in unique process information;

• a provider of real time information suitable for process control;

• applied non-invasively – there is no need to penetrate the vessel wall;

• non-destructive measurement – physical samples are neither extracted or destroyed;


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• intrinsically safe allowing measurements to be made in a hazardous environment without the cost of further protection;

• applicable to a wide range of processes encountered in secondary pharmaceutical production including fluid bed granulation and drying, high-shear granulation.

To make a measurement it is necessary to attach an acoustic emission sensor to the outside wall of the process vessel. Ultrasonic sensors use a small piezoelectric disc to convert the acoustic emission wave into an electrical signal.

An acoustic emission system consists of a number of acoustic emission sensors, preamplifiers, intrinsic safety interface, and a signal-conditioning unit. A personal computer is used to acquire and analyse the signals. The preamplifiers allow the sensors to drive very long cables, which mean that the signal conditioning unit and computer can be located in a control room away from the granulation suite.

Many factors influence the acoustic emission signal including particle hardness, particle size and the flow regime.

We have extensively used acoustic emission, outside the pharmaceutical industry, to monitor the performance of very large fluid beds. An example is the manufacture of polyolefins granules. Occasionally, this material will agglomerate causing major process upsets.

We can correlate change in the acoustic emission signals with changes in the particle properties i.e. when we change the temperature and the particles become softer and more cohesive.

Using this approach we have been able to detect changes in large fluid bed behaviour up to 24 hours before a major agglomeration incidents occur.

High-shear granulation is good application of acoustic emission monitoring.

During high shear granulation different acoustic emission signatures are obtained during dry mixing, wet granulation and wet massing.

Acoustic emission signals are very rich in information. We have used a number of different strategies for analysing and characterising acoustic emission signals. The simplest method is to convert the signal to a ‘DC level’. This works well for simple applications such as detecting particles passing through the outlet of a cyclone. Other methods of analysis include time series analysis, which has been used for kinetic studies.

In most case we use a Fourier transformation step to convert the acoustic signals into the frequency domain. The resulting spectrum is characteristic of a certain process state. The spectra are then further analysed and characterised using multivariate statistical methods including Partial Least Squares (PLS) to provide quantitative information and by ‘Soft Independent Modelling by Class Analogy’ (SIMCA) to provide qualitative information (e.g. has the end point been reached?).

SIMCA is a powerful pattern-matching algorithm. It is based on principal component analysis and models classes of signals. It enables ‘unknowns conditions to be classified as belonging (or not belonging) to previously defined classes.

SIMCA provides a statistic called the SIMCA distance. This is usually expressed in terms of standard deviations and tells how well a particular unknown (acoustic emission signal) fits a particular class.

We have used this statistic to monitor the approach to end point in high-shear granulation, fluid bed granulation and fluid bed drying.


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PLS has been used to extract particle size information directly form the acoustic emission signal. We have used this approach less than SIMCA because calibration is more difficult requiring a reference method to be run alongside the acoustic emission system.

As an aid to system validation we often deploy two sensors on a single vessel. We send a pulse from one sensor to the other. This enables us to detect changes in the sensor responsiveness form the time of model building (calibration) and using the system to detect say an end point in a production campaign.

DISCUSSION

Dr G. Cook: One of the challenges with high sheer granulation is scale-up and applying the learning say from a small-scale piece of equipment to a larger piece of equipment, how is that addressed in acoustic emission technology? Dr R. Belchamber: You certainly see similarities between small-scale equipment and large-scale equipment. I’m doing an experiment on small-scale granulation and the equipment is actually quite difficult, really due to the size of the material, your sample size. It is quite possible that in very small granulator to have 50 % of the material for instance sticking on the walls. So scale-up is quite difficult. I would say you see similarities, at this moment you cannot build models, I believe on a small granulator and expect to be able to transfer them to a larger granulator. The calibration stage for qualitative modelling is actually reasonably straightforward. It’s easier than doing a quantitative model, so it’s probably not too difficult. But I think there are quite a few challenges in that area and I’m sure there are going to be some developments, but at the moment you would not be able to transfer a model, although you can actually learn quite a lot. Prof. T. Moffat: Can you actually go out and buy these things? Or is it very much cut and stick yourself? Dr R. Belchamber: You can do both. There are a limited number of manufacturers of systems, complete monitoring systems and as I said at the beginning, acoustic emission has quite a long history of non-destructive testing, so it is actually possible to go and buy components. The companies that supply equipment for non-destructive testing, some of the systems could probably be applied to some of these things, but are not exactly ideal and it would probably involve you going to a number of different suppliers, to build a complete system. It could be done, I mean that’s where we all started.


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Processability and functionality of excipients.

Mr Steve Hammond, Pfizer (UK)

Abstract: Pfizer Global Manufacturing has a strategic objective to strive for ‘Right First Time Performance’ in our operations. The objective includes the elimination of variability within the processes we operate, thus reducing variability in the products that output from our plants. Global assessments were performed of excipients, to assess the level of variability in these key ingredients. The focus of the assessment was the “processability” to form products. Samples from the twenty four manufacturing plants around the globe were assessed for within supplier and between supplier consistency. The testing performed was focused on the physical attributes of the excipients, as it was felt that the most significant variations in the ability to process these powder materials was in their physical characteristics. To aid in understanding the physical characteristics of these ingredients, and their effect on the matrix that forms during processing, two new technologies were employed. Digital imaging of particles, where the sample is dispersed onto a glass slide and the images of ~200,000 particles are collected and processed into distributions. Chemical images were collected of the product matrix, and used to understand what the effect of excipient particle size variation is on the matrix produced. The results of the testing showed that new technologies now exist to better characterise excipients, and the effect they have on a formulation. The data collected illustrated that existing pharmacopoeial testing regimes do not properly assess materials for “processability” and thus their effect on quality of the products produced. To properly assess the effect individual excipients have on a specific process, requires focused testing on the ingredients that go into that specific formulation. By inference then the specification for an excipient will be product and formulation dependant. The conclusion is therefore that general pharmacopoial testing is not sufficient to assess the likely performance of ingredients in a formulation, and thus the performance of a product manufactured from the ingredients. Testing and specifications for an excipient need to be assessed by the company manufacturing the product. Testing needs to be based on process knowledge and the effect variation in the physical and chemical attributes of an ingredient will have on an individual process and the product it delivers. Thus the setting of general pharmacopoeial specifications for excipients is no longer relevant. Mr S. Hammond’s slides are available on page 25 of the PAT-SessionII.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 Pfizer Global Manufacturing has a strategic objective to strive for “Right First Time Performance” in our operations. The objective includes the elimination of variability within the processes we use, thus reducing variability in the products that output from our plants.


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Global assessments were performed of excipients, to assess the level of variability in these key ingredients. The focus of the assessment was to gather information on the variation in the attributes that effect “processability” to form products. Samples from the twenty four manufacturing plants around the globe were assessed for within supplier and between supplier consistency. The testing performed was focused on the physical attributes of the excipients, as it was felt that the most significant variations in the ability to process these powder materials was related to the physical characteristics of the particles that make up the materials. To aid in understanding the physical characteristics of these ingredients, and their effect on the matrix that forms during processing, two new technologies were employed. Digital imaging of particles, where the sample is dispersed onto a glass slide and the images of ~200,000 particles are collected and processed into distributions. Chemical images were collected of the product matrix, and used to understand what the effect of excipient variation is on the matrix produced. Slides 4 and 6 NIR microscopy can be used to undersand the effect of excipients on the matrix of a formulation and correlate images with performance (page 2, PAT-SessionII.pdf, EDQM internet site) illustrate these technologies. The results of the assessment showed that new technologies now exist to better characterise excipients, and the effect they have on a formulation. The data collected illustrated that existing pharmacopoeial testing regimes do not properly assess materials for “processability” and thus their effect on quality of the products produced. The first example is the effect of variation in magnesium stearate. Slides 10 and 12 Brazil and Japan magnesium sterate (page 4, PAT-SessionII.pdf, EDQM internet site) show two forms of variation that can significantly effect a formulation. The particle size distributions shown if figure 3 for example, where the high surface area material used in Japan reduced issues with tablet sticking to punches during compression. However the same material used in Brazil in a capsule formulation resulted in dissolution issues, and a mag stearate of lower surface area had to be selected. This illustrates a key point, that one size does not fit all with excipients and different products. Further to the particle size differences in magnesium stearate supply, the variation seen from supplier to supplier in the hydration state of mag stearate is also a variable that cause different effects in different products, sometimes helpful, other times resulting in processing or specification issues. The second example is the effect of variation in bibasic calcium phosphate used by Pfizer. Slide 18 (page 6, PAT-SessionII.pdf, EDQM internet site) shows the global variation in particle size of dibasic calcium phosphate. It is interesting that the Pfizer direct compression processes are largely tolerant of this variation, unless it goes to the extreme as seen in slide 18: dibasic calcium phosphate at the extreme causing a capping issue, when we find capping issues with the tablets being compressed. The third example illustrates the use of imaging to understand the effect of disintegrant particle size on dissolution. Slide 20, the PS distribution of two lots of starch used as disintegrant control problem lots (page 7, PAT-SessionII.pdf, EDQM internet site) shows the size distribution of two lots of starch used as disintergrants. Slide 15 NIR chemical images showing the variation in the distribution of disintegrant (green) within the tablet matrix.(blue, black, red), related to input particle size of the disintegrant (page 5, PAT-SessionII.pdf, EDQM internet site) shows the


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‘clumping’ effect the particle size of the problem lot has on the matrix and thus dissolution of the product. Conclusions To properly assess the effect individual excipients have on a specific process, requires focused testing on the ingredients that go into that specific formulation. By inference then the specification for an excipient will be product and formulation dependant. General pharmacopoial testing is not sufficient to assess the likely performance of ingredients in a formulation, and thus the performance of a product manufactured from the ingredients. Testing and specifications for an excipient need to be assessed by the company manufacturing the product. Testing needs to be based on process knowledge and the effect variation in the physical and chemical attributes of an ingredient will have on an individual process and the product it delivers. Thus the setting of general pharmacopoeial specifications for excipients is not relevant. General discussion on what parameters maybe considered to be included in a specification for a material within a companies manufacturing plant may be of supporting value, but such a document must promote flexibility with the testing to be performed and the type of equipment and technique used. Any guidance must not in any way restrict the use of new technologies to understand our processes and the effect excipients have on the outcome.

DISCUSSION

Dr S. Wolfgang: Could you comment more on the surface area findings that you had and also on your feeling about the functionality characteristics and specifications for instance, the fact that the USP and Ph.Eur are requiring for surface area testing, yet it’s possible the measurement of surface area alone will not allow for selection of materials properly. Dr S. Hammond: It’s certainly taking the last question first. I think that one thing we do know, that if we do want a magnesium sterate that’s going to work for a particular product, then we are relying on surface area measurements, if they are actually performed and that’s an interesting thing. A lot of plants will just rely on the certificate of analysis for surface area that they get from a supplier and one another thing, I think it’s something malencrot need to be very aware of, your gas disorption measurement is not discriminating enough to tell us whether we have a good surface area. I think the problem there is that you measure the pore size of the crystals and that has no relevance to manufacturing. What we’re interested in, is the actual surface area that’s available for a big lump of micro-crystalline cellulose to interact with. I think the specifications for things like magnesium sterate in the Ph.Eur and the USP need totally revising. At the moment I feel that they are not really relevant to process understanding or good control of manufacturing. Prof. Dr H. G. Kristensen: I mentioned in the morning that the Ph.Eur has decided to introduce functionality related tests and what I want to emphasise is that we are fully in-line with your recommendations here. What the Pharmacopoeia should do in this field is to standardise or provide users with tests which will give the possibility to use the test in developing your specifications, but a non mandatory system completely free to use, a flexible system. The Pharmacopoeia has really, in my opinion, a role in the provision of standardised test methods, which can be used by the supplier of excipients as well as the user of the excipient. But the real reason I want to make a comment is because you say that impurities are not a problem, they are well controlled. I thought that processability and many formulations were influenced by impurities in excipient materials. There


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are a number of occasions where we add impurities deliberately and we have a need to control them. I don’t think even in processability the question of impurities is irrelevant. Dr S. Hammond: I have heard rumours from a certain Dr A. Hussain that impurities in magnesium sterate make quite a difference. I have to say that we have not seen evidence of that. The overriding things for us are the surface area, the crystallinity and the hydration state. But impurities they may matter. Dr A. Hussain always tells me they do. Prof. T. Fearn: You identified a number of problems with raw materials and your response in each case has been to tighten the spec on the raw materials. You may have done this anyway, but a quality by design philosophy would say what you ought to be doing is experimenting with your process to make it more robust to those variations in raw materials. Have you done that at all? Dr S. Hammond: Certainly for some of the materials / products where we’ve had a problem we have a design of experiments going on to look at understanding exactly where the boundaries are. Unfortunately that’s a huge effort and it would be far better done at the development stage for new products and I have to give credit here to my R&D colleagues, they are doing exactly that nowadays. They are certainly characterising raw materials better than ever before and looking to do a design of experiments to understand where the boundaries are. I think they should be applauded for that.


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Implementation of PAT in automated tabletting

Dr Ivor Pegington, MSD (UK)

Dr I. Pegington’s slides are available on page 33 of the PAT-SessionII.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2

I work for Merck in Cramlington, which is one of their automated tabletting facilities. I am part of a team who are tasked with the implementation of PAT for the site and this is what I am going to talk to you about today. I will explain to you about what we see as the potential benefits and risks to the site of PAT for both new and existing products. I will then explain the strategy we are taking so that we can implement PAT and eliminate some of the risk. This will include how we intend to identify where we require PAT analysers in our processes. As part of this I will give some examples of how existing controls are being used to control and understand our processes and where this approach has helped in troubleshooting exercises. These examples and scenarios will cover raw materials receipt through to compression. Firstly I will discuss new products: For new products we can draw on previous experience of PAT within the organisation to design the operation with PAT in mind. Any methodology we could employ during the development phase is available for use to achieve some additional process knowledge. Armed with this data we would be able to tweak what we are doing to build in quality from the outset. Even if this knowledge only confirms what we already suspected it will be helpful in setting specifications for the process. For new products we should have less regulatory issues than for applying PAT to existing products, as we can put forward the PAT methodology in the original filing. Further to this a robust, forward thinking filing at this stage will reduce the regulatory burden during the product life. There is also the possibility we may use a different validation approach, something that is mentioned in the draft guidance from the FDA. The main risks we are concerned with for new products are that we may have a aggressive timelines for a product launch and so may not have the time to develop and validate the PAT methods in time for this. In these circumstances we require alternative methods to get us to market in a timely manner. Another reason we require a robust filing that will allow us to switch to the PAT method in the future. By applying PAT to existing processes we may make significant returns on our investment. The most tangible of these are considered to be reducing cycle times, especially by removing process bottle neck, and reducing the testing burden both in-process and final product. From a quality perspective however we are able to better measure and control on the critical process parameters – once identified – which may improve the performance of the product through the


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manufacturing process. The risks we have to balance this against are mainly due to GMP issues. To enable us to install PAT analysers we will have to modify the plant and or the process equipment. Depending on the equipment and its function the equipment may have to be re-qualified. For example if it is pressure rated we may need to ascertain what effect the modification has had on this. The processes will have existing validation and so any modifications to the equipment will result in the process requiring revalidation. For our site where products are campaigned this may require re-validation of more than one product. So more consideration has to be given for older products. Not a GMP issue but still of concern is our dependability on the PAT analysers. Although I have out this in the existing equipment section this is a concern if we are applying PAT to new or existing products. Failure of the PAT analyser for whatever reason will result to us having to revert to alternate methods. That is non-PAT production. If the PAT analyser has increased the sites manufacturing capacity may be adversely affected if we have to revert to alternative analysis. The sites potential is therefore linked to PAT analysers and as such we have to be assured of its reliability. At present we record a large amount of data from the existing process and this can be used to gauge information from the process. By extracting process parameter correlations we can achieve a level of PAT without the need for a PAT analyser. This data is also invaluable in ascertaining what variation there is within the allowable specification. As a large amount of historical data will already have been gathered this can be used to identify the correlations and then used for current production. The conventional sensors can be used to develop integrated process control for products and processes. To help reduce the variation observed in our raw materials ID and Qualification methods are used. As part of the holistic approach we are also using the in-house analysis and vendor certificate of analysis in the identification of process parameter correlations. We control the storage of our raw material especially in terms of temperature and humidity as you would expect. We have a lot of data gathered from the storage of the materials such as variations in temperature and humidity over the storage time and this data and the variability within it should also be considered as part of the process when identifying process parameter correlations. For Wet granulation we have quite a nice example from a troubleshooting exercise that was performed. For one of the products we observed some compression difficulties. A high number of tablets were being rejected compared to usual. As part of the investigation into this matter a data mining exercise was undertaken. As part of the data mining exercise we covered dta from raw materials specifications and equipment sensors. The granulation endpoint is determined by amperage increase of the beater as the granulation proceeds. From the data mine the baseline amperage at the start of the granulation was observed to be higher than normally observed. The chart shows the average amperage at the beginning of granulation on the x-axis for a number of batches, on the y-axis. As you can see there is a distinct increase in this value and this coincides


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with the problematic batches. On further investigation into the analysis on these batches it was found that the moisture of the combined raw materials was higher than typical, but still within specification for the individual materials. This would be expected to give higher baseline amperage and as such the theory had a sound scientific base. A simple adjustment of the raw materials specifications for this product ensured this would not happen again. As well as the baseline amperage the other process health indicators that are being considered for this unit operation for this product are final amperage and rate of amperage increase. For drying Granule in a fluid bed dryer we rarely have timed endpoints. The endpoint for the drying of the granule is commonly determined by monitoring the temperature of the exhaust air from the dryer. As part of trial for a PAT analyser we have gathered data from the drying of one of our products and as such have been able to generate this chart. The exhaust temperature is a very good indicator of process progress (and if the Prof.ile were available would be a good indicator of process health). Other process health indicators that are being considered for this unit operation are the pressure differential across the gill plate (explain) and in the catchment socks. These may give an indication of the amount of fine and heavy particles in the dryer. The inlet air temperature and airflow are also important considerations for this process. I would like to talk about now is how compression equipment is set up to control the uniformity of the tablets. The compression force on the compression machine is set up to control properties such as disintegration and dissolution. The compression force is also used as a measure to assess uniformity. The compression force is measured when the tablet is made. The lower punch height determines how much granule will make up the resultant tablet. The amount of granule is also related to compression force. That is, the more granule that is in there the higher the force will be. Therefore high and low forces can be used to reject tablets that may be heavy or light. The process can be tweaked, based on the in-process results for disintegration, hardness, thickness, etc. But in addition the compression equipment also adjusts the fill levels to maintain the target compression force. The site is very positive towards the PAT initiatives. To minimise the risk we need to identify where the PAT analysers are necessary and have effective contingencies in the event of PAT analyzers being unavailable. By observing process variability through data mining of past and current production we have identified some measures that will allow us to do this and that will allow us to gauge process health. This data is not only useful in identifying where we need PAT analysers but will increase our process control by not depending on one single measure. This holistic approach is seen as the way forward to control our processes and also health.


