ACHIEVING COST-EFFECTIVE MANUFACTURING IN A CHANGING OSD MARKET

Oral solid dosage– surviving in a new reality

FEBRUARY 2017

NEW

PH

ARM

A R

EALI

TY The world of pharmaceutical manufacturing is changing dramatically

In addition to developments in globalisation, increasing GMP demands and price pressure, pharma companies also face challenges regarding flexibility, time-to-market and cost on a day-to-day operational level.

A new playing field

Build your market footprintDEMAND / SUPPLYThe initial question you need to ask when plan-ning for a new product introduction or up-scale of capacity for an existing product is, “How do I make demand and supply meet each other while still keep-ing risk, cost and time schedule under control?”

The prime consideration in this regard is how fast you expect to – or need to – introduce the product to the market. This will also help you determine the capacity requirements for future production system. However, this demand forecast is often associated with high uncertainties about volume and timing.

RAMP-UP STRATEGYThe ramp-up strategy should take into consideration what it takes to 1) be ready for the first market introduction, which is typically at a low volume, and 2) ramp up to high volumes later. The associated capacity demand has to be established in a robust but still flexible way, supporting changes in timing and keeping both investment costs and operating costs low.

Part of building the ramp-up strategy is also to consider whether it should be a multi-product or sin-gle-product facility. In order to keep a high return of investment and utilise the capacity of the production system as optimally as possible, you should consider using the facility for producing more than one prod-uct. While, this might present challenges with regard to cleaning and cross-contamination, it is often worth the effort to evaluate the option in order to ensure a sound business case for de-selecting multi-purpose. Besides increasing the capacity utilisation, multi-prod-uct manufacturing will enable a larger organisation to operate the facility, which in turn will present bet-ter possibilities for obtaining critical mass and acquire more knowledge within the organisation.

MAKE / BUYBefore establishing new production capacity, we recommend that you look into the possibilities of using a partner/contract manufacturing organisation (CMO) for manufacturing the products. Especially for new product introductions it is relevant to evaluate if production capacity should be established in-house or through a CMO.

Parameters to consider:• What formulation technologies are required/possi-

ble considering the product profile? • Is formulation a differentiator? Does the formula-

tion make the product special compared to other products?

• Strategic fit – do you want to keep full control of all parts of the supply chain?

• Legal properties – what is the impact from IP rights, licenses and royalties?

• Cost – how are costs affected short and long term?

• Capability – do the required capabilities exist in-house or do the capabilities have to be built from scratch?

• Capacity – is the capacity sufficient? If not – what does it cost to establish sufficient capacity?

• Control strategy – are special technology platforms or process analysers (PAT) needed to control the product and process?

• Regulatory – what are the regulatory constraints related to using CMOs?

If outsourcing is preferred you need to initiate a sourcing process which includes identification of potential CMOs, evaluation and selection of a CMO (perhaps by dividing CMOs into CROs, clinical trials and commercial production).

CAPEX / OPEXIt is important to develop a business case which eval-uates investment cost and the operational cost to see if there is a positive net present value of the project. Further, it is obvious that the design of the future

Site agility: the key to your continued success

In pharma operations your timelines are shrinking. The only way for you to succeed is to operate with maximum site agility and flexibility. Your facilities need to handle changes in production demands and quality regulations fast and implement new knowl-edge and technology faster still.

facility will impact the operational cost meaning that when you make design decisions you also make significant decisions on the future operational cost.

Consider the following:• “If I spend 10% more on investment cost on cer-

tain options will I then reduce my cost of goods?”• “What will the cost of goods amount to for this

new product?”• “How can I ensure that the cost of goods is in

focus and optimised already in the design phase?”

It might be better to spend a little more on invest-ment cost if you end up with a lower total cost of goods. We address significant input for these evalu-ations later in this newspaper, as it often starts much earlier in the development process than expected. Further, the working process will include “design for LEAN” ensuring that no “waste” is designed into the facility by accident.

The cost of goods includes:• Raw materials• Staffing cost and salary• Energy and water consumption• Maintenance• Consumables and other expenditures• Depreciation

CAPEX / OPEX

Reduced Investment – a flexible concept that allows you to make only net investments and wait with expansion until you have established your market position.

70

60

50

40

30

20

10

01

Large ramp upIncremental ramp up

2 3 4 5 6 7 8 9 10

Sales forecast (high)Sales forecast (low)

Sales forecast (base)

Operational cost

Investment cost

RAMP UP STRATEGY

Oral Solid Dosage (OSD) manufacturers are facing pressure on all sides to make production more cost-effective. New high-potency drugs are launched every year, with innovative delivery platforms such as sustained release, sprays and chewing gum entering the market. At the same time, generic manufacturers are increasing production capacity, while there is a general shift to produce in emerging markets. Moreover, regulatory requirements and health, safety and environmental standards continue to grow.

Increasing demand and competition for oral solid dosage products force manufacturers to optimise productivity and cost-effectiveness. Fierce competi-tion is driven by a dramatic production increase, particularly in Asia, and by the generic drug sector, where manu-facturers increase production capacity taking over propriety products. New specialised drugs are introduced to the market, including high potency products, which put forward new and sophisticated production requirements.

More products equals new facility requirementsIn 2014, the FDA approved 41 novel drugs and biologics (including large as well as small molecules), which is the highest number in 18 years and a 52% increase from the 27 approved in 2013. In 2015, 45 drugs were approved, i.e. an additional 10% increase compared to 2014. EMA recommended 82 new products in 2014 (generics included) – compared to 79 in 2013 and 57 the year before. In 2015, EMA recommended 93 med-icines for marketing authorisation. This includes recommendations for 39 new active substances. More than 20% of these applications are forecast to be treatments for rare diseases. Today, traditional pharmaceuticals/small molecules/OSD products still make up approximately two thirds of all medical

products (by amount – not turnover).These products are typically produced in large, dedicated facilities, but as patents for these traditional products expire, and new, smaller volume products take their place, the need for large, single-production blockbuster facilities diminishes. More and more new multi-purpose facilities are built or old ones upgraded for multi-purpose

production in order to keep an accept-able efficiency.

With the advance of new, more spe-cialised products and an increase in the number of APIs that are highly potent (i.e. highly active pharmaceutical in-gredients or HAPIs), comes a need for high containment facilities, which can help to avoid cross contamination and ensure protection of operators and environment when HAPIs are used. The new trend within high contain-ment facilities is small-scale continuous manufacturing (or semi-continuous). Continuous manufacturing requires less space and supports efficiency and low cost of goods. Continuous manufacturing also enables a producer of highly potent drugs to manufacture these drugs in a safe way by eliminat-ing manual transfer steps (bin to bin). During the continuous manufacturing, the product is permanently under sur-veillance by process analysers to ensure a high level of process control.

FDA and EU GMP promotes contin-uous manufacturingEfficient technology transfer is becom-ing more and more important as the number of new products increases. These include transfers from:

1) lab to pilot scale and on to launch and large commercial scale

2) one large scale production plant to another

3) launch scale to low cost regions

With this in mind, NNE has developed an OSD design guide that enables all engineers participating in projects worldwide to work at the same high level to master projects across borders. This guideline ensures that we can help our customer build e.g. a facility in Asia with the same standard and level of expertise as in Europe. Project participants can call on expertise from various experts, specialist and SMEs from all over the world. If required, engineers in Asia can support projects in US or Europe and vice versa. This might be relevant if a ramp-up of resources is required but not possible to get locally. This way of working enables 24 hour engineering. All participants have the same access and the same documents to work with and use the same approach and method-ology.

This OSD design guide is based on a model facility, which is also an “off-the-shelf” offer for customers requir-ing a standard OSD operation estab-lished very fast. NNE has designed this facility to be compliant with current cGMP regulation related to FDA, EMA, PIC/S and CFDA guidelines.

Process developmentEfficient, state-of-the-art processes

CQA

Identity

Appearance

Assay

Impurity

CU

Low risk based on prior knowledgeMedium risk based on implemented controls

Dissolution

Materialinput

Blending Rollercompaction

Milling Lubrication Compression Coating

QTPP CPP, materialCQA, PI

Product and process development Process justification

Commercialcontrol strategy

Commercialmanufacturing

Control strategyDesign space,ranges

Scale-up andtech transferCQA PPQ

Control strategy updated to scale and include GMP controls Batch production

Define where and how to control CQAs by CPPs and using PIs

Establish manufacturing process, identify critical process parameters, material CQAs and other performance indicators

Scale and site independent and dependent CPPs, ranges

Process performance qualification

Establish multivariate derived ranges and acceptance criteria

Identify product critical quality attributes

Define the quality target product profile

UPDATED RISK ASSESSMENT AFTER IMPLEMENTATION OF THE COMMERCIAL CONTROL STRATEGY

CQA

Identity

Appearance

Assay

Impurity

CU

Low risk based on prior knowledgeMedium risk based on prior knowledge - should be considered furtherHigh risk based on prior knowledge or not known - must be investigated

Dissolution

Materialinput

Blending Roller compaction

Milling Lubrication Compression Coating

API

Blend LOD Particle size Analytical

CQAUDU /content uniformity

Process parametersManufacturing plant

Diluents

Sampling

Methods

API

MCC

API

Lactose

Operator

Temperature

Relative humidity

Training

Blender type

Number of revolutions

Order of addition

Loading

Speed

Other excipients

Less criticalMedium criticalExpected to be most critical

INITIAL RISK ASSESSMENT, CAUSE-EFFECT

ISHIKAWA DIAGRAMME

IDENTIFYING TRUE CPPS ENSURING CQAS MEET EXPECTATIONS

Quality by Design – understand and control your process betterOSD products, e.g. tablets and capsules, range from relatively simple immediate release to formulations for which the release of the API has been modified to match a predefined target product profile. In all cases, a robust formulation is best achieved by apply-ing a Quality by Design methodology which in its essence combines science- and risk-based approaches with a set of useful tools for efficient process development: Design of Experiments (DoE), multivariate modelling, mecha-nistic modeling and process analytical technologies (PAT). Timely application of these tools is key in establishing the relationship between attributes of the active ingredient, excipient function-ality, processing environment and the final drug product.