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Use of imaging to understand tablet performance

Ms Fiona Clarke, Pfizer (UK)

Abstract: Near-infrared microscopy is rapidly gaining recognition as a useful tool for pharmaceutical analysis. Currently, it is utilised retrospectively to determine the root cause of production issues. However, the major advancement for NIR microscopy in the pharmaceutical industry will be as a tool to predict critical process parameters, such as dissolution performance. In this presentation I would like to shoe some examples of where NIR microscopy has been an invaluable tool in understanding the critical quality attributes of real production issues. At the same time looking at ways to extract ‘useful’ information from chemical images and in turn how this information can be correlated to macro-scale properties of pharmaceutical dosage forms. Ms F. Clarke’s slides are available on page 38 of the PAT-SessionII.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 Chemical imaging has been advancing over the past four years as a method for pharmaceutical analysis. Chemical imaging relates to the generation of an image using chemical information. This chemical information typically is generated using a spectroscopic method, such as near-infrared spectroscopy. Near-infrared (NIR) microscopy is one method which can be utilised for chemical imaging. NIR spectroscopy is now commonly used in the pharmaceutical industry for testing of raw materials and also for tablet analysis, alternative to HPLC content uniformity testing. The reason that NIR has been successful, is that it can be used on samples without the need for dilution or preparation. This transfers to NIR microscopy, where NIR spectra can be obtained directly from a sample surface at a microscale level, typically from an area <625 µm2. Spectral data can be collected from an area, such that each spectrum represents a small area (pixel) which can be identified as a chemical species, and marked (using colour) in the overall sample area, giving rise to the chemical image. There are two different approaches commercially available which allow these images to be obtained in under 30 mins, global imaging and line imaging systems, described in slide 3 Schematic of NIR Microscopy Experiment, (page 1, PAT-Session II .pdf, EDQM internet site.) Further explanations of the technology will be covered during the presentation. The data collection stage is only part of the analysis, with >10,000 spectra per image different approaches are required to extract chemical identification from each spectrum, approaches such as principal component analysis and partial least squares regression are used. Although the resultant chemical images are useful to understand spatial distribution of chemical components within a pharmaceutical matrix (tablet or compressed blend), the interpretation of a chemical image is different from analyst to analyst and as such methods have been established which allow numerical statistics to be extracted from the image. These values are readily comparable.


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So why are chemical imaging approaches useful, and how does the technology add value to other existing analytical methods? At the microscale level an image can be obtained from a tablet or compressed powder sample. The different chemical components can be identified, and as such size and distribution of each component can be determined. This allows matrix level changes in samples to be compared and often correlated to product performance. This is quality information which cannot be obtained by any other approach. NIR microscopy allows the physical and chemical attributes of the solid dosage form to be evaluated in one measurement. To date, the technology has been utilised for retrospective problem solving, where known good and problem samples are compared in terms of their matrix level information. Variations at this level can be observed, and correlated to product performance, one such example is dissolution. There are many factors which may effect the dissolution Prof.ile of a tablet, often the true cause of dissolution changes is difficult to determine. NIR chemical imaging has the ability to examine changes at the micro-scale level, which often point to the source of variation. One such example is in a product where dissolution failures where identified in one tablet lot. On examination of the input API material, the lot used in the issue tablet lot had a slightly different particle size distribution. When NIR chemical images of the tablets were examined, the distribution of the API was found to be completely different in tablets with poor dissolution. In this example, NIR imaging was used to support a change observed in the input API material. A second example of the use of NIR chemical imaging in understanding dissolution performance, was an example where a range of dissolution values were observed for different tablet lots, ranging from 50% through to 86% at 45 minute dissolution value. The reason for variable dissolution was unknown, but NIR chemical imaging showed that the distribution of one component was different for each tablet lot, with a greater number of component regions identified in tablets with good dissolution. The number of component regions (domains) was counted for each tablet analysed, and slide 16 Plot of Number of Excipient Domains identified in Chemical Image vs Dissolution Value at 45 mintues (page 6, PAT-SessionII.pdf, EDQM internet site) shows a plot of the number of domains versus % dissolution value. This plot shows that dissolution is dependent upon the distribution of this excipient component, hence NIR imaging has not only be used to help understand the problem but also provides understanding of how the dissolution occurs. NIR chemical images have also been used in different product investigations, but part of the key to successful results is the data interpretation. Using different chemometric approaches it is possible to not only identify chemical components, but preliminary results have shown that it may be possible to determine concentration information from chemical images. Experiments were established using model 2 and 3 component systems. The data collected was evaluated using classification partial least squares analysis and a correlation between the actual concentration and the score values from the analysis was observed. As such it could be suggested that NIR chemical images may be useful for quantative analysis. One such area where this may be important is for the assessment of unit dose performance at the blend stage of production. Developments in NIR imaging technology have allowed the first ever imaging system to be developed to perform measurements within a blender unit. Such a system, would be beneficial to understand product performance at the blend stage. With the potential to predict concentration information from chemical images, it may also be possible to measure content uniformity at this stage in the process. A placebo blend was evaluated across a 5 minute blend time to look at what information could be obtained from chemical images. At the same time on-line NIR spectroscopy was utilised to determine blend homogeneity at the macro-scale level. In under 3


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minutes of blending, the macro-NIR showed the blend to be homogenous. However, the chemical images showed that the distribution of the components was not homogenous at the micro-scale level. After 5 minutes of blending the individual components appeared to be uniform, but also the concentration information obtained from the score values showed correlation to the true concentrations in the blend, this was not observed at earlier time points in the process. Overall, this presentation should show that NIR chemical imaging can be used as a predictor of product performance, in particular providing scientific understanding of what effects dissolution. It also shows how technology has advanced in a way that now allows chemical images to be obtained from with-in a blender, potentially allowing prediction of product performance during a manufacturing process.

DISCUSSION

Dr M. Josefson: I would like to ask you about those distributions in the last slide. Where does this negative come from? Dr F. Clarke: I believe that the negative value comes from the fact that the spectrums are totally dominated by the lactose. When we do are match factors we don’t see any. Dr M. Josefson: How do you calculate those? Dr F. Clarke: Basically we have been doing a classification PLS through to the pure group excipient library. Dr M. Josefson: Then I understand that they are different in the beginning. Dr R. Marbach: I have one question. About the scatter co-efficient, if I look at my skin, I cannot see details in my skin because it’s scatter. If I just do straightforward looking the smallest 3D resolved element is determined by the scatter co-efficiency. In your measurement pixel size 20 x 20 microns chosen to be matching with the scattering characteristics above your samples. Is that why it works so well? Dr F. Clarke: Good question. I don’t honestly know the answer to that. I would have to give it some thought. In terms of the mapping system the size of the area where we collect information from is defined by a set of apertures. In terms of the global imaging system it’s defined purely by our magnification and all we believe we are limited by is the diffraction. So in terms of the global imaging systems we can get down to about 5 microns per pixel. I don’t know in terms of scattering, the relationship. Dr R. Marbach: I wasn’t interested about the technical details of the imaging. If I think I’m sitting at one particular side of that tablet and I count the photons coming out at exactly that side, those photons have a history of traversing neighbourhood material and my question is, how big is that neighbourhood? What is the smallest technical resolution that makes sense? Dr F. Clarke: We believe that the smallest object we can actually see is 20 microns. Having done some experiments through my PhD studies with Prof.. Moffat we believe that if we actually set two things side by side and go from one to the other the contribution of one from the other is no more than 20 microns. We no longer see the spectrum contribution in terms of a lateral resolution.


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Dr S. L. Ali: My question is about the dissolution pattern prediction with this imaging technique. USP produces calibrator tablets for dissolution and they are a reference worldwide. All the instruments are tested for that. Do you think this imaging is a more accurate method of predicting the dissolution pattern or to put in other words the tablets being produced to have a constant quality and dissolution pattern using imaging techniques rather than the dissolution as is done? Dr F. Clarke: What we’ve just actually started in September last year, we have a new PhD. Because of the relationships we’ve identified between dissolution and chemical imaging we’ve actually started a PhD student to work with us to actually understand that. Her first experiment has actually been to look at the dissolution calibrators and actually perform dissolution and correlate these back to chemical imaging. At the moment we don’t quite have the results, but I’ll let you know as soon as we do. We’re certainly having an evaluation of them to see if we can understand things from the calibrators as well. Dr R. Davidson: Your point about the calibrators is quite relevant. We use calibrators even though we are in the European sphere. Calibrators exist basically to detect functions in the equipment, which are not covered by the mechanical and temperature measurements, which are laid down in the pharmacopoeial specifications. There are other factors that affect dissolution, namely the inclination of the equipment, that can be quite critical and vibrations. This is basically what the calibrators are for. The results obtained sometimes are a little frustrating. That’s basically what they are there for. They are not there to replace the full equipment validation of course. Relating to particle size and dissolution. I think we should be really clear on this. This will affect a certain number of actives. Not necessarily all. Not all actives in all formulations are particle-size dependent for dissolution and I’m not sure if this would not be the case of for instance the salicylic acid calibrators. Dr F. Clarke: In terms of the calibrators perhaps not, but in terms of dissolution performance we don’t always focus on the API in terms of real life samples, we’re finding a balance and certainly in one example there it was actually the excipient. So in terms of all those we’ve looked at there’s only a few of the USP dissolution calibrators we can actually use because only a few are actually a mixture that we can pool the information from. I would agree. We can look and see what the variation is and see if we do get any variation in the dissolution test that we do, but as you say it could be equipment related and not sample related.


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Applications of PAT in API manufacture

Dr Chris Killen, GSK (UK) Abstract: The benefit of the application of Process Analytical Technology is primarily in the area of increased process knowledge leading to improved process understanding and consequently better process control. This control may be achieved directly through feed back or feed forward control loops through the plant automation system, or may be indirect through plant operator intervention based on information coming from the PAT implementation. Obvious gains are made by better use of resources, de-bottlenecking, higher yields and quality, and compatibility with secondary processing. PAT is a key tool during the development process to define critical parameters to enable us to develop an appropriate control strategy. This could be through automation or through establishing control over critical unit operations.

Safety benefits can also be achieved through monitoring hazardous reactions, eliminating the need for off-line analysis and potential exposure to hazardous component and potential reaction premature termination (e.g. hydrogenation). PAT has come to be understood to be wider than the application of analytical technologies, sometimes being referred to as Process Measurement Technology, Process Understanding Technology or Process Assessment Technology. The data being assessed may be from process sensors such as a pH probe or an UV spectrometer, or may be in the form of standard plant data such as temperatures and pressures. Such data will usually be converted to process parameters such as component concentrations using chemometric models. Chemometric models may also be built with combined data sets, such as plant and spectroscopic information. Infra red spectroscopic technologies are key tools in monitoring API manufacture. Although on-line mid infra red spectroscopic monitoring can be very informative NIR is frequently more economical and flexible for plant installation. Examples will be discussed in the presentation. For any PAT implementation it will be necessary to develop an appropriate regulatory strategy. This may be informing through annual updates or full registration of the method for approval. This strategy will reflect whether the PAT method is introduced to gain better control or understanding of a process step. Another key issue is the remoteness of the process step from the final API. If the PAT method replaces a registered in-process check method then registration will be required. PAT has an impact on a Pharmacopoeia when it replaces an existing registered method. As an example HPLC analysis (carried out in a laboratory) as a registered method of analysis of a key step in the synthesis of an API might be replaced by an NIR method (carried out in a laboratory). As NIR testing is detailed in Pharm Eur, there are no barriers to its use. Alignment with other pharmacopoeia via ICH is needed. Extension to an on-line NIR would need collaborative development between regulators, academia and industry where the experience of PAT resides. The essential differences between on-line and off-line applications will be considered. Harmonisation is vital for pharma companies to meet the expectations of all regions, US, Europe, Japan, ROW. How can the Pharmacopoeia be updated more effectively? Key will be a proactive


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approach where industry volunteers to work with authorities on new applications. This will allow regulation around these methods to be developed in a common, practical and effective way. Industry and regulators should engage before submission of PAT applications. Dr C. Killen’s slides are available on page 47 of the PAT-SessionII.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 The benefit of the application of Process Analytical Technology (PAT) is primarily in the area of increased process knowledge leading to improved process understanding and consequently better process control. When PAT is applied to existing processes the existing process knowledge is supplemented by the additional data generated by the PAT. This data only become useful when they are converted into knowledge and enhanced process understanding. Understanding of cause and effect relationships then allows control to be implemented. This could be through automation or through establishing control over critical unit operations. The process control may be achieved directly through feed back or feed forward control loops through the plant automation system, or may be indirect through plant operator intervention based on information coming from the PAT implementation. It should be noted that PAT should not be considered to be the simple addition of sensor technology to processes, but that it is the whole integration of the analysis and understanding derived. PAT has come to be understood to be wider than the application of analytical technologies, sometimes being referred to as Process Measurement Technology, Process Understanding Technology or Process Assessment Technology. The data being assessed may be from process sensors such as a pH probe or an UV spectrometer, or may be in the form of standard plant data such as temperatures and pressures. Such data will usually be converted to process parameters such as component concentrations using chemometric models. Chemometric models may also be built with combined data sets, such as plant and spectroscopic information. Process variability needs to be controlled to allow efficient manufacturing. Reduction of variability is the key driver for PAT implementation both for the manufacturer and the regulator. Regulators want to see fewer process deviations and elimination of product recalls. Policing such activity is time consuming and resource intensive. Obvious gains are made for the manufacturer by better use of resources, de-bottlenecking, higher yields and quality, and compatibility with secondary processing. For new products and processes PAT is a key tool during the development process to define critical parameters to enable us to develop an appropriate control strategy. A key benefit of PAT is seen process scale up and transfer and in verification of process performance at the different scales. An example of this was given with mid infra red monitoring of a two stage process where lack of robustness had initiated a process investigation at lab scale. When an improved process was re-introduced to the plant the application of PAT demonstrated equivalent performance at laboratory and plant scale for both chemical transformations as shown below.


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Interm plantProduct plantInterm LabProduct lab

Figure 2: comparison of laboratory and plant data: product formation Conversion of intermediate to product

Safety benefits can also be achieved through monitoring hazardous reactions, eliminating the need for off-line analysis, potential exposure to hazardous components and potential premature termination of reactions (e.g. hydrogenation). An example of hydrogenation monitoring was given. It was shown that an intermediate in the process could be monitored by mid IR as shown.

-5

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0 50 100 150 200 250 300 350 400

Time (mins)

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Plant study: concentration profile

Infra red spectroscopic technologies are key tools in monitoring API manufacture. Although on-line mid infra red spectroscopic monitoring can be very informative, as shown above in the two examples given, NIR is frequently more economical and flexible for plant installation. In the third example in the presentation, the capability of NIR to be used in a multiplexed system was discussed. A single spectrometer was multiplexed in a production extraction process to 9 flow cells in different parts of the process. (A second spectrometer was used for the process stream with the lowest concentration of product with a short fibre optic link. The fibre optic links for the other


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spectrometer ran up to 60m.) The main benefit of this installation was in giving real time concentration data for each of the key process streams in the process. Without this, infrequent HPLC analysis could only provide retrospective analysis, as the process had to be moved on before the results were received. The delay in receiving such process information would frequently be many hours with consequent poor performance and loss of product. For any PAT implementation it will be necessary to develop an appropriate regulatory strategy. This may be informing through annual updates or full registration of the method for approval. This strategy will reflect whether the PAT method is introduced to gain better control or understanding of a process step. Another key issue is the remoteness of the process step from the final API. If the PAT method replaces a registered in-process check method then registration will be required. PAT has an impact on a Pharmacopoeia when it replaces an existing registered method. As an example HPLC analysis (carried out in a laboratory) as a registered method of analysis of a key step in the synthesis of an API might be replaced by an NIR method (carried out in a laboratory). As NIR testing is detailed in Pharm Eur, there are no barriers to its use. Alignment with other pharmacopoeia via ICH is needed. Extension to an on-line NIR would need collaborative development between regulators, academia and industry where the experience of PAT resides. The essential differences between on-line and off-line applications will be considered. Harmonisation is vital for pharma companies to meet the expectations of all regions, US, Europe, Japan, ROW. How can the Pharmacopoeia be updated more effectively? Key will be a proactive approach where industry volunteers to work with authorities on new applications. This will allow regulation around these methods to be developed in a common, practical and effective way. Industry and regulators should engage before submission of PAT applications.

DISCUSSION

Mrs L. Lundberg: Thank you for presenting some very interesting things here, I like your examples. A practical question, the example you gave of the different PAT applications in API production: are they fully installed? Are the operators the ones to make the decision? How have you managed to train the staff to cope with these new technologies? Dr C. Killen: Good question. The first example I talked about, what we actually did with that one was that, we were putting data through to the plant control screens. Not controlling the process, but going through to the screens, so that the operators would get warnings if anything was out of specification as far as our process should be running. In that case what they would do, they would call a chemist. On a couple of occasions I was actually called in because the thing wasn’t running properly, to verify what the data meant. In that case they didn’t really need any knowledge, they had to make decisions about calling the appropriate person who had that knowledge. The second application was a temporary installation that was run by technical staff, so the operators weren’t doing anything there. We put a mobile unit on there to get process understanding and it didn’t justify putting a permanent installation in there. Concerning the third installation, we are at the point where we are training up the operators. Two of the points there we will actually go closely upon. So the operator won’t need to interact with that. It will actually take the process forward in the appropriate way. What it will be doing, it will be looking at a waste stream and we concentrate up to a certain extent, when the concentration is


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dropping and we get to a certain point we want to recycle that. At another point we say that it is not worth recycling that, we want to put it down the drain. So we can make those decisions automatically the operator doesn’t need to do that.


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Rapid methods in microbiology in the PAT Process

Dr Sylvie Guyomard-Devanlay, Aventis Pharma (F)

Abstract: Microbiological Modern Methods are of great interest to replace the classical Pharmacopoeia methods for in Process control, leading to an increase of the quality of the manufacturing process and consequently to the quality of the finished product. First of all, elements are given to explain why these methods are poorly used in pharmaceutical fields, following by a review of commercially available technologies and at last, examples of these methods to have pharmaceutical waters, manufacturing environment and bioburden of bulk solution before sterilisation under control in real time (less than 4 hours) an almost real time (12 or 24 hours.) For pharmaceutical controls with a low expected contamination level, methods could be classified in 2 groups: real time techniques where results are available within 4 hours and almost real time where they are available within 12 to 24 hours according to the methods. At this time, only cytometry in solid phase is a real time method. The other techniques as flux cytometry, bioluminesence or impedance necessitate a step of cultivation of micro-organisms to be sensitive enough. International guidelines about PAT will help to free pharmaceutical companies for the use of these modern methods as far as they are validated for their intended use. Dr S. Guyomard’s slides are available on page 2 of the PAT-SessionII.b1.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 Introduction Microbiological modern methods give significant opportunities for improving the efficiency of pharmaceutical manufacturing and QA The methods as flow or membrane cytometry or bioluminescence (ATP) are using by cosmetic or food industries for a long time.But unfortunately in the pharmaceutical fields, these methods are not as broadly used as in the other fields for many reasons: First, the perception that the existing regulatory system is rigid and unfavourable to the introduction of new technologies, in another words, the perception is that control methods should be exactly as these described in the Pharmacopoeias. This is particularly negative for pharmaceutical excipient where an alternative method of counting associated to the Aw (water activity) will permit to monitor the microbiological quality of the excipient faster than with the Eur.Pharm methods and will better evaluate the microbiological risk of the raw material. Secondly the way of thinking is more about ‘end release tests’ than about ‘In Process Control.’


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With the introduction of parametric release for sterile products terminally sterilised in the chapter of sterility test in the USP and Ph.Eur., this began to change but due to the very bad representativity (20 samples) of the sterility test. It could be also extended to product sterilised by filtration. We all already know that the end product control gives a bad representativity of the quality of a batch and this is especially true for microbiological tests. This stays obviously true with the use of the modern methods in microbiology used only as end product tests. So, the end product control could be successfully replaced by controls through all critical steps by modern methods in microbiology of the manufacturing chain (raw materials, environments, manufacturing people, manufacturing people, manufacturing devices, process…) permitting microbiological batch release at the end of the manufacture of the product. Other reasons are:

- the difficulties to validate these methods: general validation of the method as well as validation versus the Pharmacopoeia methods (even if manufacturers of these new technologies help a lot);

- the cost of these new technologies which necessitate an economical investment higher than the agar plate method;

- the cost of the training of people to these new technologies which are very different of the classical agar plate methods. For example, all the devices working with these new technologies are linked to a computer to program the test and to interpret the result. This is far from the training of a classical microbiologist.

In fact and fortunately microbiological methods begin to be similar to other analytical methods in the QA process. I will try to convince you how alternative methods in microbiology used as IPC have the capability to prevent or decrease the risk of producing a poor quality product. After a quick review of the commercially available technologies I will present 3 examples of use of these modern technologies in the pharmaceutical fields and at last 2 global examples to the use of these methods for having under control the manufacturing of a sterile product and a non sterile products. Different available technologies for PAT Alternative microbiology methods used could be classified in 2 parts:

- The ‘real time’technologies where the result is known in not more than 4h and - the ‘near or semi real time’ technologies where the result is known after 12, 24 or 48h

according to the technologies. Some nuances should be done since a “near real time” technology could lead to a “real time technology” if the contamination level is more than 300 to 1000 micro-organisms per inoculum. In fact the “near real time” technologies have at this time a bad detection limit and necessitate having an incubation step where microorganisms have to growth to go through the detection limit. So these techniques are in fact an association of ‘classical’ microbiological method with a faster way to detect. This quick review (slide 7, page3, PAT-SessionIIb1.pdf, EDQM internet site) gives only the technologies commonly commercially available today for the use as alternative methods of count in the pharmaceutical industry fields for in process control (IPC) to control the microbiological quality along the process. This list is not limitative and we know that new technologies as DNA/RNA will appear in the near future. Moreover, brands in this slide are only examples, but other brands based on the same technology exist and could be used as far as they have been validated. The only methods for real time technology is the cytometry in solid phase (4h) as Chemscan, from Chemunex. Other methods as flux cytometry (Bactiflow, Chemflow from Chemunex),


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bioluminescence in liquid phase (Advance from Celsis, Pallcheck from Pall), bioluminescence in solid phase as Microstar from Millipore) and Impedance as Bactometer (Biomerieux) or Rabit (AES) are “near real time” technologies since an incubation step of 12 to 48h is necessary according to the techniques to detect the low level of micro-organisms present in pharmaceutical industries. Cytometer with high-speed laser, (Chemscan)

Cytometer with high-speed laser, (Chemscan) is able to count bacteria, fungi, on vegetative or spore forms with no requirement for cell multiplication. Microorganisms are concentrated on membrane. The labelling of viable microorganisms is performed directly on the membrane and the membrane is scanning by a high-speed laser, which detects the labelled elements The weakness of this technique is the numerous steps to prepare the sample before the detection, which are not automated and need well trained analyst to be performed.

The different steps are following: - A filtration of samples, classically until 200 ml through a 25 mm diameter, 0,4 µm porosity, black polyester membrane; - A counterstaining procedure, which uniformly labels background material; - An activation step to activate stressed µorganisms and transforms spores to vegetative cells - A fluorescent labelling step: 30 min at 30°C. At this step the viability substrate is taken up by cell, enzymatically cleaved by esterase present into micro-organisms to release fluorochrome, which is the fluoresceine. This step necessitate the integrity of the membrane of the microorganism as well the presence of enzyme activity, so this step necessitate the viability of the micro-organism (2 labelled E. coli in fig 1)

Figure 1: 2 labelled E. coli - a scanning of the membrane filter: detection of fluorescent events (detection of the fluoresceine uses an excitation by laser at 488 nm and treatment of the emitted fluorescent signal at 515 nm) and data processing to specifically count labelled micro-organisms. This is the most critical step. The major discrimination factors are the colour fingerprint: the fluoresence detected should have the fluoresceine spectra properties, the light intensity, the size and the signal shape (gaussian for micro-organisms not for particles).

- At last, a checking step: to differentiate visually labelled µorg. from the other fluorescent events, not so obvious in some case.

The advantages of this technique are the rapidity to obtain a count (less than 4 hours), the sensitivity (1 micro-organism par filtrated volume) and a correlation with agar plate method for pharmaceutical water.


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The disadvantages are first that no automation is available for the preparation of the sample before the detection, so even a well trained analyst could have difficulties in case of analysis of numerous samples, secondly that it could be sometime difficult to prove the identity of the fluorescent events: particles or stressed micro-organism (in doubt, all the detected elements are counted as micro-organism for the final result) and thirdly that the cost of this equipment/reagents is high. Flux cytometry Flux cytometry uses the same principle of detection. Microorganisms are labelled by a fluorescent viability fluorophore.The sample to test is injected in a liquid flow and viable microrganisms present can be detected as they pass through a flow cell cytometer (figure 2) which count fluorescent elements. The major difference of the 2 technologies is the detection limit, which is about 300 microrganisms per sample for flux cytometry. To increase the sensitivity, it is necessary to add a pre-incubation step. This transforms the method to a ‘near real time’ method and to a semi-quantitative method. Figure 2: flow cell cytometer Bioluminescence: The principle of measurement is the detection of ATP present in viable micro-organisms. The ATP (Adenosine Triphosphate) is a well-documented marker for cell viability. The detection of ATP present into microorganisms is performed using an enzymatic system luciferine/ luciferase with emission of light in presence of ATP. The emitted light is proportional to the quantity of ATP but the quantity of ATP into microorganisms is variable from one micro-organism to another. The emitted light is measuring with a bioluminometer and is expressed in RLU (relative light unit) for bioluminescence in liquid media or in CFU/filtrated sample for bioluminescence in agar media. If the product to analyse has a high level of contamination (about 500 to 1000 micro-organism), the detection is rapid (less than1h). A better sensitivity could be achieved with filtrated products. In this case, after filtration, the membrane is incubated into the media and the result is expressed as presence or absence in the quantity corresponding to filtrated volume. For low level of incubation, it is necessary to increase the number of microorganisms with an incubation step in culture media (liquid or solid agar according the techniques) for 12 to 48 h according the used techniques. After this time, in liquid or solid media, one single cell susceptible to growth will go from 1 to 1000 and will be detected in RLU or as a micro-colony. The value in RLU obtained with the analysed sample is compared to a threshold value. The result is expressed as


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positive in x g or ml if the value in RLU obtained with the analysed sample is more than the threshold value. For the techniques using incubation of the membrane on agar media, a camera CCD detect the micro-colonies and results are expressed as µCFU/sample. This last technique is quantitative but has a small range of linearity and could be only use for filterable products. The major benefits are the capacity of some devices using this technology to process simultaneously a large number of samples, to have an automated way of detection with electronic data and result interpretation and to decrease the duration of the test to 12-24h. Another advantage of this technique using the incubation step in liquid media is that it could be used for non-filterable and filterable products but the inconvenient is that it does not offer quantitative information but a presence/absence determination in the analysed quantity. If more than 1 quantity is analysed, the system may offer a semi-quantitative determination. Steps are different according the techniques, an example of the Celsis technology is following - filtration of samples through 45 mm cellulose ester membrane to concentration micro-organism or 10 g of non filtrated product into 90 ml of buffer; - membrane into a vial containing 10 ml of Letheen broth or 0.1g of sample into 90 ml of Letheen broth; - incubation 18h at 30-32°C with linear mixing: 250 rpm to obtain micro-organic growth - cleavage of aggregate with glass beads and mixing(important for fungi); - 50 µl of the incubated media in tube placed in the bioluminometer; - Addition of reagents: (ADP, extractor agent and Luciferin & Luciferase); - Light Measurement: result in RLU; - Expression of results: Presence or absence in the filtrated volume or in the incubated quantity of product versus a threshold set up to 3 times the negative control.

Impedance: The principle of measurement is that when micro-organisms multiply in appropriate growth media, they produce small ionic metabolites highly charged from big organic nutriments weakly charged leading to the modification of electric properties of the culture media. These changes of impedance measured by the conductance (or the capacitance for some technique) are monitored with electrodes included into the culture vessels and in contact with the culture media. Parameter of detection is the time to obtain a certain impedance variation. This detection time is as shorter as the initial inoculum is higher. For low level contamination as it could observed in pharmaceutical fields, bacteria detection occurred by 24h and is very obvious to observe and yeasts and moulds, detection occurs by 2 days but it is not so clear. For yeasts and moulds, which produce lower quantity of ionic molecules, some technique uses a combination with measurement of production of CO2 in presence of KOH giving an increase of the impedance. The major benefit is the capacity of the technique to process simultaneously a large number of samples and to have an automated way of detection with electronic data and visual aspect of the variation of impedance reflecting the growth curve of the microorganisms and to decrease the duration of the test to 48h.


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These systems do not offer quantitative information but a presence/absence determination in the analysed quantity. If more than 1 quantity is analysed, these system may offer a semi-quantitative determination. A better sensitivity could be achieved with filtrated products. In this case, after filtration, the membrane or half membrane according the used culture vessel is incubated into the media and the result is expressed as presence or absence in the quantity corresponding to filtrated volume. This method could be used for non-filterable and filterable products and is very simple. Only 2 steps are: - sample preparation as classical method: 10 g in 90 ml of phosphate buffer; - 200 µl of this suspension introduced in the detection vessel containing 1 ml of specific media; - incubation at 32.5°c for bacteria and 28°C for yeast and molds and automatic measurement of impedance for 48h. Examples of use of alternative methods - Example 1: Microbiological control of Water Water is the most frequently used starting material in the pharmaceutical industry and the most risky starting material on microbiological point of view to produce a poor quality product since it could be or lead to a high-contaminated media. The microbiological control of water represents an important in process control since the microbiological quality of pharmaceutical water guarantee: - the manufacturing process; - the microbiological quality of the finished product; - the safety of the finished product (Bacterial endotoxins.) Qualification of the production system and monitoring of routine testing should ensure that water of good microbiological quality is continuously being produced. The quality of routine microbiological testing of water could be greatly increased by using rapid alternative methods in microbiology giving result of the contamination level of water from 4 h to 24 h according the chosen method, comparing to 5 days for the classical method on agar plate described in the European Pharmacopoeia (chapter 2.6.12). These methods lead to a real time (4 h) or near real time (24 h) knowledge of the microbiological quality of water. Moreover the earned time is a precious time to take corrective actions. Setting action and alert limits specific to the quality of water and to the method used guarantee to have water always under control. I would like to point out on the level of this alert limit specific to the method used. For Chemscan technology, it is commonly admitted to have a result a little higher than this obtained with classical agar method. It is difficult to be sure that the detected elements by the Chemscan are stressed microorganisms (which do not growth in the conditions of the agar plate control method) or false positive fluorescent elements. For the purpose on IPC of water, the important thing is to monitor the microbial quality of water with the limit obtained with the alternative method used so with the alert and action level determined with this alternative method even if this limit should be higher than the recommended limit in the European Pharmacopoeia monographies of pharmaceutical waters. This kind of problem is one of the reason of the slow development of this new technology. Guidelines for the PAT process could help to change this idea.


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For the three types of water described in the European Pharmacopoeia (Purified water (PW), Water for injection (WFI) and High purified water (HPW), What are the criteria to select an alternative method for microbiological water testing ? - Methods should be able to detect a low level of contamination for WFI or higher level for PW; - Method should be equivalent or better than the compendial method (better because the alternative method could detect stressed micro-organisms non-cultivable on R2A agar in 5 days and because faster to give the result of the microbial count;

- Method should be able to be validate according PDA N° 33 guideline.

Which types of alternative rapid methods can be used to monitor water systems ? The method of choice is the solid-phase laser scanning cytometry (Chemscan technology from Chemunex), which meets all the criteria. From the sampling to the result checked, less than 4 hours are necessary. Two other methods, based on bioluminescence detection could be used. Bioluminescence or ATP detection being not enough sensitive to detect 1 microorganism, an incubation step in culture media of 18 hours prior to detection is necessary. From the sampling to the result checked, 24 hours are necessary. Association with quantitative kinetic method to monitor bacterial endotoxin giving a result in 1 hour with a sensitivity of 0.005 IU of endotoxin/ml, COT and conductivity giving a result in less than 1 hour, are a good way to follow quality of water in real time and is part of a parametric release. Sampling plan for analysis with the alternative method could be the same sampling plan than for Pharmacopeia methods. But if there are too many samples, only critical points could be chosen to be analysed by the alternative method. Critical points could be defined as sampling points where the result could lead to the reject of the manufactured batch or critical by the conception of the water installation. These critical points could be chosen during the qualification process of the method, which can be performed by classical or/and alternative methods. For water, sample preparation consists of sample filtration and detection. - Filtration of WFI: 200 ml for Chemscan, 200 ml and 10 ml for other techniques. - Filtration of PW or HPW: 10 and 100 ml for all techniques. - Detection: variable according the techniques: Membrane is labelled for the Chemscan and the membrane is scanned. Membrane is introduced into culture broth and incubated (18 h, 37°C) for bioluminescence in liquid media and a portion of liquid media or all media is tested for the presence of ATP Membrane is introduced into culture broth and incubated (48 h, 35°C for bacteria and 20°C for fungi) for impedance. Change in impedance is recording along the time until 48 h Membrane is set on agar plate and incubated for 12 h for bioluminescence on membrane (Microstar). Bioluminescence reagents are vaporised on the membrane. microcolonies become fluorescent and will be detect by a CCD camera. How express are the results ? - For Chemscan the result is a direct count of microorganisms given within 4 hours expressed per 100 ml for WFI and expressed per 100 or 10 ml for PW. - For bioluminescence in liquid media, the result is a semi-quantitative evaluation expressed as less than 1 microorganism per 200ml or less than 1 per 10 ml. (see table 1) within 24h. - For bioluminescence in solid media, the result is a direct count of CFU expressed


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per 100 ml (WFI), per 10 or 100 ml (PW). Impedance could be used but result available in 48h with expression of result as presence or absence per 10 or 200 ml (WFI), per 10 or 100 ml (PW). Fitrated Volume 1 (Q1 ml)

Filtrated volume 2 (Q2 ml)

Result Q1

Result Q2

Interpretation Conclusion

10 200 + + > 10 µorg./100 ml > action level 10 200 - + ≥ 1 µorg./200 ml and

< 10 µorg./100 ml Alert level

10 200 - - < 1 µorg./200 ml Under control Table 1: Interpretation of bioluminescence for WFI testing Example 2: Bioburden before sterilisation First of all, it is necessary to analyse the manufacturing process to identify where are the critical steps. Sampling of bioburden should be done at these steps. The quantity to filtrate should be chosen to have the expected level of detection.The alternative methods which could be used are theoretically the same as for water testing but our experience is better with bioluminescence since false positive has been observed with some product tested with the Chemscan technology. Example 3: Air sampling for A and B sterile classes One cubic meter of air is sampling on membrane (Sartorius) or on a soluble synthetic polymer (Biopolym’air/Chemunex- evaluation on going) by impaction. The biopolymer is dissolved and the obtained solution is filtrated through membrane. The membranes from biopolymer are analysed by Chemscan or are incubated for 18h for bioluminescence and analysed with the bioluminometer. For Chemscan the result is a direct count of microorganisms given within 4 hours expressed per m3. For bioluminescence in liquid media, the result is a semi-quantitative evaluation expressed as less than 1 microorganism per m3 within 24h in case of negative result. For bioluminescence in solid media, the result is a direct count of CFU expressed per m3 within 24 h. Global example 1: Microbiological controls of a non sterile product as capsules - Dry raw materials: Excipients, DS. The microbiological risk is evaluated by performing Water activity (Wa); if Wa ≥ 0.6: the microbial monitoring of the dry raw product is done by bioluminescence. If Wa < 0.6: at least 1 batch is analysed to evaluate the initial contamination and if no contaminant, nothing or skip testing for the following batch; - Water Purified water is tested on the used manufacturing location by Chemscan or bioluminescence. - Environment: Air sampling by impaction or filtration and swabs for surface are performed during manufacture according to the sampling point considered as critical. Samples are analysed by bioluminescence or Chemscan. - Monitoring of manufacturing people could be done after sampling by swabs or biopolymer and samples are analysed by bioluminescence or Chemscan. - End product control:


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If Wa of the finished product is ≥ 0.6, this product is analysed by bioluminescence, if Wa < 0.6: nothing is performed or skip testing. Global example 2: Microbiological controls of a sterile product as parenteral - Dry raw materials: Excipients, DS: Same approach than in section 2.4.1. - Primary packaging: Process validation of Bacterial Endotoxin test (LAL), contamination by Bioluminescence or Chemscan. - Water WFI water is tested on the used manufacturing location by Chemscan or bioluminescence on the used manufacturing locations: - Environment: Same approach than in section 2.4.3. - Bioburden of critical manufacturing steps

These steps should be determined. Bioburden before the sterilizing filtration could be critical especially for biotechnology products: the analysis could be performed by Chemscan or Bioluminescence. - End product control If parametric release has been registered, Sterility test is not performed (Terminally sterilized products). In the other case, sterility test is mandatory and should be performed for the other sterilised products. There are no method available now in the pharmaceutical fields to perform rapid sterility test (risk of false positive). Knowing the bad significance of a satisfying sterility testing, a development of parametric release for a wide range of product will be better than to try to adapt alternative methods to sterility testing. Conclusions: The microbial alternative methods are useful and in many aspects better than the Ph.Eur. methods as far as they have been validated for the targeted use. They permit to routinely have manufacturing process under control by monitoring in ‘real time’ to ‘near real time’, the microbiological quality of raw materials and water, the environmental manufacturing facilities and Bioburden of the manufactured product at determined critical steps of manufacturing. They also permit in qualification process to help to set up the good maintenance. International guidelines on PAT will give a regulatory framework for these innovative techniques and will encourage their use. International guidelines on validation of these modern methods in Microbiology as PDA N°33 or USP or chapter in preparation in the Ph.Eur. facilitating the use of these alternative methods will encourage to perform them in Pharmaceutical fields. Thanks to the team of the microbiology laboratory of the Aventis Paris Research Centre for their contribution to the development and validation of these alternative methods for monitoring of raw material including water, environment of pharmaceutical manufacturing and bioburden before sterilization.

DISCUSSION


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Dr T. Bourquin: You presented different methods, which for some of them, these methods are not new, but they have been developed 20 / 25 years ago. For you, what do you think about why and how to explain the main reason why these methods are not so developed in pharmaceutical / chemical industry? Dr S. Guyomard-Devanlay: For me the main reason is regulation. In the pharmaceutical field people use exactly the pharmacopoeia methods, so if they have to validate, it’s a big job to validate these kinds of methods and it’s more useful to apply classical European Pharmacopoeia methods and the same thing for regulatory point of view. It’s easier to present in a dossier pharmacopoeia methods even if we know that these methods are not so good to monitor the quality of products. Dr T. Bourquin: I think your point will be a preamble for the discussion for the round table this afternoon because finally these methods exist and are not used, or poorly used. Dr S. Guyomard-Devanlay: In fact, they are used but not on the dossiers. There are not many dossiers registered with these kinds of methods. We register products for bio-burden before sterilisation with these methods. So we register the two methods, the classical method and the alternative methods in the dossier for API. Dr T. Bourquin: We did that as well for finished products. It was done in Spain but it took 2 years to register. Dr S. Guyomard-Devanlay: Yes, it’s longer, but because we are here today I think this will change. Dr S. Lonardi: I’ve been involved in the registration of new rapid micro in GlaxoSmithKline so just to say that FDA accepted the registration of my remittances in 20 days. Dr S. Guyomard-Devanlay: This is good and I really think that the methods, the most simple to register and validate at this time are bioluminescence techniques useful to test contamination of products. I know that there is also some registration with Chemscan, but we could have some big interference with some kind of product with Cheminex technology. Dr R. Davidson: Thank you very much for your presentation, I found it most interesting. However, you focused mainly on quantitative aspects rather than the qualitative aspects. Perhaps you would be interested in knowing that we are currently using FTIR for qualitative identification of bacteria. There is also the GC Sherlock system, which is a gas chromatography system for identification of bacterial strains and typing of bacterial strains by the fatty acid profile of the membranes. So could you please comment on the new techniques for the qualitative aspects, because many of these tests, we should comply with compendia requirements that have limits for specific micro-organisms, so it’s not just the quantitative aspect. Dr S. Guyomard-Devanlay: It was difficult to present all methods and I think that for PAT, quantitative or semi-quantitative methods are more important for this philosophy of control. But about modern methods in microbiology, we are also using in the laboratory the Sherlock system to identify micro organisms. These methods and others like DNA and RNA technology will be presented in the texts in the European Pharmacopoeia and examples of validation to register with these kinds of methods will be presented in this chapter. I can’t remember which method we have for identification, but I know that we have the Sherlock system, DNA / RNA, Fourrier infra rouge


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and probably other ones. These will be described in the European chapter and if I remember well it is also described in the PDA chapter 33. So you have to follow the next developments and you will have a lot of information about the use of these methods. I can say for the new Pharmacopoeia of the future. Dr G. Fischer: I have a last question out of curiosity. Real time means different things to different people, so I understand that in microbiology you have different time frames. Is that 4 hours for real time test methods? Is that the sort of borderline? Dr S. Guyomard-Devanlay: In fact it’s less than 4 hours for the Chemscan technology but because everything is manual, there is no automation, we have to perform many samples at the same time. For Chemscan 4 hours are a maximum to have a validated result. I am waiting ships technology and Fourrier transformation infrared, which can give results in less than 4 hours. But this is not completely validated, especially for water ships technology will give identification and count in the same time, so it will be a big progress, but not this year. Probably in two years. Mr G. Ritchie: What you presented in one presentation I saw spread out throughout a whole day. You did a good job. The existence of the European Chapter, the proposed existence of USP or modification of the 12 23 and the existence of the PDA 33 document may pose some problems in that you have different existence of these rapid micro methods in different articles. How do you see reconciling these three? What would you like to see done? Dr S. Guyomard-Devanlay: The first text we had available was the PDA 33 guideline, which was the basis for our work. After there was the USP chapter, but it’s not so different, and when we write the Ph.Eur chapter, we try to put validation as an example, not something to follow exactly. We give the philosophy to follow and after we give examples because it’s simpler to apply statistical tests if you do know which test to apply. It just gives examples we can follow because it’s useful to follow, but it’s not mandatory to follow exactly validation we propose in the Ph.Eur. So for me there is, in my opinion, already harmonisation between these three texts.