A systematic, science- and risk-based approachAs a first step, the product’s overall quality parameters are defined in the quality target product profile (QTPP), e.g. dosage form, dosage strength and release characteristics. In the next step, a cross-disciplinary team of experts identify the attributes of the product critical to the patient, CQAs (critical quality attributes) and influencing factors related to the raw materials (excipient-CQAs) and processing technology (critical process parame-ters; CPPs). Excipient-CQAs and CPPs are then ranked by criticality using quality risk management tools such as cause-effect diagrammes (traffic light), Ishikawa diagrammes, process hazard analysis (PHA), and failure mode effect

*The following reference describes how a company effectively uses prior knowl-edge to streamline the development of roller compacted tablet products: Allesø et al. Presenting a rational approach to QbD-based pharmaceutical development: A roller compaction case study. Eur. Pharm. Rev. 2013. 18(6). 17-24.

analysis (FMEA). Risk assessment is an iterative process, initially relying on prior knowledge* and then updated on a regular basis as new process knowledge is gained during develop-ment and later tech transfer. Process indicators (PIs) are also important to consider as they reveal the current state of the process in real-time using instrumentation often already installed in the process equipment. Through underlying mathematical models the PIs can suggest how to adjust the CPPs and, if relevant, the attributes of the raw materials, for the process to remain in a state of control (i.e. CQAs within acceptance criteria). Following the first sets of appropriately designed experimental campaigns, the design space or the multivariate-based ranges for the CPPs and/or material attributes are specified and from here the first control strategy is determined. The first control strategy is usually restricted to

Quality The control strategy effectively handles known variability in the raw materials thus ensuring robust processes and a consistent product quality.

Adapt to change The systematic methodology applied to process development, from its early stages to commercial scale, provides flexibility to predict and proactively handle raw material variability that might otherwise compromise drug product quality. Besides the obvious advantag-es to a commercially running process, this flexibility may also be valuable during drug development. For example, if the API route of synthesis is being optimised in parallel with the formulation development work, unusually high variability in particle size and morphol-ogy may be encountered. The QbD work already available may be used to predict and mitigate the impact of such changes on the processability of the formulation.

Process validation (PV) FDA’s guidance on process validation (2011) states that “a successful validation programme depends upon information and knowl-edge from product and process development”. Batches manufactured across the different scales: lab-scale, pilot-scale and commercial scale, shall no longer be handled as isolated tasks merely connected by a handover. A QbD methodology and the notion of “design to manufacture” supports this lifecycle PV concept. Tools from the QbD toolbox, like risk assessment and analysis of correlation patterns by e.g. chemometrics, can be used to link the information collected at various scales and provide true process understanding.

On-going (continued) process verification (OPV/CPV)

Both FDA and EMA require a monitoring programme to demonstrate that the process remains in a state of control. With the increased level of process understanding gained from the QbD approach, the criticality of the material attributes and process parameters are well understood, thus simplifying the setup of an OPV/CPV monitoring programme.

Ownership and collaboration

QbD is highly cross-disciplinary and the combined use of risk assessment and designed experiments enables the visualisation of often highly complex processes. This increases each team member’s feeling of ownership and makes it easier to understand and communi-cate – either holistically or in detail – the entire production process from raw materials to final product.

Maximising LEAN outcome

As a part of QbD-based product and process development, various attributes related to the formulation (e.g. lubrication content, gran-ule size) and CPPs have been explored and challenged as basis for selecting their optimal level(s). Maximising the process capability of the commercial process using LEAN principles is therefore not restricted by non-optimal settings on the process equipment fixed during development (e.g. inability to reach maximum press speed for tablet compression). QbD and LEAN combined is about “doing the right things right”.

BENEFITS OF QBD TO THE PHARMA INDUSTRY

Risk 1 .....

QBD

APP

ROA

CH

What to monitor and how to act?

Steering a process effectively, requires insight on: 1) which process indicators (PI) can be mon-itored in-line that predicts final product quality attributes (CQA) and 2) What to do when PIs are not where they should be – i.e. how to adjust critical process parameters (CPP). During process development you need to identify PIs and estab-lish relations between CQA and PI and between PI and CPP in order to make a control strategy.

lab and pilot scale and needs updating for tech transfer to commercial scale and local site conditions. The control strategies are essential outcomes of QbD, as they define if relevant param-eters are varied or fixed, in order to ensure that product quality (CQAs) is within specifications.