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89



Software validation

Dr Ciro Cottini, GlaxoSmithKline (I) Abstract: PAT aims to ensure a better understanding and control of pharmaceutical processes, which could strongly support the primary goals of software validation, namely to provide confidence that the code is suitable for purpose and the data collected reliable and secure. A risk-based approach is considered, together with any improvements to current validation methods that may be required to support the PAT approach and increase the level of confidence. The use of automated tools is proposed, as is software certification as a means of obtaining mathematical certainty. The role of academies as partners in the development of cutting-edge solutions is considered, together with a practical example concerning an automatic tool for the regression analysis of a Programmable Logic Control (PLC). Dr C. Cottini’s slides are available on page 2 of the PAT-SessionII.b2.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 Facts

Software (SW) validation plays an important role in all our activities. It is increasingly

present in the pharmaceutical field. While a new technology could have been supplied with very simple software in recent decades or even with no software at all (just firmware, for example, where a simple test machine is concerned), it is almost impossible to buy new technology or a new instrument today that is not provided with software for controlling its functions or helping users process, manage and store the data obtained. An immense variety of software is available, ranging from truly complex applications – typically business or management systems (Information Systems), or software designed to control entire processes (Manufacturing Execution Systems) – to simpler applications such as PLCs or the spreadsheet SW used for calculations. The primary goal of all SW validation is to provide confidence that the code developed is suitable for purpose and that the data collected is reliable and secure. PAT is a relatively new but growing approach launched by FDA to ensure better understanding and control of pharmaceutical processes through, for example, real-time measurements and multivariate statistical analysis. This mathematical support could become very complex, depending on the complexity of the processes themselves, and data manipulation with reliable outputs is a vital need. Very robust software is consequently required.

Validation

It is beyond the scope of these brief proceedings on software validation to cover the well-known V system or other detailed technical aspects that go beyond the basic requirements and main steps necessary for the development of an effective, sound system.

Once the project group has been set up the validation team needs to: - select the most suitable system from those available on the market on the basis of user requirements


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- verify the supplier’s quality system by carrying out a thorough audit; this should result in a report analysing any gap between the customer’s needs and the vendor’s capabilities

- work out an action plan to improve the supplier's performance, bearing in mind the need to build an effective partnership to cater for potential future needs

- be ready, if necessary, to manage any possible gaps that the supplier cannot fill.

In order to achieve the required quality level beyond the scope of the immediate operation, the validation team also needs the know-how to ensure:

- the transfer of a technology system suited to the users

- the practicality of the validation procedure, as the approach could be extremely variable and the most appropriate application is really a matter of experience

- the goal of optimising the introduction and day-to-day use of the system.

Moreover, the validation team has to apply a risk-based approach throughout the validation exercise, focusing on the more critical aspects, for example the transmission protocol between an instrument and the SW and paying less attention to minor matters, for example the display options. It is quite natural for the PAT approach to concentrate on the present validation methods. Are they sufficient to fully support the PAT approach, or are improvements needed to increase the level of confidence? As we have noted the more complex the model driving a technical process, the more critical the reliability of the data managed. We believe that these three main points are crucial to meet this challenge and achieve the targets set:

1. Partnership with academy

2. Introduction of automatic/automated tools

3. Moving from SW validation to SW certification. Partnership with Academy Since cutting-edge technology is needed for modern pharmaceutical processes, it is essential to consider and initiate close collaboration with academies. Collaboration does not just mean developing a particular technological solution to obtain an immediate benefit (off-the-shelf solution). Universities need to be regarded as partners in the widest sense. They are in a position to feed the industrial world with new ideas and new methodologies and scientific approaches, while industry, with its experience and know-how, can refer practical problems and as yet unresolved issues to the academic world. A virtuous circle resulting in "continuous innovation" could be established in this way. Automated Tools and SW certification A number of the automated tools that have been on the market for commercial purposes for some years can be adopted to achieve better validation process management. For example, modelling language can be used during the design phase to avoid ambiguities in the software. Likewise, automatic tools can be used to monitor any changes made to the system more


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effectively, just as automatic testing and cross-referencing tools can be used to save time and improve performance. It is, however, important to understand that though these aids may help management during the SW validation exercise, they do not improve the level of confidence in the SW itself. An automatic test tool can carry out tests more rapidly than an operator, but if the test is not created properly the tool will simply perform the wrong test. Existing SW validation techniques offer a good level of confidence, but they have some significant limitations: Test cases are based upon experience. There is no standard way of creating a test. A test can sometimes be inappropriate, often vague and in some instances even impossible to perform. The best solution for certain critical functions that cannot be tested appropriately, is to obtain indirect information by testing other functions of higher scope. Moreover, finding dead code can be extremely hard work even if we own the source code. Whatever the case, any source code review requires significant effort if a good quality result is to be achieved. Finally, impact analysis is very complex after a change, even with simple SW. We could define these techniques as probabilistic and heuristic: probabilistic because they cannot guarantee SW robustness, heuristic because they are very much based on experience. The next goal is to move from validation to certification, progressing from a probabilistic process to a deterministic, "science-based" process. Validation provides a good level of confidence, while certification provides mathematical certainty. With certification, it will be possible to create test cases with precise mathematical models or perform automatic dead code detection. Most important of all, it will be possible to carry out an exact impact analysis after every change. One might wonder why we do not yet use this technique. There are a number of reasons: - Total certification of a function is not always achievable, sometimes only partial certification can be achieved - Efforts to develop mathematical models are not as yet very far advanced - Although this approach was conceived three decades ago, the theory is still being developed and some of the mathematical steps still have to be fully proven -The pharmaceutical industry has not been involved (or interested) until now, unlike the aerospace and aeronautical industries for example. Practical Example Now it seems to be the right time to adopt this approach and investigate this technique seriously. At GSK we have developed a case study for local academy: “developing an automatic validation tool for the regression analysis of a PLC”. The impact analysis following a change is one of the most onerous activities in the life cycle of a system. Impact analysis means understanding the possible influence of a modification on the entire source code, and consequently which tests need to be performed to restore the same level of confidence achieved before the modification. Until now, the only way of doing this was to perform a manual check, which requires considerable time and effort, the test analysis after a modification can sometimes cost more than the original tests during development. PLCs have been chosen because of their widespread use in practically every machine or plant. PLCs are normally equipped with fairly simple SW, and the language used in the code is


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simpler than other languages used in SW. A road map has been designed to put the automatic tool in place. Firstly, we have to create an abstract model for the SW and for the test. Afterwards, an interpreter will be developed to automatically create the model for the actual PLC SW and tests. The following step will be the development of a prototype to carry out the impact analysis. Eventually we will fine-tune the prototype and create an interface to ensure ease of use. We have established a strong partnership for this pioneering work with the “Abstract Interpretation” group of University of Verona over the past two years. Conclusions The current SW validation methodologies are still valid but the proposed SW certification offers a more good science approach; obtained data will result more reliable and secure and at a lower validation cost. PAT is introducing timely measurement systems that will require a wider use of SW, great benefits should be obtained adopting SW certification. We believe that a dialogue between Academy, Regulatory bodies, SW Vendors and Pharmaceutical Industry is not only desirable but also essential.

DISCUSSION

Dr I. Unlusayin:Vibrational analysis techniques are less informative than compared to mid IR or other techniques. More mathematics, statistical matters have to be used, such as PCA, PLS, MLH. You can use more capital letters if you want. I mean chemometrics. Since limited availability has invalidated so fair packages, especially for chemical imaging techniques. We have already seen negative results yesterday on some slides. Remembering to keep-it-simple principle, how do we convince them if we have an audit by the regulatory agencies? Without clearly defined procedures, basic requirements or acceptance criteria? Like defining other analytical methods? Dr C. Cottini: I think we have to change our point of view. We have to begin to collaborate with the regulatory bodies to put this new approach in place because the real point is how confident we are in our software. If we need a higher level of confidence, we need to move towards these tools and I hope the regulatory bodies will follow us. Dr A. Hussain: I think in terms of software validation the concept pharmaceutical software is not as complicated as some of the software we have been looking at from our department of defence to the aviation industry and so forth. I think there are a lot more examples out there on how you can focus on the reliability of software rather than validation of the software, I think there are a lot of lessons to be learnt from the other sectors. Mr F. Despagne: Don’t you have a concern that implementation of this certification approach will just add a huge multiplying factor to the cost of the projects? It would certainly require a significant amount of money on the pharmaceutical companies side and also on the vendor’s side. I think the model is nice but I’m just trying to see how you can implement that realistically within the next years without just bankrupting the instrument vendors?


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Dr C. Cottini: We have to find a way. The main objective of mentioned tools for SW certification is to reduce actual complexity and costs of SW validation. This result can be achieved only with a cooperation between industry, academies, regulatory bodies and vendors.


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Qualification of PAT instruments in contrast to conventional analytical systems

Dr Steve Hammond, Pfizer (UK)

Abstract: PAT instruments by their very nature will be imbedded into a process. Probes inserted into vacuum dryers or reactors. Remote reading heads mounted on moving blenders. These engineering considerations render the conventional way of qualifying the performance of the instrument impractical. Coupled to this is the nature of the measurements, which will be in real time, with the results fed straight to process control systems, immediately affecting the outcome of the plant. The risk to the product from these systems also calls for a change in the approach to instrument control and qualification. The fundamental reason for qualification of an instrument is not to satisfy a compliance need, a tick the box test. The reason for qualification is to protect the measurement being undertaken from a “change” in the measurement system, due to malfunction or simple ageing. In that regard it is useful to assess how each qualification test we use mitigates the risk posed by the instrument to the data being collected by the measurement system. When the tests performed for qualification, of NIR instruments for example, are assessed for risk mitigation ability, some deficiencies in the recommended pharmacopoeial testing becomes obvious. The lack of relevance of NIST traceable standards to the real life measurement is the most obvious. It is evident that the USP tests are designed around convenience to show compliance, and not really to test the ability of an instrument to collect reliable data. This paper will discuss ways in which the risk the instrument poses to reliable data collection could be mitigated for on-line NIR instruments, as an example of a risk based approach to instrument qualification. Dr S. Hammond’s slides are available on page 8 of the PAT-SessionII.b2.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 PAT instruments by their very nature will be imbedded into a process. Probes inserted into vacuum dryers or reactors. Remote reading heads mounted on moving blenders. These engineering considerations render the conventional way of qualifying the performance of the instrument impractical. Coupled to this is the nature of the measurements, which will be in real time, with the results fed straight to process control systems, immediately affecting the outcome of the plant. The risk to the product from these systems also calls for a change in the approach to instrument control and qualification. The fundamental reason for qualification of an instrument is not to satisfy a compliance need, a tick the box test. The reason for qualification is to protect the measurement being undertaken from a “change” in the measurement system, due to malfunction or simple ageing. In that regard it is useful to assess how each qualification test we use mitigates the risk posed by the instrument to the data being collected by the measurement system.


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When the tests performed for qualification, of NIR instruments for example, are assessed for risk mitigation ability, some deficiencies in the recommended pharmacopoeial testing become apparent. The lack of relevance of NIST traceable standards to the real life measurement is the most obvious. It is also evident that the USP or EP tests are designed around convenience to show compliance, and not really to test the ability of an instrument to collect reliable data. Examples of this gap are seen in figures 1 and 2.

Figure 1 Spectra of NIST reference std and water vapour Figure 1 shows the spectrum of the NIST traceable standard with very broad peaks, that do not adequately measure the wavelength accuracy of an instrument, compared to the simple use of the natural water vapour that exists in the instrument, that can be used as a standard providing high resolution peak position assessment, and a true assessment of instrument performance.

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Figure 2 shows the typical range of absorbance values that we would encounter when testing blends by NIR. The requirement is for the instrument to have a linear response across the absorbance scale we are using. That is a micro absorbance scale, which we do not qualify. Instead we test the macro liner capability of the instrument over a complete absorbance unit using traceable standards. There is no match to what is sensible in terms of mitigating the risk of instrument malfunction. We test what we can using the “traceable” standards available. Figure 2 shows the used linear range for a blend assay and the instrument qualified range. There is no sensible correlation between the test use and compliance testing. In future we need to develop qualification testing of PAT instruments that is built in and automatic. It is possible to have transmission standards built into the instrument optics. Foss began this with polystyrene rare earth paddles, it has been taken a step further by Axsun, with the inclusion of acetylene gas cells. See figure 3.

Figure 3 shows the proposed optical system for continuous performance verification in the Axsun spectrometers. For routine performance checks the S\N ratio is one of the most important calculations we can make. This becomes particularly relevant if we use the sample we want to measure as the reference material. This is a simple measurement to perform and can tell us a lot about the relative performance of an installed on-line instrument. Particularly with the rapid scanning diode array instruments available today. Conclusion. The pharmacopoeias need to introduce flexibility and science based testing into the procedures for qualifying analytical instruments that are to be used in the process environment. The pharmacopoeias need to think in terms of recommending strategies for testing the performance of on-line instruments. Suggest ‘what’ might be measured, but must at all costs avoid recommending ‘how.’ There must also be a recognition that the idea of a traceable standard is just not realistic, in the light of the variety of instruments and sample interfaces that exist now, and

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those that are rapidly developing. There is a need to be able to use what is scientifically justifiable, and fit for purpose.

DISCUSSION Prof. T. Moffat: I’d like to just discuss the last point you had about traceable standards. One of the great things about traceable standards is that they are the same across the whole of the world. I don’t see any reason at all why you shouldn’t start off with a traceable standard whether it comes from NIST or somewhere else and use your own secondary standard to match against that and from that moment forward your practical samples become traceable back to NIST. All you need to do is to start off with a traceable standard and then match everything to your own secondary standards. Is that not a possibility? Dr S. Hammond: It’s a nice idea but the problem is that the traceable standards out there don’t cover the wavelength range you need, you have peaks missing where you need them or the worse case is the resolution you can achieve with them just isn’t good enough. If NIST decided to validate something like acetline as a traceable standard that would be a good thing. If NIST decide to take it upon themselves to very quickly keep up to date with what are the standards that industry use, then again that’s not a problem. The problem I have is that they develop a standard, which has poor resolution and doesn’t fit the purpose and even if you did decide to use it it’s almost impossible to get. If NIST produce standards that are applicable then that’s fine but if NIST are not capable or can’t move fast enough to do that, which is their experience, then they become a real drag on what we’re trying to do. Mrs I. Maes: I can indeed agree with what you propose and I encourage this approach of using real samples as the kind of reference. Also perhaps in other industries this kind of discussion has already taken place 10 – 15 years ago. Perhaps Tom Fearn can confirm that and in the food industry there’s a discussion of using real samples compared to reference samples. It has already been discussed so we don’t have to re-invent the wheel every time and just look to these kinds of conclusions, which have been made in other industries earlier. Another remark I would like to make is by using these internal gas cells as standards, we are checking the performance of the instrument but normally the configuration of the instrument consists of spectrometer often also fibre and a probe. How do we test the performance of that part of also the instrument? That means measurement of real samples is really something we have to do, because then you are also checking the fibres and the aging of the fibres and the probe. Dr S. Hammond: That’s exactly the point. I think you’d use internal gas cells to check the stability of the instrument, but that’s only 50% of what you want to do. Using real samples and measuring the signal to noise and wavelength repeatability using the samples is exactly that. You test the system rather than the spectrometer. Mr G. Ritchie: I’m happy to say that your pleas have not fallen on deaf ears since the F-PAT meeting. I went back, discussed earnestly some of the issues that you raise and since the last meeting of the PAT project team is at the top of the list and the number one priority is to address the issues of the chapter of 11 –18. That being said there’s two things, which stand out in my mind. One of them is along the lines of what Prof.. Moffat was suggesting. There are current applications that are robust and are used day in and day out in the laboratories with the current configuration of a lab instrument. They have to continually be supported and I think one of the issues I am aware of is the lack of the standard, especially the wavelength standard needs to be addressed to support current


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laboratory use. What needs to be straightened out in the chapter is the anticipated future use and that is going to be addressed. There’s going to be a differentiation between what you anticipate would be used in a process versus what is currently being used and what needs to be supported. I think I suggested to you that – what do I do, throw the baby out with the bath water? I don’t think we want to do that. So that is being addressed. For other applications I think there has to be a concerted effort. You can look and see a concerted effort to do harmonisation in ICH with other aspects of this PAT and it’s a little disconcerting when you don’t have an attempt to harmonise in your own back yard. That needs to be addressed. Participation within a respective organisations and agencies with the respective industry people, there has to be active participation. Otherwise what you’re going to perceive to happen is people are going to want to move forward anyway and in my role I have to act as a brake or a clutch. That’s the situation so there has to be active participation and an acknowledgment that if you are going to harmonise and do these things around the world you probably want to stop and look at what we are doing in our own backyard also. Dr A. Hussain: In many aspects through our PAT committee discussion, we discuss some of these aspects and the draft PAT guidance as it came out. We see the need for flexibility and we need a validation for their intended use, so the guidance went in that direction. Traceable reference standards, reference standards are important for many different aspects. There are different ways of handling that and again the guidance kept it open for that, to use the sample itself as that. My major concern is, if you approach this as a lab based method you are actually posing more risk and that’s the thing we want to avoid. We would like to work with the companies to resolve that. Dr S. Folestad: I fully agree with your comments here and I think it’s important that we really recognise that the current analysis that we use in laboratories are designed for that purpose. What we’re now talking about are sensors that should be designed for it and fit for purpose for process vessels, which is something different and to be a bit critical, the current transformation is like boxed research speculators that we started off with, but we are approaching a faze where we see the emergence of more design and dedicated process sensors based on these techniques. However they require different ways of checking their performance and being fit for purpose. I think it’s important that we really recognise that even in ICHQ6A there is actually a very good phrase, which I often like to quote which says that technology is continually being developed. Such technology should be used when it is considered to offer additional assurance of quality. I think that is the kind of philosophy we should have in focus here and often it’s science that designs the basis that we need to have developed first and standardisation and harmonisation come afterwards. Dr S. L. Ali: I do not know if you refer also to the present document on NIR methods from the Ph.Eur., which is available for the wavelength verification. Of course there were for the FT-NIR and NIR instruments the water vapour line, which is used and not only arrays but also the methylene chloride, which has three peaks throughout the range. As you mention later you have in some instruments the built-in acetylene so this method line will arrive beside this real earth oxide standards that have been taken into account. Dr S. Hammond: I think a lot of the present laboratory instruments have very good internal stabilisation systems and there is nothing wrong with that. I think that’s the way to go. All analysis should be automatic in terms of their qualification stabilisation. There is nothing wrong with that.


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Relationship of in-process specifications to expectations for the final product –

Moving from the sample to the batch

Dr Arne Torstensson, AstraZeneca (S) Abstract: Process Analytical Technology (PAT) offers new ways of controlling and monitoring processes as well as in –process material characteristics. This will have a great impact on the Pharmaceutical Industry’s future way of operating. The traditional way of setting specifications and limits during manufacturing will be challenged when PAT is introduced and fully exploited. The dialogue between Authorities and Industry is therefore of utmost importance to establish a common regulatory platform for PAT. Specifically, it must allow rapid and flexible introduction of new technology. The presentation will discuss the implication of PAT, material and process performance measures, on specifications and its relation to Product Quality. Dr A. Torstensson’s slides are available on page 17 of the PAT-SessionII.b2.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 Introduction

Process Analytical Technology (PAT) offers new ways of controlling and monitoring processes as well as in-process material characteristics. This will have a great impact on the Pharmaceutical Industry’s future way of operating. The traditional way of setting specifications and limits during manufacturing will be challenged when PAT is introduced and fully exploited. The dialogue between Authorities and Industry is therefore of utmost importance to establish a common regulatory platform for PAT. Specifically, it must allow rapid and flexible introduction of new technology. The implication of PAT, material and process performance measures, on specifications and its relation to Product Quality will be a challenge for all parties involved, Pharmaceutical Industry, Regulatory bodies and Pharmacopeias. PAT based Control A typical manufacturing method for a conventional tablet formulation is described in Figure 1. In the figure it is indicated a number of potential places where PAT based controls can be introduced to further assure that the in put material and manufacturing process are under control and that the resulting final product will be of the intended quality. However only value adding controls should be introduced where it has been established that a critical process step exists from a Quality Risk Assessment for a particular product and process. The choice of measuring technique should be based on scientific principles and will be in most cases product specific.


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Figure 1. Example of a typical manufacturing process for a tablet formulation Relationship of PAT based information to the final product quality The material/process information collected during the manufacturing process is most often related to the final specification clauses as a combination of information elements and not as a single direct correlation as illustrated in Figure 2. For example the resulting uniformity of dosage units is often a combination of in put material characteristics (e.g. particle size distribution of drug substance) and how it is processed (e.g. granulation and tabletting). To predict the uniformity of dosage units for a batch only the relevant in process information are used.

Figure 2. Relation of material/process information elements with finished product specification. Specifications and Limits The introduction of PAT will challenge the way specifications and limits are set. It must be up to the responsible manufacturer to decide a proper PAT program and its related limits to best control the manufacturing of a specific product. Those limits to be used must be based on sound statistical principles to accomplish the intended control and also be related to the PAT tool capability. It is also most likely that introduction of any standards in this field will be of little help

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because the PAT program and its related limits must be product specific. The product quality target however will remain in the specification of the finished product. Conclusion Product specifications should be based on patient safety and efficacy requirements and should also support continous process and product quality improvement. Also any material and process performance measures should relate to Product Quality targets as defined in the finished product specification. Finally the regulatory enviroment must facilitate industry to the use of innovative and rapidly changing technologies that adds value to the overall Quality Assurance.

DISCUSSION

Mrs C. L. Heinze: In the beginning of your presentation you stated that the real time release will come sooner than later. How far do you think we are from real time release and what will it take to get there? Dr A. Torstensson: I think there are interactions already with our regulatory colleagues and of course we shouldn’t run too fast. I think as we have heard there is an open mind, an acceptance for the concept. But finding the proper way, the right documentation etc.. and to fit into the current system – it will take some time. I don’t see that there are any barriers any more. I think we have to be careful about ourselves, that we don’t ourselves build barriers. Dr A. Hussain: In terms of harmonisation and innovation, when you have a standard, when you have harmonised standards, how can you be innovative? That was the question in my mind. Talking to Jean- Louis Robert, the EUPAT team and FDA PAT team, the way I think we have approached that is not to harmonise the guidance, but more in terms of how you would approach that. If you really look at the PAT Guidance, it is a very high level framework guidance. It doesn’t tell how to do anything except gives you a signal that we are ready to work with you and here is a flexible regulatory process. The way to support harmonisation is a direct communication between the EU PAT team and the sponsors and the FDA PAT team and their sponsors. That probably is the most efficient way to support innovation and harmonisation already because it’s more science based. It is more case by case, rather than writing a standard or writing a general chapter. Dr S. Wolfgang: I just want to make a couple of comments: One on behalf of the quality people from my organisation who are not here. How are going to deal with the possibility of having out of spec results and the need perform investigations of 00S results? This in the realm of real time release is one issue that I see and another is in terms of the sampling and testing and verification of homogeneity of your batch or lot? I see that there’s a lot of technology there, but some of the practical concerns like this need to be addressed. Dr A. Torstensson: If I may comment on the out of spec situation, I think that first of all you should have specifications, which are needed, don’t write specifications on everything because then you run into problems. If you have out of spec specifications for critical attributes, you have to deal with that as you deal with that today. I don’t think that’s a different situation.


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With respect to sample sizes, the sample sizes should be science based and I think our limits should be based on statistical models and not rigid specification limits. Then you have to decide the actions to take and before hand if you get any results outside and make a proper investigation. Mr G. Ritchie: On one of your slides I just wanted to point out, there seems to be, and you talk about nomenclature, an artificial attempt, maybe purposeful I don’t know, to separate out limits in terms of tolerance limits, acceptance limits and validation range from the other aspects of specification. In my understanding specification is a composite of the test, the method and the acceptance limits. I don’t know if there’s an intent to change that connotation from an end product specification to tease out the parts of specification when we go to in-process. It seems to me that you still have the same three parts, their emphasis is different, but they still exist together. Can you comment on this? Dr A. Torstensson: What I would like to show with that picture is that we have a non-stringent use of this. I agree that the basis for these limits is what you are saying. But I think we need a more stringent use of these words, that we could have a more clear discussion with each other.


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Design and implementation of quality systems based on PAT.

In-depth process understanding to improve quality

Dr Staffan Folestad, AstraZeneca (S)

DISCUSSION

Abstract: Process Analytical Technology (PAT) is a strategic area of new technology that will have a major impact on the Pharmaceutical Industry’s future way of operating and that is likely to lead to major changes in regulation of Drug Product Quality. PAT enables quality of materials and processes to be assessed both in real-time and in more depth. The enhanced process understanding provides new opportunities for advanced process control and prediction of product quality. In all, this will reduce long production cycles, improve quality consistency and improve manufacturing efficiency. However, it will also enable smarter development, and predictive scale-up and tech transfer of new drug products. Indeed, manufacturing inefficiencies are often locked in before phase III development which is why the major benefits from PAT require PAT to be integral to new product development.

In this context, the presentation will discuss design and implementation of Quality systems based on PAT. It will emphasize that PAT is not a goal itself or, a matter of only interfacing analyzers to manufacturing processes. Rather, it is a holistic approach towards in-depth process understanding from Pharmaceutical Development and onward. As such, the new paradigm shifts the emphasis from current Quality Control and rigid GMP compliance to the assurance that the right product will be made through better control of drug manufacture throughout its lifecycle. Because of slightly different perceptions/interpretations of PAT in the current discussions there is, however, some confusion on the impact of PAT for future Quality systems. The aim of this presentation is therefore to clarify key scientific elements and outline how the will provide the basis for progress in Drug Quality. Topics needed to be further discussed will be addressed. Dr S. Folestad’s slides are available on page 24 of the PAT-SessionII.b2.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2

DISCUSSION Dr G. Fischer: You mention several time a supporting structure, which is important, would you go so far as to give recommendations, what would be the key elements in terms of structure, organisational settings etc that have to be there for a company that wants to be successful with PAT implementation. Dr S. Folestad: Generally speaking it takes some 3 – 5 years to build a support structure, not because of recruiting or getting the right competences and skills in place, but it’s very much about changing mind sets, changing conscience, changing ways of working and it requires the holistic


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approach. Sometimes internally I provoke the people and I ask a huge number of analytical chemists who are extremely skilled how many of you have developed a method for tablet assay? Everyone has. They are extremely skilled. How many of you have seen a compressor in the manufacturing area. I think a handful maybe. That captures what it’s all about. To take the holistic approach, that requires a different way of interacting and you can learn from other industries here. They have already experienced these kind of common aspects. Dr T. Bourquin: I am interested especially in high quality systems and at the beginning of your presentation you raised an important question concerning the transformation of quality systems for the future. Do you think that the development of Q8 and Q9 will be sufficient? Will we be obliged to re-write current GMPS? Will it be an occasion to move towards ISO? Dr S. Folestad: A primary answer would be that Q8 and Q9 are opportunities. That is the basis. We should recognise the new harmonisation there as an opportunity. I think the challenge there is that moving into more flexible regulation and having a quality system that transforms from reactive to preventive also requires a kind of living document and I think that’s a challenge. We are quite biased by standardised templates, documents, how we interact between industry and the regulatories – a key aspect here. We really need to think about how we can best communicate continuous improvement. There are a number of challenges yes, but we should recognise them, the current situation as an opportunity. Mr D. Shiels: I’ve listened to a lot of speeches and presentations these last couple of days. Nobody has really talked about the cost implementation of PAT. Most pharmaceutical companies live on the continuous release of blockbuster drugs on a consistent basis to the market. You have touched on product life cycles, which means the orderly management of a series of blockbusters. It was yesterday a comment from the FDA that if more people use PAT they would have more resources available to approve more drugs, so more blockbusters could be released. The question is, how can what you have just said there, be related to the money man who must finally decide to invest in PAT and the selling point to them must be a quicker and more continuous release of blockbuster drugs? Dr S. Folestad: I think it’s important to consider that the release of the product based on PAT is the ultimate scenario, it’s not the basic scenario, the basic scenario is to have robust processes and generate consistent quality and that is in reality to be able to fully rely on your supply chain, which means that to make that rational and cost efficient. For example, this industry is quite good in generating data, but I would like to say that less than 10 % of the data that is generated is transformed into information, so there is an opportunity even with quite simple and cost efficient approaches to really add value. I agree, when it comes to tools and technology the two advanced in process sensors. They are not off the shelf readily available today. They will be. They will become more and more available in the coming years and decades. But even simple sensors tests can actually add value. If we start to just introduce the mind set, for example, the current quality controls are tests for accounting, not for productivity. We recognise when the product is out of spec. I would like to use the metaphor – it’s like driving on a street and we are only notified when we are in the ditch. The question is, how did we arrive in the ditch? We had the process recipe, the process method, but we are actually operating with a fixed steering wheel and in reality when we drive our own car we don’t have a black front screen, we actually have some kind of information that we are on the street, that we are on track. That is what PAT is about, how we do it in reality will always be dependent on process and product. The important thing is that we need to get the black cover on our front screen away.


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Continuous processes: New concepts compared to batch processes in philosophy.

Dr David Rudd, GSK (UK)

Abstract: The recent infatuation of the pharmaceutical industry with Process Analytical Technology (PAT) stems from an appreciation of the potential benefits which can be obtained – that is, improved process understanding resulting in the development of more robust products and manufacturing processes and enhanced commercial Prof.itability arising from reduction in cycle times, minimised waste and reduced inventory. These aspects have been appreciated and realised in other manufacturing sectors for a number of years, largely due to the use of continuous manufacturing processes which themselves necessitate a PAT monitoring and control approach. The incorporation of PAT into the pharmaceutical sector now allows continuous manufacture to be considered by first intent – and this results in a number of potential issues in terms of product quality assessment and the contribution which can be made by the pharmacopoeiae to address these points: a) In a continuous process, how is 'the batch' defined? b) Is there an equivalent to the batch manufacturing record? c) In the absence of 'end product' testing, how is batch quality demonstrated? d) What are the consequences of using novel analytical monitoring technology? e) How do we develop reference standards for these new monitoring technologies? f) Are current data treatment techniques adequate? g) What are the negative consequences of obtaining vastly enhanced data sets? The presentation will address these questions and will offer some suggestions as to how those involved in the development of the pharmacopoeiae may help resolve these issues. Dr D.Rudd’s slides are available on page 17 of the PAT-SessionII.b3.pdf; http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2 This presentation isn't really about PAT. We've had some excellent presentations at the conference and heard a lot about PAT. But what we haven't heard much about is 'where PAT might take us'. That's what I plan to address during this talk. For me, PAT is interesting in its own right, but I'm much more interested in the implications and opportunities which PAT creates for pharmaceutical product development and manufacture. I believe that we have a real opportunity to make a step-change in the way that our industry operates – by bringing a stronger science base into our development activities and achieving significantly


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enhanced manufacturing processes which show improved efficiency, yield and cycle times, for example. Batch production of pharmaceuticals Let's take a look at where our industry stands now. Traditionally, most pharmaceutical products are manufactured on a batch-wise basis. This reflects the original way in which pharmaceutical products were manufactured, perhaps by a local pharmacist using classical, manual methods. And this approach has a number of advantages from the quality perspective – advantages which we take for granted: It is clear what constitues 'the batch'. When we refer to 'the batch', it is obvious what we mean and we can establish and demonstrate 'batch' quality against pre-determined specifications using laboratory-based analytical testing. Moreover, we can compile discrete batch records which can be used to demonstrate 'batch' quality and which provide a permanent account of the manufacturing and testing processes. Pharmaceutical manufacturing efficiency So, what's the problem? Well, this slide shows the kind of inefficiency and level of waste which we routinely tolerate during large-scale pharmaceutical manufacture. This is typical data from one of GSK's high-volume solid dose products – but it could have come from any of the major pharmaceutical company's product portfolios. This data is nothing special. What you can see is that we tolerate huge lead times. Six weeks in this example. Our manufacturing equipment is only being used to about 30% of its capacity – and actually that is quite good. But that means that for 70% of the time, this equipment is lying idle. We routinely build in levels of waste of at least 5% - and in some cases as much as 50%! Think about that. You wouldn't tolerate that in any other industry. "Here's your new car. Only three wheels". "Oh, that's fine". Or you go to the bank and ask for €100. "Here's €80". I don't think so. Pharmaceutical manufacturing efficiency So why do we tolerate it in pharmaceuticals? Well, the main answer is that each pharmaceutical company is probably about as bad as each other. When we benchmark across the pharmaceutical sector, where's the problem? It's only when we start to compare with other industry manufacturing sectors (foods, petrochemicals, plastics etc) that we begin to realise just how much room there is for improvement – and that, of course, is at the heart of the FDA PAT intiative.


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Why, then, are some of these other manufacturing sectors so much more efficient than we are? Well, one reason – not the only reason, but probably the major reason, in my view – is that these other sectors employ continuous manufacturing processes by first intent. Some people think that continuous processes are only useful for high volume product streams with limited diversity. No. Continuous processes offer a number of huge potential advantages over and above simply being useful for high volume products. Manufacturing site rationalisation, Six Sigma capability, late stage product diversity to name but a few. But that topic is for another day. Today we are interested in the pharmacopoeial implications – not the rationale for continuous processing itself. Use of PAT in continuous processes Clearly, PAT has become well-established many years ago in those manufacturing sectors which operate continuous processes due to necessity. If you operate continuous manufacturing processes, you do not have the luxury of relying on end-product testing. By the time you generate your laboratory data, the damage is done. Any process which is running out of control will have continued to manufacture unsuitable product and this will need to be discarded to waste. What is needed is a 'real time' monitoring capability which will allow the process to be brought back into control within a very short time-frame – and this, of course, is the essence of a true Quality by Design philosophy. So, continuous manufacturing processes rely heavily on 'real time' monitoring and control (ie PAT). And, while the pharmaceutical industry may be doing things back-to-front compared to other manufacturing industries (ie PAT is coming first, with continuous processing coming second), the advent of PAT now means that continuous manufacture by first intent becomes an option –with all of the attendant advantages mentioned earlier, and several others to add as well. Implications OK, so that's fine. But what about the pharmacopoeial implications? Well, let's think about things from the quality perspective first. What I'd like to do in this part of the presentation is to raise a few issues, but then offer some ideas as to how these issues might be addressed. I don't like just raising problems. I think that it is important to try to offer solutions at the same time. So, this slide summarises some of the quality implications of continuous manufacture by first intent. Many of these are important from the pharmacopoeial perspective. How do we define the batch? What does a batch record look like? How do we demonstrate product quality if there is no end-product testing? Should we continue to use conventional analytical testing methods and techniques or is there a need to develop and use novel analytical monitoring technology? What about reference standards? If the PAT data is more complex, what data treatment techniques need to be employed and, if we are generating data continuously on multiple samples throughout the batch, how do we deal with the inevitable (huge) increase in 'out of specification' results?


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Definition of 'the batch' I think that the definition of 'the batch' is relatively easy to address. I'm very happy to steal ideas from other industry sectors and here's what they do in the food industry. The Weetbix 'batch' starts on a Monday morning and finishes on Friday evening. This allows the weekend to be used for cleaning and maintenance etc. Analytical monitoring is done off-line, but with a sufficiently rapid turn-around of results that it becomes equivalent to 'real time' and allows process modifications to be made to ensure product quality. If there is a problem with product quality, the relevant time window which contains non-compliant product can be easily identified and this part of the production stream can be diverted to waste or re-cycled or whatever. 'Batch' records This slide represents my attempt to show what a batch record might look like during a continuous manufacturing process. It is the composite of batch operating conditions, process variables' status reports and statistical process control of key measurable attributes, for example. One good example is the 'Conductivity versus Time' plot which shows that the right ingredients have been added at about the right times and at about the right rates during an aqueous suspension preparation. So, rather than rely on operators saying that they have done the right thing – and getting their colleagues to countersign to that effect – here we have a continuous record that the right things were done. This is the kind of thing that I think Quality Assurance managers and Qualified Persons will need to be come more familiar with. Certificate of Analysis…or Certificate of Conformance? Another lesson that we can learn, this time from the bottled water industry, is that actual 'batch' data becomes unnecessary if we are prepared to claim conformance with specification rather than insist on actual batch data appearing on Certificates of Analysis. If I'm trying to demonstrate compliance with specification for a batch of tablets, is the actual mean drug content really important or am I simply trying to show that it lies between 95 to 105% of nominal? Does it matter that the mean drug content is 99.8%? As long as I'm sure of my facts, and I have the data to back it up, conformance with specification is all that we are really interested in. General chapters for novel analytical monitoring techniques It is clear that many laboratory-based measurement techniques do not necessary make a successful transition into the 'real time' (generally on-line) monitoring environment. HPLC, for example, is one of our major laboratory QC techniques, but is finding limited applicability in a PAT sense. In contrast, there are a number of techniques, some of which are relatively new to the pharmaceutical industry, which are showing themselves to be particularly useful in 'real time' applications.