The QbD approach is encouraged by health authorities to ensure that processes remain in control, thereby minimising the risk of drug shortag-es and the impact it could have on patients.

Juggling investment versus manufacturing cost

The need for compliant and safe facilities, cou-pled with the growth in low-cost production from emerging markets, has made it critical for OSD manufacturers to find a balance between investment in modernisation and running costs. Automation of processes can eliminate

Continuous manufacturing

many of these risks and offset costs. This includes in-facility transport of product containers with automated guided vehicles (AGVs) and automated docking to process equipment with high containment.

Continuous processing can be the solution for new products. It brings benefits in production stability as well as in product control. Continuous processing is a perfect fit for small and medium size output products. Continuous processing also supports processes that require containment. As the process is closed from start of batch with automated weighing until the final tablet is ejected, no open or manual product transfer to other containers and units is required. Batch systems are usually much bigger and require more process rooms or square metres and the approx. room ratio is 1:4 m2 in favour for continuous. It reduces the GMP footprint as well as the space for technical area.

Batch production is typically suitable for large volume mono-productions or old existing products where re-register-ing or product development and new formulation would be too costly. Nevertheless, equipment manufactur-ers are currently developing contin-uous production equipment to also increase the size of the continuous lines and continuous thus might be possible for large volume production in the long run. Currently, systems

with up to 200 kg/hr are available but systems with estimated aimed batch size of 400 kg/hr are expected to reach the market soon.

NNE cooperates with leading suppliers for this technology and has a track record of supporting customers with this technology worldwide as well as supporting the equipment suppliers in further equipment development. This knowledge also enables us to provide our customers with extensive, reliable support when executing a project that involves continuous manufacturing lines. NNE can support you from the devel-opment of new products, industrial-isation of new formulations on this technology as well as feasibility study to handover of a turnkey solution in continuous manufacturing. Continu-ous systems are very compact, bring a high product reproducibility, demand less space compared to batch oper-ations and they require less support equipment, less intermediate handling and less intermediate storage in be-tween process steps.

Faster to market with continuous manufacturing developmentData shows that new products devel-oped using continuous manufacturing are “faster and cheaper to market” and consume less API for develop-ment (typically only 10% compared to a batch trial setup). Continuous manufacturing is probably the next major step in OSD manufacturing. The advantages listed below have driven several “big pharma” companies to invest in continuous processing:• Fully closed process • Small GMP footprint• Reduced tech area• Reduced intermediate storage space

and low inventory

• High automation level based on PAT and process modelling

• Low variability of products high yield• Low operating cost low capital cost• Faster time to market • Lower development costs (reduction

of quantity of API) • Reduced scale up between labs,

development and production scales• Flexibility in production/supply size

(by adjustment of manufacturing time)

• Consistent and high quality of drug products

• Increased process control with PAT (process analytical technology) is key when implementing continuous manufacturing

FLEX

IBIL

ITY

Modular engineer-ing equals fast-track projects, easy reuse and high flexibility

Establishing the right capacity in the right time is crucial, and one way to achieve this is to use a modular approach, where facility design is broken down into logical modules. This enables parallel activities, giving the project additional flexibility and making project changes more feasible.

Continuous Manufacturing line CONSIGMA from GEA (from weighing via, granulation, drying, sieving, blending, tablet compression)

Layout for a multi-purpose continuous manufacturing facility

Layout for a standard multi-purpose batch manufacturing facility

SuppliersNNE has a close relationship with many of the suppliers of OSD process and fill equipment. These relationships make it straightforward to design OSD facilities. During projects, these suppliers work hand in hand with our process and building engineers to deliver a successful project on both sides. NNE has executed projects that contained almost all existing OSD processes (storage, raw material check, powder/solids handling, dispensing, sifting, milling, dry and wet granulation in either high shear or low shear or fluid bed, extrusion, drying, coating, blend-ing, direct compression, roller compaction or compression tableting and packaging).

In the past years NNE has made projects together with the top tear sup-pliers, e.g. GEA, Glatt, Bosch, Anhydro/SPX, Fette, Korsch, GEA Courtoy, Waldner, DEC, Amixon and Lödige on almost all continents.

Standard OSD facilityNNE has developed a standard OSD facility design for a multi-purpose facility on the back of our many years of experience building OSD facilities worldwide. The OSD design guide supports a fast engineering approach and provides a standardised design document to design OSD facilities for NNE affiliates all over the world. Every project participant uses the same approach and design documents.

One major choice needs to be made before executing a design; do you want horizontal flow or vertical flow?The standard OSD facility shown here is based on a horizontal flow in spine concept (see layout multi-purpose batch manufacturing facility.) This design comprises the possibility of producing multiple products in a safe way compliant to all authority requirement. The design facilitates the possibility to upgrade later to use potent APIs by using a second barrier concept, here the PAL/MAL to minimise potential cross-contamination. This design enables a flexible process setup – also in the possible future extension.