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I've listed a few of the major ones here. Clearly we need the Regulatory Agencies and the Pharmacopoeias to recognise the usefulness of these techniques, so that industry can continue to develop and exploit their capabilities. An obvious way to do this would be to write General Chapters for those techniques which seem to have reached a sufficient stage of maturity. Multivariate statistics I mentioned earlier about bringing diverse data sets together to constitute the batch record. In fact, the problem is worse than that. Many of the measurements we are now making (near infra-red, acoustics etc) actually need multivariate data treatment techniques to unravel all of the information they might contain. This is just a feature of the relative complexity of the properties which these analytical techniques measure (particle size, granularity of solids, elasticity, spectroscopic properties etc) compared to titrimetry or colorimetric analysis, for example. As such, more sophisticated, (or 'multivariate') data treatment techniques (sometimes referred to as 'Chemometics') are required. This is an area where the Pharmacopoeias could usefully help us by developing general guidance regarding the suitablity of various data treatment techniques for different applications. Reference standards Some of the newer measurement techniques raise interesting questions about reference standards. Look at these. How do we provide reference standards for imaging techniques? Yes, that is a picture of me taken using a thermal imaging camera and, while we can calibrate the temperature scale, how do we equate this to a particular pixel within the overall image? What about effusivity? Will one sensor respond to a given stimulus in exactly the same way as a supposedly identical sensor? These are points which need to be addressed by the development and ratification of suitable reference materials. The most extreme case is that of acoustic emission. Look at the pencil in the top right picture. This is not someone writing up a laboratory record. This is the currently approved reference standard for acoustic emission measurements. You break a standard pencil, using a standard hand (joke!) and expect the acoustic sensor to detect a standard signal. We can clearly do much better than this. Probablity of outliers This topic is one which a lot of people are making a great deal of fuss about, but which, for me, seems relatively straightforward. Maybe I''m missing something. We recognise that our 'real time' monitoring capability allows us to measure vastly increased numbers of samples – maybe even every tablet from a batch. This means that conventional pharmacopoeial specifications (for example, content uniformity for tablets) need to be further developed to reflect the dramatically increased sample sizes. It seems to me that this should be a relatively simple mathematical exercise. If we make a few assumptions about the nature of the distribution of individual tablets within the batch, it should be possible to dervive a new set of acceptance criteria for different sample sizes which are consistent


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with those which currently form the pharmacopoeial specification based on testing sets of ten, twenty or thirty etc tablets. If I'm right, maybe somebody could get on and do it - because we cannot continue to apply current criteria and expect not to get more and more apparently 'out of specification' results as we measure increasing numbers of tablets. Summary So, here's the Summary. For me, the major advantage of PAT is that it allows introduction into the pharmaceutical industry of continuous manufacturing processes by first intent. This is a major factor as we attempt to bring the Quality by Design philosophy into our process development and application. There are a number of implications, however – which I hope that I have brought out in this presentation – and where the Pharmacopoeias could help significantly. I include the development of General Chapters, guidance on the use of multivariate data treatment techniques, development of reference standards and conformance schemes as the most important examples. Thank you very much indeed for your attention.

DISCUSSION

Dr J. Timmermans: In looking at your last slide I recognise very much the need for recognition by regulatory agencies and pharmacopoeias for new technologies. However, in the past the role of pharmacopoeias specifically has really focused on established technologies, for example the HPLC chapters really appeared 10 – 15 years after HPLC was commonly used within the industry. Personally I foresee that we are at the onset of the use of PAT and a lot of the technologies and applications are still being developed. So, why do you believe it’s beneficial right now to get technology and potentially even application specific guidance, when we don’t really know yet in which direction we are going to take this? Dr D. Rudd: It’s a good question. I think the answer is that a lot of the so-called new technologies that we are talking about are maybe new in terms of pharmaceutical applications, but I think a good example is acoustic emission that Ron talked about yesterday. That’s a very mature technology, not in pharmaceuticals but in other industry sectors. If you argue that the role of the pharmacopoeia is not to talk about the applications but simply to provide a framework for the principles of the methodology, then I think you could argue that a number of so-called new technologies are actually mature enough to be included. Acoustics is a very good example of that. In contrast some of the newer technologies, some of the imaging technology, some of the tomography things I have mentioned. I think that isn’t necessarily as mature as we would like and it may be very much premature to think about monographs for those techniques. So I think we should simply put emphasis on those techniques that are mature even though the applications to pharmaceuticals may be novel. Dr J. Timmermans: Do you not believe that if you were to generate a chapter on acoustic emission you would recognise that as an acceptable PAT? But by not having a chapter on imaging, we slow the acceptance of an implementation of those technologies?


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Dr D. Rudd: I would look at it more as a motivator to get something written if we really do believe that imaging techniques have a role to play in the near future. You can’t do everything immediately, that would be nice, but we can’t do that. Let’s at least tick off the ones we can and make sure the others follow quickly.


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SESSION III: PAT AND THE PHARMACOPOEIA

FINAL ROUND TABLE DISCUSSION

- Impact of PAT on Pharmacopoeia standards - New general chapters - Expectations of users - International Harmonisation: - The need to prospectively harmonise pharmacopoeial monographs and methods With the participation of: Prof. Dr H. G. Kristensen (Ph. Eur), Dr. J.-L. Robert (EMEA), Dr G. Ritchie (USP), Dr A. Hussain (FDA), Prof. T. Moffat (RSPGB), Dr J. Berridge (EFPIA) and Dr C. Potter (EFPIA).

Prof. Dr H.G. Kristensen: Thank you for being back on time - still we are a little delayed. I will make sure that we close this session 3 on PAT and the European Pharmacopoeia in time, which means quarter past 3 at the latest.

We have one hour to, what in my opinion is the most important part of this symposium, namely to identify how to proceed from now. I have a panel here containing some distinguished speakers: the 2 regulators, Ajaz Hussain and Jean-Louis Robert, two people representing industry, John Berridge from Pfizer and Chris Potter from AstraZeneca. They are both very much involved in the ICH process and Tony Moffat who has joined the NIR working group. Finally we have two people representing the Pharmacopoeias, Gary Ritchie the USP and the European Pharmacopoeia.

We have had 1 and a half days with presentations on PAT and very good talks, wonderful speakers. They have addressed the item which they were asked to do – namely what is the impact of PAT on the pharmacopoeia and pharmacopoeia standards and what can the pharmacopoeia do in the future to facilitate the development and regulators acceptance of PAT. We have also heard very diverging proposals and viewpoints from the speakers. I hope we can catch up a little in this final round discussion. The aim is to reach some conclusions, may be not very specific, but conclusions on how to proceed from this point.

I have had my lunch together with the panel and we agreed that we will start by giving the panel members the chance to make general statements and after that I’d like to have a discussion with the panel and also with you on how to proceed from today and from this point. So, not to waste too much time on my talking I will ask the panel if any of you want to make statements now on how to proceed.

Dr J-L. Robert: Yes, thank you chairman. I would like to apologize because I will have to leave a little earlier and so I am grateful that I can start.

Firstly I would like to congratulate the organiser for this meeting and if I can make a first conclusion - very straightforward – we have a lot to do. As we are more focusing on the role of Pharmacopoeias on PAT in the future, I will therefore not go into detail of all the different contributions. But as I already stated yesterday in my talk, I said of course Pharmacopoeia is, has been and will always be, a tool for standardisation and harmonisation, a fact you should be aware of and we should also really take advantage of it. PAT concept is a vast, very fast moving field where I think it is very important to maintain flexibility in this area.


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The ICH Q8 and Q9, which means pharmaceutical development and risk management which are discussed currently at ICH, are very good tools to try to go ahead with this concept; my proposal for the moment would be, before we define really the exact role of the Pharmacopoeia, that we should wait for the outcome of these discussions on pharmaceutical development and on the risk management. I am sure that during these discussions, we will identify issues, topics where they need more reflection about harmonisation because also industry should be interested here, to be sure that we have common standards and that we have harmonised these standards internationally.

So, we will be able to identify, at least during the Q8 discussion, topics which we then can be given to the pharmacopoeias, but to the 3 pharmacopoeias, Japan, USP and European Pharmacopoeia in order to ask them to harmonise some of these issues in the same way as for Q6A. Of course we will have to ask Pharmacopoeias probably to be a little faster than they have been on Q6A. This is something we need also further to discuss with them.

I would like also to come back to a question which was raised by Dr T. Bourquin about Q8 and the minimum standard and additional optional standard or optional information which can be submitted to the authorities. I think it is very clear that the concept in Q8 for the moment is that we do not want to have different quality standards for the drug products. So I heard also yesterday industry saying that we have good quality with the current situation, that we have good quality on the market and I think with the minimal requirement or minimal approach if you like, which represents the current EU standard, I think we will keep this standard. With the optional information it’s for sure that industry will then be able to have more flexibility for instance in the manufacturing process and it will be easier for them to have change controls eventually also if they wish to come up with real-time release etc. So this is in fact the basic approach to Q8, but definitely there should be no different standards on the European market. Thank you.

Prof. Dr H. G. Kristensen: Thank you. Any other members of the panel? Tony?

Prof. Moffat: I will just say a couple of things. The pharmaceutical industry is a global industry and just to put it into perspective, the contents of the European Pharmacopoeia are also published in the British Pharmacopoeia which is used by 28 other countries as well. So, as well as the 35 odd countries that use the Ph.Eur directly, there are another 28 which use these contents as well. I would like to see the same monograph appearing in the EP, the USP and the JP as we move forward. Not harmonisation, actually the same thing. As a scientist that is what I would like to see.

As we’ve been talking about the monographs, I would like to see very high level monographs on PAT and on the utilisation of techniques. This so that they don’t constrain you in the pharmaceutical industry who need to use them. Because they are high level, they don’t need to be changed very often, but on the other hand if they need to be changed they should be changed very rapidly. I also believe that Pharmacopoeias should lead the application of science in the pharmaceutical industry. I think it started to do that with some of the general chapters and I think that’s absolutely right and proper. Further to that, the kind of general chapters I would like to see are the kind of things Dr D. Rudd mentioned. I think those are very sensible suggestions and the kind of standards for calibration that Dr S. Hammond mentioned too. I think we do need to address those because some of those are currently not suitable for purpose.

I would just like to finish up by saying that some of the general monographs about techniques were written specifically with the QC bench laboratory instruments in mind. I think as we move into PAT and on-line or at-line applications, they are no longer appropriate and it may be that we have to break those chapters into 2 parts – one which is applicable in a QC laboratory and one which is applicable as an on-line PAT application. Because to write one monograph to encompass both of those things may be a bit difficult, so two parts for different purposes may be appropriate.


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Thank you Chairman.

Prof. Dr H. G. Kristensen: Thank you. Dr A. Hussain

Dr Hussain: Well, I think these one and half days were quite exciting and illuminating for me. The Programme Committee did an excellent job putting this programme together. My task I just want to share with you, is just somewhat summarising what I said in my presentation. If you look at our system as a drug quality system, there are 3 major components to this system. One is industry, I mean industry is responsible for innovation and producing quality products and that’s where the responsibility lies. Then you have the regulators, especially because we are in my way of thinking, surrogate customers who have to make sure that the quality standards are adequate for the intended use of safety and efficacity. Now, much of this is dealing with private standards, innovation is private, it is not a public standard. If it is a public standard, it is no longer innovation. And so, I think it is very important to keep that in mind and then you have the compendia, which is a very important part of our quality system. But compendieal standards are public standards, and these are developed years after a new drug is on the market generally and therefore customers or consumers give them an opportunity to test, if they wish to test these products and I think it provides a very important leg of our quality system.

So I think from our perspective, innovation in pharmaceutical manufacturing particularly has not occurred and efficiencies have suffered as a reason for not being innovative in this case. I think from a regulatory perspective, we are trying to remove regulatory uncertainty. Perceptions are more damaging than reality in this scenario. So regulatories are sort of working in the private statute more to remove the hurdles or perception through a team approach to review inspection and a U team or PAT team at FDA and so forth. Now by the time you are ready for public standards or what I call market standards, the scenario is different. So I always struggle in terms of trying to rush into putting chapters and so forth. I have to keep in mind what is the goal of that and I think in many ways there is a challenge because in the US at least with the schools of pharmacy moving away from basic sciences and or analytical sciences in their curriculum who is reading the pharmacopoeias? It is one part of the pharmaceutical industry, not all of them, so I doubt whether product development or production engineers actually know what the pharmacopoeia is, maybe I’m wrong. I hope they do.

So I think you have to be very careful in how you move forward here because pharmacopoeias do have a very important role and there is a perception of uncertainty associated with understanding pharmacopoeias and I think if pharmacopoeias start out with removing that uncertainty I think that will be very helpful and I think all the time their role in PAT would clearly evolve. So I think there is a period of time where things will be uncertain, but will resolve very quickly, I hope.

Prof. Dr H.G. Kristensen: Thank you very much. I hope in Europe the situation is different with regards to reading the pharmacopoeia. But listening to the speakers yesterday and today I would say some of you should read the general notices, maybe to understand a little better how it is constructed and how it is aimed. Anyone else wishes to make a statement? Dr J. Berridge?

Dr J. Berridge: Thank you Chairman. I think Dr C. Potter and I would like to try a double act here on behalf of industry.

It’s just quite incredible to step back for a moment and think that all of us here have lived across 2 centuries and to think about all the new words, terms and phrases that we have heard as we moved into the 21st century. We’ve heard of GMPs for the 21st century. We hear much more now about risk-based approaches. We hear about manufacturing sciences. A lot of these terms are actually new. PAT isn’t new and Dr S. Hammond and I go further back in Pfizers history than either of us


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would care to remember, but I can certainly remember talking with people like Steve several decades ago about applying PAT in the pharmaceutical industry. So it is not new.

I think this meeting has been very useful in focusing our attention to the partnership that should be blossoming between the 3 critical parties that Dr A. Hussain identified, for example the regulators, the industry and the pharmacopoeias themselves. And from an industry perspective the only way forward for us, that I think we would see, would be that these are working as I think Prof. T. Moffat suggested, working hand-in-hand to a common agenda, to a common time-scale and with a single output. My good friend here on my right, Dr C. Potter, is an EFPIA representative to Q4, which is the group that’s looking at the implementation of harmonised monographs. It would be nice if we could work you out of a job Dr C. Potter, because the monographs are actually identical, the wording is identical as Tony said. So I think that we would ask that the pharmacopoeias focus on their core business, as Ajaz has talked a little bit about. There’s a role here for the PDG, the pharmaceutical discussion group, in helping us all to move together, in step, where the pharmacopoeias can help in perhaps 3 or 4 specific areas. One is removing the barriers, we’ve heard a lot over this last day or 2 about some of the barriers that need to be removed.

Interesting the comment a little earlier about do we need 2 types of general monograph, one for lab-based work, one for process-based work. I personally have a little difficulty with that, because I am not sure where one stops and the other starts, but lets not put something in place - if it’s a good idea that’s fine, but if it’s not such a good idea and stops things – then, I think we need to take care. I think that we’ve heard also that there are some areas where the pharmacopoeias can have a role in developing a tool-box. I’m going to ask Chris perhaps to give some specific examples, but what is that tool-box, what are those things that the pharmacopoeias could work at that would actually help us? And maybe as part of the discussion in this last session, you the audience can help in identifying what can be done by the pharmacopoeias to help and areas which they should steer clear of – because we’ve heard both over the last day or so.

Then as we make this forward progress we certainly need to agree the priorities, the priorities that help us all, the priorities that help bring needed medicines to patients faster and that brings me to the time-scale. It needs to be fast, it needs to be much faster than we’ve achieved with the harmonisation of the 11 procedures that were identified in Q6A. So, we can do that though with an agreement on prioritisation. And maybe Chris I could turn it across to you at this stage to perhaps give some examples of tool box items or areas where you think there is value in the pharmacopoeias being active and perhaps some areas where it might be appropriate just to hang back and wait.

Dr C. Potter: Thank you Dr J. Berridge. Some of these lists are taken from presentations that we’ve heard over the last day and a half and a couple of them are potential barriers that I’ve heard from colleagues from other companies and as well from within my own company that get in the way of application of PAT, at least it makes life very untidy and potentially difficult. So let’s look at potential barriers that I’ve heard about and I think some of them have been exemplified.

First of all, we got uniformity of dosage units, I think a fair number of speakers mentioned that. We need to look at that, in terms of it’s application in the PAT world. The other one that came up and Dr J-L. Robert doesn’t totally agree with us of course, is the general chapter or the general note for guidance on NIR that has caused a lot of difficulty within European industry. That really is quite hard to see how that fits in the PAT world. We heard from Dr S. Hammond about equipment qualification and particularly reference standards. I think we need to catch up that and see that that doesn’t get in the way of PAT applications.

One that’s not been mentioned but I’ve heard several times is HPLC. That application of HPLC monographs as written in the pharmacopoeia is very difficult when HPLC is applied to PAT


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applications. Some thoughts for future general monographs and really I guess we’re looking to the audience to agree or supplement what I am saying. I think the highest message I’ve heard is nomenclature and definition. There is a lot of difficulty with different definitions, different nomenclature. There are problems with common understanding. Even PAT itself, is it a tool-box or is it a system? I’m not sure, clearly we have one definition in one region and others of us have got different definitions. Maybe just because of history. And then there’s the shopping list of general methods that have been alluded to. Dr D. Rudd spoke about some of them and Sylvie also spoke about new microbiological methods. I think our priority would be to remove the barriers rather than moving onto new things, but I would look to the audience for their view on this.

Prof. Dr H. G. Kristensen: Thank you. To Mr G. Ritchie.

Mr G. Ritchie: I’ll keep it short and sweet. A lot of issues that I have been concerned with currently, I think everybody has addressed. The fact that I am here I think, underscores the fact that USP recognises the importance of moving fairly quickly on some of these barriers, perceived or not to facilitate and keep PAT speedily moving along. I’m not going to address any more issues. But one thing, I am surprised about is, I began about 3 or 4 months ago as I took more of a prominent role dealing with ASTM, dealing with my own Chemometrics committee and now on an international level. I took it upon myself to get a hold of Walter Shwart’s “ Economic control of quality of manufactured product” first published in 1931, dealing with the specific issue of the statistical process in quality control. I’m surprised looking round this room of the many people that haven’t read this book. I would urge you to get the re-issue the 50th anniversary, commemorative issue of that book and read it. Because in it is everything I think we are talking about today and even some tools that we can apply tomorrow on the essence of what we are trying to do to decrease variability and increase quality. That’s the essence of that book. That’s what I will say.

Prof. Dr H. G. Kristensen: Thank you Mr G. Ritchie. I would like to make a follow-up on what was said by Dr C. Potter and then ask the audience for your comments on the proposals made by Dr. C. Potter.

I have noticed during the discussions we have had yesterday and today that there is no discussion that we will keep the pharmacopoeias specifications for dosage forms, market place specifications they were called by Dr A. Hussain. It means that we will have a situation in the future where we have specifications of the type we have now in the pharmacopoeia maybe adapted as mentioned by Dr C. Potter. We will have companies working hopefully with PAT procedures, we will have companies working on batch release and GMP, we will have a spread in the industry which is much bigger than I think we have today if we look on the legal aspects, pharmacopoeia aspects and that’s a difficult situation. This was one of the reasons why I thought and the EDQM thought that we should have this PAT conference now to get an impression of what is necessary to do. Shall we do something now or shall we wait?

Since the European Pharmacopoeia is a public enterprise, is funded by the states, I will absolutely not urge that we go into any actions immediately. It’s a question of priority. There could be other items that are much more important just now than the PAT aspects. The question is what do we need to do? Is there a need for industry that something is done by the pharmacopoeias in the field of PAT, maybe Dr J-L. Robert is right and it’s a wise proposal to wait Q8 and Q9 which could be in a years time or so, to see what is needed? Maybe we should go into the question of nomenclature mentioned by Dr. J. Berridge? Maybe we should begin to consider some of the general methods we have heard from Mr G. Ritchie in his slide presentation, that some work is going along in the USP?

I have no doubt that we will do our utmost from the European Pharmacopoeia and the EDQM to harmonise with USP and the JP that’s superior to anything else when we are going into a new area.


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Having said that I have just a comment on the barriers mentioned by Dr C. Potter. Dosage uniformity, I stated it already in my introduction yesterday that I see difficulties in the traditional way of expressing acceptance criteria by sample size limits and acceptance criteria in the pharmacopoeia and maybe it has to be done differently. It will be a lengthy discussion but I would be pleased to have started. There were comments from Dr S. Hammond on NIR and it’s standardisation and qualification. I’m pretty sure Dr S. Hammond hadn’t seen the new monograph on NIR instrument from the pharmacopoeia, but I’ll add to his comments on qualification that what the pharmacopoeia monograph requires is a qualification done by comparison with a standard preparation. We don’t require any compliance with any reference preparations from the Pharmacopoeia. The only place where the pharmacopoeia is mandatory is in the question of raw materials in identification and limits test for purity, where you have to use the specified standard preparation.

So, concerning the barriers I feel that the number in the test for dosage uniformity, the number and the sample size is really a problem that has to be considered. Those were the barriers he gave priority to and then Dr C. Potter mentioned the general monographs. I will ask the audience if you have any comments on how to proceed and on what has been said by the panel now. Don’t hesitate – it’s an important time, because whatever we decide it will be done tomorrow.

Dr T. Bourquin: I have prepared some notes to support my comments. So, first of all, with the next 40th anniversary of the European Pharmacopoeia, which is closer now, I think it’s really time to change. For me quality is not a concept, quality is reality. Quality is done on the shop floor, quality is not done here in this Sofitel, even if the area is very excellent. But the quality is done on the shop floor, so we need to be very realistic.

When we have an issue in quality, first of all we investigate, secondly we put an action plan into place, with key leaders. We get the commitment of these key leaders to succeed and to be sure that at the end we succeed and we put some key performance indicators in place to ensure the follow-up. So with what was said during these days, I think now it is time to put an action place into place. If I just comment about the European Pharmacopoeia, the aim of the European Pharmacopoeia is to provide a set of legal requirements, useable in case of serious events in front of the court. This is the main aim of the European Pharmacopoeia. With PAT concept we do need to adapt the aim of the European Pharmacopoeia. The European Pharmacopoeia is officially in charge to develop and provide legal requirements, but also should be in charge to contribute to development of pharmaceutical technologies with a risk and science-based approach. The consequence of that would be to split the European Pharmacopoeia into two parts. One part, the legal requirements, this is a code, this is a law, and another part which could be called development of pharmaceutical technology. The other consequence would be to re-write the general notices, to explain clearly to users, to regulators and to inspectors how it works and how the European Pharmacopoeia and Pharmacopoeais should be used.

I say that because I had the opportunity in the past to train people in France concerning the European Pharmacopoeia and the usage of the technical guide. The first question I asked the trainees was, “Did you read the general notices of the European Pharmacopoeia?” Each time the answer was no. So if we don’t read that, we don’t know how it works. Therefore, first of all we need to be sure that everybody knows the general notices. And I think the priority, and it should be, for me, the first action in the action plan among a long list of actions.

The first action is to draft a proposal on how the European Pharmacopoeia should be used, in the light of PAT, and other concepts because at the end we are going to refurbish all quality systems. So the general notices for me, are a key point, because they have to explain clearly how it works, to users, to regulators and to inspectors. At the end we are inspected by people who do not interpret as


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us, in some cases, how it works. We’re speaking about strict compliance instead of speaking about risk mitigation. For example in the general notices, one point which is very important for industrial people is to be sure that we will not be obliged after introducing new technology to force us to re-perform the current test and to be seen by an inspector as being out of the law, if we don’t do that. We need to be sure that there is a possibility of flexibility, and we have spoken very often about flexibility. We need to be sure that flexibility exists and provides the freedom to use what is really relevant. I think the best example that we have today is the sterility testing. It is a pity to see that this test is not at all relevant in terms of statistics. This flexibility will provide at the end a better level of quality and safety, which is for us, quality tehcnicians, the most important thing is our objectives and for patient.

Another comment, I do not think that regulation is a barrier. I think that industry has to discuss and really discuss with regulators as partners. We need to insist. If we are not heard, we have to shout. To say that we have better technologies and we want really to use these, because it’s better. I think if we are able to provide good files, regulators will accept news in the end. There is no reason to be in contradiction with that. So it’s our role in industry to insist and to provide good files. If we are consistent with what we think, I think we will succeed.

Also another point. I would like to congratulate all of the presentations that we had during these one and a half days because these presentations were excellent, a high level of PAT was already used before the timing.

Prof. Dr H. G. Kristensen: Thank you very much and thank you in particular for your comments on the General Notices. I hear your viewpoint.

Dr J-L. Robert: Can I just add (because then I will have to leave afterwards) Thierry, I have read the General Notices, I can’t tell you when, but I read them at least. The point that you mentioned was already in my presentation yesterday. I think the PAT concept is already included in the General Notice, how it is stated now. You do not have to perform all the tests, if you can also show from process testing that you can comply with the monograph. I think maybe you could precise the wording, I agree with you, but I think the elements of the PAT concept are already in the Notices. The same for parametric release and sterilisation tests, I think these are also already in the General Notices, but also in the specific chapter on sterility testing. Regarding the discussion between regulators and industry, I agree with you, and yesterday said that we look very much for mock submissions within the PAT team, because we would like to know how data will be submitted, how information will be submitted and in order to discuss this. These are submissions, maybe we should not call them submissions but they are more documents we receive which are parallel to the marketing application, in order just to discuss and to come up with a common understanding. That’s also why my initial proposal was that we need more discussion before we try to harmonise all these topics because industry is a little afraid about the regulatory uncertainty and we are a little afraid of what we will receive and this is something which we have to try to find together and a common solution (just my statement as I will have to leave. I would like to thank you very much for all your contributions. Thank you.)

Prof. Dr H. G. Kristensen: Before you leave Jean-Louis, just one question. Applications based on PAT technology, have you seen them in Europe?

Dr J-L.Robert: No

Prof. Dr H. G. Kristensen: which means it’s a premature discussion maybe.

Dr J-L. Robert: No, no discussion is ever premature. I think we have to discuss it before we get such a submission. It is important and is something I should have perhaps mentioned. In the


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centralised procedure, we have a scientific advice procedure and maybe industry should take advantage of it. I would also urge industry maybe if they have questions, or maybe they would like to submit something like the PAT concept and you want to have advice. Do it perhaps in the centralised procedure with the Quality Working Party instead of going nationally because this is a topic which interests all the licensing authorities in the European Union. In order to avoid problems in the Mutual Recognition process better to go centralised right from the beginning. Thank you.

Prof. H.G. Kristensen: Sylvie.

Dr S. Guyomard-Devanlay: I would like to mention sterility tests. You can replace sterility tests as an end product control only for products terminally sterilised. So, I think this is not enough and we should extend the parametric release to other ways of sterilising because I think the sterility test is very bad and especially very bad for, for example, aseptic processing or products sterilized by filtration.

Dr J.L. Robert: Yes, I will not answer to you now because this is a long debate. I agree with you, we have introduced parametric release only for terminal sterilisation. Anyhow, this is a guideline which we have been drafted together with our GMP inspectors, they have also quite firm opinions on aseptic processing. So if you have ideas or proposals as to how we could improve, aseptic processing and to introduce better controls based probably on the technology which you have mentioned in your presentation, we can always think about it and re-open the discussion. That’s not a problem..

Dr F. Erni I think we have to realise that the pharmaceutical industry is a rather global exercise and I think it is most important to realise that if you look at manufacturing this is probably the most globalized aspect of the pharmaceutical industry. So I think we are in a very unique situation that we are starting to discuss about whether we need in the Pharmacopoeia any monographs on PAT. I think even more than actually agreeing as to whether we need one or not, I think we should agree that if we are going to have a PAT monograph or something like this in the Pharmacopoeia let’s have it at least harmonised right from the beginning.

So I think this is one of our very strong requests that we don’t start with disharmony if you look at this global world. I think we should have on the agenda in Washington at the PDG meeting, whether we are going to have that harmonisation right from the beginning before publishing any drafts in the different regions on PAT. I think yes we probably need some activities of the Pharmacopoeia in certain areas and I would also put the priorities rather in eliminating hurdles, like for example in the Near-Infrared and HPLC monographs. However, I think there is also need for some adaptation of other monographs where we actually analyse tied to a very small number of samples and I don’t think it’s only the content uniformity alone. Let’s also talk about dissolution rate where we actually have an even smaller number. If we have a PAT concept that would replace dissolution rate testing, giving us an opportunity to have instead of the 6 or 12 tablets, maybe 600 or 6000 or all the millions of tablets we are producing under control - what are we going to have as legally acceptable specification and acceptance criteria?

Prof. H.G. Kristensen: Thank you – yes please John.

Dr J. Berridge: So yes Dr F. Erni, I think you raised some very good points and when we were sitting at lunch time just talking about the opportunities that this afternoon’s session would provide, we did mention the value of the PDG group of discussion in Washington, the opportunity in Washington and in fact we compared the role of the PDG group with the Q4 process which is really something which happens after the PDG group have reached an appropriate level of harmonisation. But I think what emerges from that and what emerges from your comments, Dr F. Erni, is that we in industry actually have an obligation to identify the areas where we think the PDG can actually help


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us. So I think that if people do have ideas on something that should represent this ideal state of one monograph harmonised from its conception through its publication, then these conferences or these kind of meetings, all working through various industry related associations, we have the opportunity to be proactive and say this is something we actually need. I think that would be a far better process than saying in five years time, this particular monograph is a barrier to innovation.

I would like us to agree that after this meeting there is no such thing as a barrier to innovation and we can actually move this agenda on, by making positive suggestions on areas and Chris identified just a couple. So let’s identify those and let industry also help in this process of enabling the appropriate business focus and prioritisation for the Pharmacopoeias to work on and work also with our experts that sit in the various pharmacopeial expert groups, to actually make this happen. But I think we do have an obligation in industry to actually do something to help in that prioritisation.

Prof. Dr H. G. Kristensen: Of course it would be very difficult at this meeting in 15 minutes from now on to have an exhaustive list with priorities on what to do. I think the proposal to continue the discussion in the PDG is very constructive because PDG meets twice a year and every time it meets there are meetings with the industrial organisations in the 3 regions and also with the excipient manufacturers, which gives a possibility to make proposals and influence the working programme. I think it’s a good proposal to take it this way round.

Mr G. Ritchie: I think one of the best observations that came out of the discussions we had at lunch and also reinforced here is the observation that the General Chapter could serve as a vehicle to first clarify and address a very basic premise for the Pharmacopoeia and that’s the use and interpretation of methods in the Pharmacopoeia. It was suggested that the one use has a very real legal implication and the other use is for development. I say this because the situation that we ran into with the misuse and application for the 11–19 NIR (USP Chapter) comes about from misinterpreting the existence of the standard for a particular need and then using it inappropriately where if you read the chapter (USP 27 NF 22 2S) it suggests very clearly that the standards should only be used when appropriate and if not appropriate alternative standards should be used. If that (appropriate use of standards in general chapters) was addressed right up front in the General Notices better than it is now I think we wouldn’t run into those situations. That’s one instance where general notices could be used to mitigate future interpretation issues. We’re going to run more into that I think, the sterility or the misappropriate use intentional or whatever of rapid micro tests. So, the PDG could focus on harmonising how we would use and interpret these chapters and monographs in the near future with the rapid development of these new technologies. Just an observation.

Dr S. Folestad: Ten years back my colleagues and I went through the different guidelines and pharmacopoeias and when we worked on developing Process Analytical Technology tools and implementation. We actually we couldn’t find any barriers in there or anything that was against this way of working or introducing new technology and I’ve already quoted the ICHQ6A phrase there that new technology should be used when it can add value to quality assurance. But reality is actually a range from interpreting those paragraphs in that way. I mean there is nothing against it, so we will be free to use it if we can justify that it adds value. But again reality is that on the other side, because we have some variability in organisations, different industries, agencies, we always come to those who interpret the same paragraphs, as long as it is not explicitly stated that you’re allowed to do it, you’re not allowed to do it. That’s reality so I think the introductory part of existing guidelines to pharmacopoeias is upfront explicitly states that it encourages innovation, pragmatically to communicate both to industry regulators as well as to agencies. I would really welcome some kind of letter jointly with all the agencies and pharmacopoeias explicitly stating that


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you encourage innovation and also explicitly stating that you in fact encourage proposals in this way. Interpretation should be made in the positive sense, in the scientific sense.

Prof. Dr H. G. Kristensen: Thank you Staffan. There’s no doubt that the message going out from here is that the Pharmacopoeias encourage the introduction of PAT and its development in the pharmaceutical industry. It has been mentioned by a couple of the comments we have had from the audience the question whether General Notices take into account the introduction of PAT. I think from the presentations made yesterday by Dr A. Hussain and also Dr J-L. Robert, it has been made clear that we can consider PAT technologies as alternative methods. The problem is that the use of alternative methods, at least in the European law frame requires a validation against the existing pharmacopoeia methods and there I have a problem, which is why I am coming back to the sample size and the way we are expressing quality requirements.

It was shown very clearly yesterday in the presentation made by Dr A. Swanson on the content uniformity test. He presented a graph showing the operations characteristic and it’s strongly dependant on the sample size. If you begin to compare PAT technology with a huge number of measurements with a dosage conformity test with 10 or 30 samples, you can run into difficulties unless you define where on the OC-curve you are. Are you under producers risk or consumers risk? Which end of the curve do you find yourself and where do you wish to be?

On the validating question there remains a barrier or a difficulty for the implementation of PAT and I agree completely with what has been said by Dr C. Potter. Other issues have been mentioned, but I can’t see that they represent barriers. However, I will ask people from industry here after the meeting to provide us with information on the barriers, where are they? I think there is a willingness, at least in the European Pharmacopoeia, in the EDQM and the Pharmacopoeia Commission to remove these barriers if we can identify them. The question on sample size, I think, has to be discussed by Q8, ICH. How to transfer PAT measurements or data into batch release standards, or how to compare batch release standards, because it must be a very general issue, which is not only a question for the pharmacopoeias but also for the regulators. If the pharmacopoeias solve this problem solely it will lead to very long discussions and confusion because it means that we have to introduce our quality requirements in terms of statistics.

Who is to express himself more? Any comments? Where to go? That is my question, how to proceed from now? What is the next step?

Dr D. Rudd: I just wanted to expand on the comments you were making about validation of methodology, particularly new methodology and this is really a plea from a user. I think this concept of comparison with existing methodology is extremely dangerous. If nothing else it will limit the performance of the new technology. Remember my, maybe one-man crusade, but my crusade against the dissolution test? If we’re having to continually compare with existing methodology that has short-comings dare I say, then there’s an immediate limitation on the capability and I think what we have to try to remember is the true quality measure, if we’re looking at a process or a product, what we’re really interested in, is not necessarily meeting a finished product specification, that in my opinion is a means to an end. What we’re looking at is confirming quality, maybe in vivo performance, maybe bio pharmaceutical performance is what we’re really interested in. If we’re taking for example, an acoustic measurement, which may be predictive of dissolution behaviour, maybe, that’s really not the point. If we’re able generate a PAT Prof.ile during a process that is actually predictive of bio pharmaceutical performance, there are plenty of ifs there. We don’t want to refer back to an arbitrary product standard, for example involving dissolution. So, it’s a plea, really saying let’s keep a perspective in terms of what we’re trying to demonstrate and let’s not be constrained or limited, because I think this could be a barrier, if there is inadequate methodology already in existence in the pharmacopoeia.


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I hope that’s clear, controversial maybe.

Prof. Dr H. G. Kristensen: I understand there is a need for discussion and clarification here but I will add to what you have said, that even dissolution testing is a surrogate for something else, so it’s not so important to validate against this dissolution test, which in itself represents a lot of difficulties.

Mrs L. Lundsberg-Nielsen: First of all, I would like to congratulate this very good meeting. I think it has been said a lot of times, but I would like to say it one more time, that we have to look into what we have to submit to the regulators and to be very sure about that, because that’s actually where I see a barrier today. How much data will be needed? What about specifications? Limitations? How often can we update them? How should the procedure be when updating things? Because we are actually trying to get process understanding, process knowledge and we’re not interested in doing a lot of re-submissions because we gained this small knowledge. I know it’s part of the whole PAT concept, but it’s actually what we have to look into.

Prof. H.G. Kristensen: I’m leaning back on your comments because it’s not the pharmacopoeia, it’s nomenclature and standards and what you’re talking about is regulatory guidance.

Mrs Lundsberg-Nielsen: That’s right but we still also have in the pharmacopoeias standards that we follow and it’s actually also in the regulatory part, so for me it’s linked.

Prof. H.G. Kristensen: More comments from the audience?

Mr K. Leiper: I think it’s been an excellent meeting and I think it’s put some things on the map. I think one of the things that is maybe not quite put on the map is that the real rational behind the PAT initiative is about process understanding. An awful lot of where we’re focusing in the pharmacopoeias is that we’re still using the capital A as analytical. It’s very important that this is put into the right perspective because what we’re trying to do is promote minimum standards for patient safety. And patient safety will be the term and by-process understanding.

We’ve actually heard today about processes where we throw out 10 %, 15% even 50%. Now, how well are these processes understood? It takes me back to the first comments about sampling because if you don’t know anything about your process capability, you can’t really put a decent sampling plan in place. And I think it’s also important that we realise that the Pharmacopoeia is one piece of this jigsaw and it’s quite interesting that when we look at what’s happened across the Atlantic in FDA when they started with the PAT initiative, they began to find that there were issues we were validating processes that are patently not understood. So we had to go back and re-visit what GMP was saying. Maybe this is a time for the Pharmacopoeia to go back and just re-visit what it’s role is going to be in this new world.

Mr G. Ritchie: I’d like to reinforce that, Dr K. Leiper. The issue of a product centred specification where Dr D. Rudd referred to it as the means to the end, that’s not the issue anymore. The issue is the process understanding and the key to the process understanding is what is the assessment? I think we’ve referred to it as assessment in a past meeting, rather than analysis, of the signals that you’re getting back from your sensors. What is it telling you about the process? If you look at the variability of all of the elements that come into contact with your process, including the process composition, at the end of the day the process is talking to you. So, when you understand those measurements it no longer makes sense to just only talk about elements of the specification. That reinforces I think, Dr K. Leiper, what you’re trying to say.

Dr A. Hussain: I think it’s a difficult challenge and question because process understanding and process know-how is not a public standard and so you have to keep in mind it is not a public standard. I have to reflect back, in the sense, to a workshop that was organised by FDA in St Louis


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in 1993. It was an AOAC conference which dealt with Near-Infrared. It was based on process controls and new approaches to process control at that time and one of the reasons in many ways FDA sort of put a stop to NIR in 1993 from that meeting because on the panel we had some FDA staff saying Near-Infrared can never become a public standard or a compendia standard and that actually ended the discussion on NIR in a regulatory sense. The reason they said that was, it’s a systems approach, you bring physics and chemistry together, it’s not like HPLC, because when you bring physics and chemistry together then the physics is different from each product. The chemistry is the same. So the public standard, it cannot become a public standard, it is a private standard. So I think based on what I think Dr K. Leiper said in this instance, our focus from a regulatory sense is based on process understanding to support innovation and to a large degree that is and will remain a private standard. Pfizer will approach it differently to AstraZeneca or Aventis and so forth. So I have some hesitation, with respect to how do you manage that. The chemistry is easy to regulate from a legal sense. Physics is not. So keep that in mind.

Dr C. Potter: I think we would like to make the comment that I’m struggling to find evidence that process variability has an impact on patient safety. I think that’s a little strong to say, but I think the public standard, which is around, more the chemical and biological features of the dosage form, is critical to patient safety, or could be critical to patient safety. It often isn’t, but could be. Whereas process variability tends to be, I think I very much agree with Ajaz, variability operating well within the public standard. Variability has little if no impact on patient safety. What it does have impact on, I think, has been spoken to by many speakers, is the efficiency of manufacture, movement of supply down the supply-chain and the benefits that gives, not only to the supply-chain but critically to manufacturers themselves. I think most speakers have spoken to the advantages of that.

Prof. Dr H. G. Kristensen: Do we have more comments from participants? Please don’t hesitate.

Mr G. Ritchie: I have a question. If there was an actionable item that you would like to see the EP, the USP, the FDA and the European Regulatory Agency move toward in quick order, what would it be, that in your mind would show a good faith and a good understanding of the concern of the industries relief, if you will?

Dr A. Hussain: Leave the regulators out - just talk about pharmacopoeias!

Mr G. Ritchie: Well, ok…

Dr A. Hussain: No, regulators are moving. We have the EUPAT team and FDAPAT team already!