Real time release testingOnce you have developed your process using a QbD approach and have a clear understanding of material, CQAs, CPPs and process indicators (PIs) and you have controls in place to ensure consistent product CQAs, it is possible to replace conventional end product testing by real time release testing (RTRT). At NNE, we have experience in:• establishing real-time end-point

determination of e.g. blending, granulation or drying processes using e.g. NIR spectroscopy

• establishing and getting design spaces verified and approved for flexible manufacturing

• establishing RTRT programmes where typical CQAs like identifica-tion, assay, uniformity of dosage units and dissolution are controlled during processing

This information can then replace con-

ventional QC testing results for batch evaluation and release.

For many CQAs – depending on the formulation and the specific process – typical process steps like blending, granulation (dry or wet), extrusion, drying, compression or coating are critical. In most cases you can control the CPPs and in-process material CQAs using simple sensors as process indicators (PIs) or more advanced process analysers and control loops. One example is blending: The process is controlled by NIR and is automated to stop once blending has reached its endpoint rather than after a certain time. Thereby you ensure blend ho-mogeneity, which is often very critical to both assay and content uniformity (CU) and uniformity of dosage units (UDU).

Dissolution is another example of

where heavy, time consuming QC test can be replaced by a mathematical for-mula and calculated even before the tablet is coated. During development of a fluid-bed granulation process, DoE was used to understand the correla-tion between tablet dissolution, CPPs and material CQAs and to establish a formula for calculation of dissolution. The granule particle size measured in real-time by laser diffraction, lubricant specific surface area, lubrication time and compression force were the vari-ables in this formula. The model was developed and the equation verified at commercial scale. It is now approved by health authorities and replaces routine QC testing of dissolution.

Today not only “big pharma” is imple-menting in-process controls and RTRT for their processes. Examples are seen both for new products – where PAT solutions often based on NIR, Raman

or laser diffraction and designed during the development phase – and for legacy products where historical data makes the foundation for optimisation of the control strategy to include PAT with or without RTRT.

Controlling a process in real time is often the biggest business driver. No matter the type of batch release, in-process testing provides the data and knowledge to ensure that the pro-cess remains in a state of control and minimises the risk of costly ‘surprises' during commercial manufacturing. For continuous processing, PAT and real time process control are necessary elements of the control strategy and the information from these controls can be used to not only control the process and trace the process but also for building an RTRT strategy.

FACILITY LAYOUTSDepending on the type of production (single-product production, batch pro-duction, continuous production) there are different layout scenarios. A layout usually reflects the demand of the facility with a 100% load in the future. Additionally, a layout/design take into account possible future expansion. These expansion possibilities can be foreseen at an early stage of planning. It can thus sometimes be essential to determine the production strategy of a facility. The production strategy – be it batch or continuous – is for example vertical product flow or horizontal flow. Sometimes horizontal flow is more compact and reduces your GMP footprint, if you choose the right pro-cess equipment. Expandability can be an interesting challenge if the ground the facility stands on is small and re-stricted. Then a vertical flow can be an advantage. NNE has an extensive track record of different types of facilities tailored to the need of customers and in compliance with cGMP, EHS, and all regulatory bodies. These facilities are built in Europe, Asia, North and South America and Africa.

The continuous line shown here en-ables the continuous manufacturing a product from weighing of raw material to the finished tablet or capsule. In this setup, with the diversion of product to tablet press or capsule machine, you can produce either tablets or capsules. Due to the continuous process, you cannot produce both formulations at the same time. For traditional batch manufacturing, we chose a spine concept. The advantages of this include easy access and easy extension to either the right or left side of the building. Additionally, we went with a second barrier concept to avoid cross contamination and increase the safety to avoid APIs and product migrating through the building. The shown PAL/MAL (personal/material air lock) setup here can be built either as a sink or bubble and is not considered as a GMP step change but as a secondary product safety barrier.

Containment HAPI

NNE is active participating in major pharma-ceutical associations and authority panels. We are first in line when new drafts, hand-books and guidelines are presented.

So when ISPE Affiliate Germany, Switzerland and Austria held a containment workshop in Bad Dürkheim, Germany and the new

When we deliver facility projects, we work based on a global engineering model, Our Model. This model ensures that everyone on our projects works with the same well-prov-en methods and best practices worldwide, and they are flexible enough to adapt to yours.