Mr G. Ritchie: Understood! Then what would it be, in terms of the pharmacopoeia, other than the harmonisation, if there were some key things you would like to see as action items accomplished?

Prof. Dr H. G. Kristensen: OK Mr G. Ritchie you raised the question but got no answer and it doesn’t matter. What we have heard during this discussion is that the harmonisation of the methods, new initiatives are of the utmost importance.

I think the outcome of this discussion is that we should give priority the remove the barriers for the introduction of PAT in the pharmaceutical industry rather than give priority to new initiatives. The barriers, we have to identify them and I have to ask industry to give us the evidence, to give it to the pharmacopoeial discussion group hopefully when they meet next in Washington. What might the barriers be, let’s have a discussion of whether the pharmacopoeias can help to solve these.

On the Notice for Guidance mentioned by Dr C. Potter, we cannot do anything. It’s another place, but it will be a great help to have them identified. I had hoped that an outcome of this meeting would be the identification of some general methods, new general methods to be elaborated in the


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regime of PDG or international harmonisation. But it has been said strongly by Jean-Louis Robert and I think also supported by Dr A. Hussain that we should await the discussions and the first results of the work in the ICHQ8 and Q9.

There is a nomenclature issue, which of course will be taken up by Q8, maybe the pharmacopoeias can join the nomenclature discussion. We will have to await what to do with General Methods and we will have to await what to do with Revised General Methods and adaptation to the PAT. We had the discussions in PDG with the industrial organisations.

So immediately what will happen is that EDQM will make a report of this conference. They ask the speakers for the manuscripts to be sent to the EDQM as soon as possible. The slides and abstracts will be put on the EDQM web site, where you can find them. The report will be reported to the Pharmacopoeia Commission in June and of course there will be a discussion at this session also on how to proceed in this field. My recommendation to the Commission will be to have it discussed in the Pharmacopoeial discussion group and that initiatives should be started by the PDG, both on new General Methods and Revised Methods. On the general chapter on PAT I don’t know what the decision will be, but it is clearly under elaboration by the USP.

Before closing I will ask my colleagues here, if they have things to add.

Dr A. Hussain: I just want to thank you and the EDQM for a wonderful conference – very useful.

Mr G. Ritchie: I am delighted the USP was invited and hope that as we proceed forward that the barriers that do exist, the ones that have been identified and discussed, we can quickly address, maybe together.

Prof. H.G. Kristensen: We will do so.

So, I will close this meeting by thanking the speakers for their very very good contributions. You have heard it from many sides today that you did a good job and really made a contribution to our understanding of the role of the Pharmacopoeia and what needs to be done by the pharmacopoeias in this field. I will thank the audience for participating in this meeting and of course I thank the panel also for joining this discussion. Have a safe return back to your homes. Thank you.


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BIOGRAPHICAL NOTES

Dr Ron Belchamber graduated in Chemistry from Imperial College, London in 1975. He obtained his PhD in Analytical Chemistry from the University of Alberta, Canada in 1981. After doing postdoctoral work at the University of Swansea, Wales he spent 9 years at BP Research Centre as a Team Leader, specialising in process analysis. For the last 11 years he has been Managing Director of Process Analysis and Automation Ltd, Farnborough UK, his main area of interest is acoustic process measurements. Dr John C. Berridge is Vice President Pharmaceutical Sciences, Pfizer Global Research & Development at Sandwich, Kent, UK. He received his BSc in Chemistry and Maths from the University of Reading in 1971 and a PhD in Organic Photochemistry in 1975, also from Reading University. He joined Pfizer Central Research in 1974. His research interests have been directed towards high performance liquid chromatography, with special emphasis on the use of chemometrics to aid method development. Over 40 papers and a book have been published and this research has been recognised by the award of the Chromatographic Society’s Jubilee medal in 1989. More recently Dr. Berridge has been involved in the ICH processes, representing Europe in the Quality topics, initially in the development of the guidelines on impurities in drug substances and their dosage forms, more recently as Topic Leader for the Common Technical Document (Quality). At FIP’s 55th World Congress in Stockholm in 1995 he was presented with an IPS award for his outstanding contribution to industrial pharmacy and in September 1997 he was awarded the Royal Pharmaceutical Society Chiroscience award for his services to the pharmaceutical industry for his work within ICH. Mr Bob Chisholm is International Technology manager based in AstraZeneca Engineering in the UK. Bob graduated BSc (Hons) electrical and control systems engineering from Glasgow University in 1970 and joined the ICI then the worlds third largest chemical company. His career has spanned a number of ICI Businesses and he moved from the petrochemical division to the then ICI Pharmaceuticals division in 1989 to set up and manage the engineering science and technology development group. Bob initiated technology initiatives in the area of spectrometry, chemometrics and real time computing and this led to the adoption of such techniques, particularly Near Infra Red Analysis in Zeneca (the successor to ICI Pharmaceuticals) which merged with Astra two years later. The company sanctioned a potent tablet facility (PTF) in Germany in 1990 and Bob’s technology teams were responsible for the technical project management including the equipping of the facility with cradle to grave on-line NIR analysers ethernet networked via a server to a data management computer system, effectively the first fully equipped PAT facility in operation. The PTF will be submitted to regulatory authorities in 2004Q2. Ms. Fiona Clarke obtained her degree in Forensic and Analytical Chemistry from the Strathclyde University in Scotland. She studied for her PhD at the School of Pharmacy, University of London under the supervision of Prof.. Tony Moffat. Since 2001 she has been Manager of the Root Cause Analysis Team in Pfizer investigating production issues utilising novel technology, including NIR chemical imaging. Dr Ciro Cottini is Manufacturing Technology and PAT expert within Engineering department of GlaxoSmithKline Parma, Italy. He is graduate in Physics at Padua University with a thesis on bi-dimensional correlation algorithm for infrared spectroscopy. He joined GlaxoSmithKline 4 years ago working on computer and compliance validation department.


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Prof. Tom Fearn is a graduate of the Universities of Oxford and London in the UK. He obtained his PhD in Statistics from University College London in 1975. After 11 years working at the Flour Milling and Baking Research Association he returned in 1989 to University College London, where he is now Professor of Applied Statistics and Head of the Department of Statistical Science. Dr Gerd Fischer obtained his PhD in chemistry from the Johann Wolfgang Goethe-University in Frankfurt a.M (Germany) in 1983. He joined Hoechst AG (1997 – 2000 Hoechst Marion Roussel, after 2000 Aventis), Frankfurt a.M., in 1984 as laboratory manager and project leader in medicinal chemistry. In 1993 he joined API production as quality manager. From 1996 to 1998 Gerd Fischer was head fo the Quality Assurance Unti at Frankfurt API production site. Between 1998 and 2001 he lead Quality Operations (QA/QC) in API chemical production. From 2001 to 2003 he was responsible for Quality Management in Global Process Development. Since 2003 Gerd Fischer leads Strategic Initiative for Process Analytical Technologies in Aventis. Prof. Staffan Folestad, obtained his PhD. in Chemistry 1985 from the University of Göteborg. As an Associate Prof.essor he directed research activities comprising development of Capillary Separation Techniques, Laser-Based Spectroscopy and Ultra-Trace Analysis. At 1994 he joined AstraZeneca (ex Astra Hässle). As a Senior Principal Scientist he has been leading global R&D activities in Process Analytical Technology (PAT) during a decade. He is currently the Director for the AZ Center of Excellence for PAT where his research interests comprise development of advanced in-situ Process Sensors and in silico Process Modeling. Since 1999, he holds a part time position as Prof.essor in Analytical Chemistry at Uppsala University and is board member of the Center for Chemical Process Engineering at Chalmers University of Technology. Dr Sylvie Guyomard Devanlay, obtained her degree in Pharmacy from Paris V university in 1980 (France). She obtained her internship examination in Paris and a Post-Graduate Degree in Biological control in 1981. She worked as internship at hospital from 1981 to 1985. She obtained her pharmacist hospital examination in 1985. She obtained her Ph.D in Microbiology in 1988 (Paris). During the period from 1987 to 1990 she was hospital pharmacist at Ambroise Paré and Cochin hospitals in Paris. She joined Biowhittaker company from 1991 to 1992 as scientific consultant for Europe for LAL testing. In 1992, she was appointed by Rhone Poulenc Rorer as microbiologist assistant for Quality Control of Institute of Biopharmacy in Antony. She developed her career as world-wide director of microbiology in Pharmaceutical Quality analysis in 1999 with control and validation of new drugs for microbiological tests (sterility test, microbial limit test, challenge test, bacterial endotoxin test environmental monitoring and development of alternative methods in microbiology as the Chemscan system at Rhone Poulenc Rorer. Following the merge between Rhone Poulenc Rorer and Hoescht Marion Roussel companies, she is currently Head of Microbiology in Analytical Sciences department at Aventis Pharma in research center of Paris (Vitry sur seine). She was member of group 7 of the European Pharmacopoeia for microbiological assays of antibiotics from 1993 to 1998. Since 1998, she has been member of group 1 and since 2003, expert for France in the European Pharmacopoeia working group about Modern Methods in Microbiology. Dr Steve Hammond is Director of the Process Analytical Support Group, Pfizer Global Manufacturing Services, based in Sandwich, UK. Steve graduated from the Royal Institute Of Chemistry, London. His working career began as an analytical chemist in mining research with Anglo American Corporation, followed by three years with Unilever as an analyst in their perfumes division. In 1979 Dr Hammond joined Pfizer in the UK, working as an analytical chemist in the Fermentation Development Group, where he gained an interest in NIR spectroscopy.


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In 1988, Dr Hammond was asked to set-up and run a specialist Process Analytical Support Group for Pfizer Global Manufacturing. The group has the responsibility for developing and supporting the use of Process Analytical Technologies in all of Pfizer’s 80 manufacturing plants around the globe. Techniques developed for process analysis include NIR, Mid-IR, Raman, UV, Fluorescence, imaging, acoustics and microscopy. Dr Hammond has authored or co-authored many scientific publications on the pharmaceutical applications of NIR and contributed many oral presentations on this subject. More recently Steve has been part of a team of people pioneering the use of imaging for understanding the matrix formation of pharmaceutical formulations. Dr Ajaz Hussain currently serves as the Deputy Director of the Office of Pharmaceutical Science (OPS) in CDER, FDA. Prior to this appointment he served as the Director, Office of Testing and Research. He currently holds adjunct faculty appointments at the School of Pharmacy, Purdue University (Adjunct Prof.essor of Industrial Pharmacy) and School of Engineering, University of Michigan (Adjunct Prof.essor of Pharmaceutical Engineering). He is a Fellow of the American Association of Pharmaceutical Scientist. Prior to joining the FDA he served as Associate Prof.essor of Pharmaceutics at the University of Cincinnati. He trained at the Bombay College of Pharmacy (B.Pharm.) and received his Ph.D. degree in Biopharmaceutics from the University of Cincinnati. During his graduate education he was awarded the Merrell-Dow Scholarship to acquire Industrial Pharmacy training at the Merrell-Dow Research Institute. Dr Mats Josefson obtained his degree in chemistry and mathematics from Gothenburg University in Sweden (1978). He studied for his Ph. D. at the same university and obtained his Ph. D. in Chemistry (1983). During the period 1983-1984 he was research assistant at the Department of Analytical Chemistry, Gothenburg University. 1984-1985 he joined the NMR lab at Syracuse University as a postdoctoral fellow. He started to work for Astra in Mölndal 1985 and developed his career as spectroscopist and chemometrician. He is currently Associate Director at Pharmaceutical Analytical R&D, AstraZeneca R&D Mölndal, Sweden. Dr Chris Killen graduated in Chemistry in 1974 from the University of Bristol, England. He received his PhD. from the University of Bristol in 1978. He then took a position with Beecham Pharmaceutics as a Development Chemist in the Development Department in Worthing, England. He has held various positions in Beecham, SmithKline Beecham and now GlaxoSmithKline, in Worthing, England, and now at a GSK manufacturing site in Irvine, Scotland. Dr Killen now holds the position of Process Analytics Leader in the Antibiotics and Primary Supply network with responsibility for implementation of process analytics in API manufacture world-wide. Prof. Dr H. G. Kristensen obtained his degree in pharmacy from the Royal Danish School of Pharmacy, now The Danish University of Pharmaceutical Sciences. He received the PhD degree in 1968 and the DSc degree in 1981, both within the field of particle technology. In 2002, he was awarded Honoary Doctor at Uppsala University, Sweden. His field of research is the formulation, processing and quality control of oral solid dosage forms. He is Sectional Editor of the European Journal of Pharmaceutical Sciences. Prof.. Kristensen has been involved in pharmacopoeia work since 1976 where he became chair of the Danish Pharmacopoeia Commission and a member of the European Pharmacopoeia Commission. At present he has the chair of the European Pharmacopoeia Commission. He has previously chaired the Group of Experts on Dosage Forms and chaired several Working Parties, e.g. Standard Terms, Water qualities, Methods of Sterilisation and Inhalations.


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Mr Silvano Lonardi is Manufacturing Technology Champion in the Technology & Engineering Standards & Innovation Department with GlaxoSmithKline Operations, Parma and Verona sites, Italy. His experience spans more than 30 years with GSK where he held a range of technical management positions. He is currently a member of a number of Committees for the introduction of technological innovations in the pharmaceutical industry. In addition he is a regular contributor at symposia throughout Europe and the USA. Dr Ralf Marbach has the following qualifications: Electrical Engineering (MSEE) 1988 and Dr.-Ing. (PhD.) "Methods for the IR Spectroscopic Measurement of Blood Glucose" 1993 from the University of Dortmund, at the Institute for Spectrochemistry and Applied Spectroscopy (ISAS) in Dortmund, Germany. MBA from Indiana University of Pennsylvania 1997. From 1993 to 1999 in various technical and managerial positions in US biomedical companies, developing spectroscopic and imaging-based analytical instruments. Joined VTT Electronics in Oulu, Finland as Senior Scientist and Project Manager in 12/1999. Prof. Tony Moffat graduated in pharmacy (1965) followed by a PhD (1969) and Dsc (1984) degrees all from Chelsea College, University of London, England. During 1969 – 1970 he was Assistant Prof.essor at Baylor College of Medicine, USA. This was followed by 23 years in Forensic Science Service, England. Since 1994 he has been Chief Scientist at the Royal Pharmaceutical Society, London, England and Head of the Centre for Pharmaceutical Analysis at The School of Pharmacy, University of London. He is a member of the British Pharmacopoeia Commission. Dr Chris Potter graduated from Exeter University in UK with a degree in Chemistry, and obtained a PhD. from Imperial College, London University, UK in organic chemistry and biosynthesis. He worked for Beecham Pharmaceuticals as a formulation and analytical scientist from and moved to Sterling-Winthrop Research and Development from where he had management positions in analytical development and pharmaceutical development. Chris joined ICI Pharmaceuticals as Head of Analytical Development (UK), a position he held with Zeneca and AstraZeneca when he transferred to become Director of Project Management and Chemistry, Manufacturing and Control Documentation for a UK and a US site. Chris has been a member of EFPIA’s ad hoc Quality Group since 1996 and during this period was EFPIA topic leader for ICHQ6A, Specifications for new drug substances and new drug products. More recently, Chris is leader for EFPIA in the ICH part of pharmacopoeial harmonisation, ICH Q4.

Mr Gary Ritchie obtained his Bachelor of Arts in Biology and Masters of Science degrees from the University of Bridgeport in the United States in 1979 and 1982. He began his career in 1984 as an analytical chemist at Danbury Pharmacal, Inc./Schein Pharmaceutical Inc. In 1991, he took a position at Purdue Pharma LP. as a method development chemist. Also during this time as a principal scientist in the Pharmaceutical Analysis, New Technologies Group, he distinguished himself by establishing, under the sponsorship fo Purdue Pharma, L.P., and chairing an ad hoc committee known as the Near Infrared Validation Working Group (NIRVWoG). With the assistance of the Pharmaceutical Analytical Science Group (PASG) and the auspices of the Pharmaceutical Quality Research Institute (PQRI), he helped to revise and update the United States Pharmacopoeia General Chapter <1119> »Near-Infrared Spectrometry » which is now official in the USP. Since that time, he has extensively researched, published and presented on various topics and themes covering analytical methods, Chemometrics, as well as statistical issues related to the validation and implementation fo NIR methodologies for use in GMP environments.


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Mr G. Ritchie joined the United States Pharmacopeia (USP) in June of 2003 as Scientific Fellow for Process Analytical Technology (PAT) and liaison in the Information and Standards Development group. As the Scientific Fellow for PAT, Gary is responsible for assisting in the development and implementation of USP’s strategy for standard setting for PAT. In addition, he will act as a liaison for various general notices and information chapters. Mr G. Ritchie is the chairman of the ASTM E13.11 subcommittee on Chemometrics and is also a member of the newly created ASTM Committee E55 on Pharmaceutical Application of Process Analytical Technology. He is also a member of the American Chemical Society, the Society for Applied Spectroscopy, the Coblentz Society, and the Council for Near Infrared Spectroscopy, of which he is an associate editor. From 1999 to 2001, he served as secretary of the New York Section, Society for Applied Spectroscopy. Dr Jean-Louis Robert, PhD, is a chemist, head of the department « Service du Contrôle des Médicaments » (Department of Control of Medicines, an official medicine control laboratory) at the « Laboratoire National de Santé « (LNS)(National Health Laboratory) in Luxemborug. He obtained his diploma in chemistry and Ph.D from the University of Basle (CH) and a post-doctoral training at the Pharmaceutical Institute of « Eidgenössiche Technische Hochschule » (ETH) in Zurich (CH). He spent one year with a pharmaceutical company before joining the LNS. He is since 1995 a member of the Committee for Proprietary Medicinal Products (CPMP) at the European Medicines Evaluation Agency (EMEA) in London and Chairman fo the CPMP/CVMP Quality Working Party. Within the Internation Conference on Harmonization (ICH), he is rapporteur for the Guideline Validation of Analytical Procedures, EU-topic leader for the Common Technical Document-Quality (rapporteur for step 4 and the implementation working group) and rapporteur for the revision of the guidelines on impurities Q3A and Q3B. At the European Pharmacopoeia, he is a member of the group of experts 10 B (synthetic products). He serves as a pharmaceutical expert at WHO. Dr David Rudd graduated in 1973 from the University of Manchester in the UK. He then obtained his PhD at Imperial College, London under Prof. TS West in the field fo Analytical Chemistry. Initially, David worked for the Wellcome Foundation as a chromatographer before moving to Sterling-Winthrop R+D as Head of Analytical Method Development. He joined Glaxo Group Research in 1981 and has been involved in all aspects of pharmaceutical development since that time. David currently has responsibility for Process Analytical Technology within the Pharmaceutical Development Group of GlaxoSmithKline R+D and has been active in helping to develop regulatory guidance with FDA and EMEA. Dr Alistair Swanson graduated in 1980 from Glasgow University and obtained his D. Phil. in Physical Organic Chemistry in 1983 from the University of Oxford, UK. After a year as a Research Fellow at Cambridge University, he moved to the University of Leeds as a lecturer in Organic Chemistry. Alistair joined Pfizer at Sandwich, UK as an NMR spectroscopist in 1987, and has held a number of positions in both Discovery and Development. He is currently a Senior Director in Pharmaceutical Sciences, with responsibilities including progression of projects from Phase 2 to approval, and for the development and implementation of new analytical technologies. Dr Arne Torstensson obtained his PhD in Chemistry in 1982 from the University of Lund, Sweden. Ater a 1 year post doctoral visit at the Technical University of Denmark he joined AstraZeneca R&D Mölndal, Sweden. He is currently Associate Director for Product Analysis and taking part in the development of new products and corresponding quality controls. He is also member of the Analytical Chemistry Division of the Swedish Chemical Society.


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FINAL LIST OF PARTICIPANTS


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edqm pat proceedings, 2004

Documents

pat initiative

pat experiences

implementation of pat

pfizer uk

glaxosmithkline uk

msd uk

london uk

dr alistair swanson