Flexible and reliablefacility projects– anywhere in theworld

NNE and ISPE containment workshop

CHEMICAL INHALATION RISK ASSESSMENT FOR HIGH POTENT PRODUCT

NNE has developed a tool to make a chemical risk assessment for high po-tent products. The tool enables to quickly make an inhalation risk assessment at different process steps where highly potent chemicals are used. It is part of an initial health, saftey and environment (HSE) evaluation if potent ingredi-ents have been identified. This tool has a background in a

Handling highly potent active pharmaceutical ingre-dients (HAPIs) in oral solid dosage (OSD) production accelerates the need to upgrade existing facilities or build new ones.

OSD API PRODUCTION SERVICES• Highly-potent API containment strategies• HAPI risk assessment• Definitions of information about hazardous and

other pharmaceutical processes• Necessary containment equipment solutions

Safety and regulatory compliance are key factors when dealing with highly potent APIs used for e.g. oncological dosage forms. The main challenge lies in protecting the production staff and the environment while also protecting the product from contamina-tion and complying with local regulations. NNE’s engineers provide expertise within GMP requirements and highly potent technology. We help you to design and construct facilities that produce highly potent OSD APIs in a safe and contained manner that com-plies with all local and international regulation and requirements. NNE has built multiple facilities in the past years that involve handling of potent material down to less than 30 ngr/m3 (OEB5) and has been involved in upgrades to bring existing facilities to a state-of-the-art level to ensure safe operations and avoid contamination and migration of highly potent API in a facility. Measures for required operator pro-tection mainly depend on:

• The danger of the product (OEL)• The physical characteristics of the product (liquid,

powder, tablet, etc) • The type of process (dispersive or not)• The amount of product handled

• The frequency of a task/process• The duration of task• The transmission path (skin, inhalation, etc)

Whichever type of protection and containment you go with, the selection must be the result of a detailed chemical risk assessment (room by room, process step by process step, by type of product, exposure time per operation, etc). Often the choice of equipment and control strategy is made by an interdisciplinary team with competences within pro-

cess, building, HVAC, utilities, waste. It is important to decide if future unknowns need to be considered as provisions to be implemented from the beginning. In addition to the “standard” containment task, NNE has executed projects where protection strategies for operators and environment against radiopharma-ceutical contamination was required. These projects are rare but have been executed to our customers’ highest satisfaction.

1) Only inhalation risk assessment is considered

chemical database that contains a collection of various potent APIS including their properties according to their material safety data sheets (MSDS). With the output of this tool, NNE can engineer the right solution to each process according to the occupational exposure limit (OEL) requirements.

OEL: OCCUPATIONAL EXPOSURE LIMITOEB: OPERATIONAL EXPOSURE BANDCAT: CATEGORY ACCORDING TO ISPE

G 1 / 1Very low pharmacolog-ical and toxic effect

EffectCAT / (OEB) OEL

< 1 µg/m3

1-10 µg/m3

10-100 µg/m3

100-1000 µg/m3

1000-5000 µg/m3

G 2 (2)Low pharmacological and toxic effect

G 3a (3)

Medium pharmacological and toxic effect

G 3b (4)High pharmacological and toxic effect

G 4 (5) Very high pharmacological and toxic effect

Risk assessment if anIsolator is necessaryfor open handling

ISPE Containment Handbook was released NNE was present. Only a few weeks after its release, it was clear that the industry con-sider this book as a guideline and as a new standard to be applied.

Maintaining high quality in the completion of a high potent OSD

CustomerRoche Shanghai, China

Facility/areaThe facility boasts 2,500 m2 produc-tion area distributed on 2 levels.

ChallengeTime pressure and a tight deadline

SolutionAgile and flexible engineering

Project durationAugust 2012 – 2015

Services providedPre-concept design, conceptual design, basic design and EMCMQ (en-gineering, procurement, construction management and qualification)

Roche’s OSD manufacturing facility in Shanghai plays an important role in strengthening the compa-ny’s pharma business. Under the management of NNE the project was completed within an ambi-tious deadline and to high quality standards.

Referred to as SHiP II – short for Shanghai High Potent plant II – this highly complex project aims to enhance Roche’s existing high potent production capacity. This is achieved by adding a new facility adjacent but connected to the existing high potent oral solid dosage manufacturing at the company’s site in Shanghai and improving the handling systems for higher operator safety.

One of the purposes of the SHiP II facility is to support other facilities at the site – especially in improving the adjacent SHiP I – through unified purified water and high potent waste

water system treatment. Additionally, to accommodate the customer’s future needs – and safeguard against risk – the design included a site storage facility with an explosion-proof room for components of the production.

A strategically important projectSHiP II is one of the initiatives in Roche’s 2018 master plan to develop its Shanghai site and the first fully integrated pharma hub in Asia Pacific. Hans Tanner, Head of project manage-ment China, explains the background for the project: “After a thorough analysis and feasibility study conducted during the Shanghai Site Master Plan-ning Initiative in Q2 2012, it was clear that we needed to build additional highly active production capacity for China and for global supply. All this comes under SHiP II.”

From the outset, it was a focal point to maintain high quality standards, while at the same time keeping to a

tight and fixed deadline in Q3 2015. This meant that the primary objective across every aspect of planning, design and construction was to maintain quality without losing momentum.

Working effectively across bordersThe project began more than 10,000 kilometres from Shanghai – in Basel, Switzerland – where the pre-concept was started in August 2012. NNE staffed the pre-concept with nine process engineers from Switzerland and four Chinese architects/engineers based in Shanghai. As the pre-con-cept was carried out in Europe, a key challenge was how to transfer this knowledge to China. Although time pressure was mounting, it was essen-tial to achieve this transfer smoothly and seamlessly without affecting the schedule or quality.

The design was transferred to China at the start of basic design (BD). The core members of the original European

team continued to provide support throughout the project and two European engineers were on site to support during the equipment installa-tion and qualification phases.

From the beginning, Roche put much focus on involving the users in order to optimise project solutions. Klaus Illum, Head of Project Governance at NNE elaborates, “Early planning of user involvement as well as early dedi-cated inspections by the user, made the transfer from project to user very smooth.”

Despite a number of challenges along the way, NNE was able to successfully complete the SHiP II project in early 2015. As a result of this achievement, NNE was awarded a new project at Roche’s campus, involving many of the SHiP II engineers who are leveraging their experiences and lessons learned from SHiP II in the new project.

Our pharma consultants are with you all the way from project idea through project execution to ramp-up and beyond. Through focused pharma engineering we help you obtain and maintain an optimal production so you can always deliver on demand.

End-to-end support from consultants specialised in pharma

Tech transferIn the attempt to continuously discover new products as well as next generation products, the industry is developing new product candidates at an accelerated rate.

In 2014, the FDA approved 41 novel drugs andbiologics (including large as well as small molecules),which is the highest number in 18 years and a 52%increase from the 27 approved in 2013. In 2015, 45 drugs were approved, i.e. an additional 10% increase compared to 2014. EMA recommended 82 new products in 2014 (generics included) – compared to 79 in 2013 and 57 the year before. In 2015, EMA recommended 93 medicines for marketing authorisa-tion. This includes recommendations for 39 new ac-tive substances. More than 20% of these applicationsare forecast to be treatments for rare diseases.

In addition to the increasing number of new approv-al, generic versions of major blockbuster products will likely become available in different markets in the near future due to patent expiry. Demographics and local market forces in emerging markets such as the public-private partnership models drive the business of promoting access to these products. This places emerging markets in a position to lead the way in the innovation of flexible, multipurpose and cost-effec-tive manufacturing.

The technology required for local manufacturing is often sourced from established technology providers that already have ongoing programmes for devel-oping and updating products. Ensuring successful technology transfer from these technology partners is crucial for a fast establishment of local pharmaceuti-cal manufacturing.

Pharmaceutical products can be highly complex and the notion that “the product is the process and the process is the product” is widely acknowledgedby the regulatory bodies. This underlines the impor-tance of product and process knowledge and project execution to support successful technology transferand market entry on time.

NNE was born and raised with the process and production understanding of a pharma-biotech company. Our global coverage coupled with our vast project experience has provided us with the compe-tences and know-how to execute on matters such as technology transfers and process qualification with great success. Technology transfers involve several cross-disciplinary elements ranging from GMP com-pliance, regulatory affairs and technical know-how as

well as human resources which may not be available in the existing organisation.

Thanks to our global presence, NNE can support your technology transfer by making an interdisciplinary team available covering several areas including:• GMP compliance• Regulatory demands• Product understanding• Technology and process knowledge• EHS compliance (e.g. containment)• Control strategy• Supplier evaluation• Supply chain management• Start-up of production and qualification• Project

“The goal of technology transfer activities is to transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realization. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach and ongoing continual improvement”

(ICH Q10)

TECHNOLOGY TRANSFER PLAYBOOK - LINKING BUSINESS NEEDS WITH PRODUCT UNDERSTANDING AND PROCESS KNOWLEDGE

Business

Product

Process

Quality and compliance NEW APPROACH TO PROCESS VALIDATION Process validation is not only a regulatory requirement, but also very good business. If you understand the process you can predict the outcome and ease optimisation of the process and product. Of course it also proves that the process is safe and effective. Process validation is about collecting and evaluating data from the process design stage through commercial pro-duction. The data establishes scientific evidence that a process is capable of consistently delivering quality products meeting its predetermined specifica-tion and quality attributes. Process validation of a product lifecycle can be divided in three stages as illustrated in figure 1. Ref. 1. US Food & Drug Adminis-tration, Guidance for Industry, PV: General Principles and Practices, guideline, 2011 and 2. EMA Guide-line on process validation for finished products, EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1.

In order to consistently deliver quality products and ensure the safety and efficacy of your products, quality must be built into the design and manufac-turing process at every step right from the beginning. This can only be done if process understanding is present.Process understanding is essential in supporting qualification and process validation activities. Process under-standing and proof of mitigation effec-tiveness can be achieved by applying Six Sigma tools such as Gage R&R studies of the measurement system and Design of experiment (DoE).

RISK-BASED APPROACHProcess understanding is directly linked to risk. Hence quality risk management play an important role as it aims to diminish the risk inherent in any phar-maceutical production.

NNE can help set directions and strat-egies for companies wishing to pursue

the implementation of science- and risk-based process validation for new and existing products.

WHERE TO START AND TIMING The new process validation approach applies to both new and legacy prod-ucts. For new products the process validation approach should be initiated already during development of the products. This may e.g. require addi-tional training and maybe even new resources.

For legacy products, stage 3 must be applied based on prior knowledge and a risk assessment must be established identifying critical quality attributes (CQA) and critical process parameters (CPP) for legacy products. Identifica-tion of a control strategy (simple or advanced) must be performed and the data obtained must be trended using statistical tools.

The question is where to start with legacy products? A good starting point is to make a priority list of all your legacy product, including justification of the priority.

FUTURE REQUIREMENTS – QUALITY METRICS FDA’s new quality metrics programme is supposed to be a tool to help plan-ning GMP Inspections.

• The objective is to measure the quality of a products or processes.

• Quality is the fitness for intended use of the product, relevant to patients and quality. It is a measure of a site’s ability to manufacture products fit for intended use. It is also an objective measure of the effectiveness including the pharmaceutical quality system.

TYPICAL CHALLENGES

• To learn about the new approach-es and to understand the impact on your organisation

• To learn how the new approach impacts development projects and legacy products

How can NNE help?• With a training programme

adjusted to your specific situation

• With a workshop which will kick off and deliver a process valida-tion strategy plan and identified list of deliverables

• With training and/or execution of risk assessment, statistics such as DoE and “stage 3” monitor-ing program.

• With training and education within process validation in gen-eral (e.g. ECA, ISPE, FDA).

• Objectiveness of systems associated with the manufacture of pharmaceutical products.

• Based on future quality metric reports, FDA will use a risk-based approach to plan inspections.

• The UK healthcare authorities are using a similar risk based approach to plan the frequency of GMP inspections.

• The proactive nature of the future will be based on science and risk, having the patient as the main focus. The regulation are changing to be more forward looking and to facility innovation.

Market

Target product profile

Facility and technology

1. Process designThe commercial process including the control strategy is defined based on knowledge gained through development and scale-up activities

3. Ongoing/continued process verificationOngoing assurance is gained during routine production and monitoring that the process remains in a state of control. 2. Process validation

The process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. It can be divided in two sub-stages: A) process validation design and qualification of the facility, utilities, equipment and processes and B) process performance qualification

Emerging markets represents the major growth engine of the global pharmaceutical industry with a high unmet demand and very little local manufacturing. To unlock this huge potential, you’ll have to look at the enablers and critical points in technology transfer.

A successful technology transfer has the end goal in mind from the beginning

FIGURE 1

Fill finishNNE masters all aspects of the fill finish world (blistering, wallets, bottles, sachets) and our track record for projects related to fill finish is impecca-ble: We have executed countless projects involving blistering ( plastic and aluminums), vial filling, blow fill seal, cartridges filling, bottle filling, inhaler devic-es, cartooning, boxing, wrapping and palleting. The

expertise is extensive and we manage projects in sterile, aseptic, containment and even nuclear environments. NNE has more than 50 specialists worldwide to support you with your task and challenges. We have strong relationships with all suppliers of fill finish equipment and cooperate closely with these suppliers to ensure that you project is a success.

Tianjin

Bangalore

Shanghai

CopenhagenKalundborg

Hillerød

Morrisville

Chartres

Basel

Lyon

Brussels

Montreux

Paris

Frankfurt

Offices

San Francisco

(Bad Homburg)

(Research Triangle Park)

(Emeryville)

Global reach – local knowledge

NNE is an international company specialised in pharma engineering. We help pharmaceutical companies bring products to market by providing flexible, compliant and future-proof solutions.

We have close to 2,000 professionals delivering global knowledge and best practices, all dedicated to supporting our customers globally and on local sites. Through focused pharma engineering we enable our customers to deliver on demand. NNE.com

Our oral solid dosage experts

Jacqueline VuGlobal Technology Partner

Jacqueline Vu has worked in international pharmaceutical engineering for more than 20 years. She has broad experience of working with feasibility and front-end studies as well as with conceptual design, detailed design, logistics and selection of material handling equipment and assistance to construction.

Jacqueline possesses extensive oral solid dosage (OSD) project experience with a particular focus on automated OSD plants (automating material handling systems, gravity flow, closed systems and OEE improvement).

Sven Oliver GottliebPrincipal Consultant

Oliver has worked with oral solid dosage (OSD) for more than 13 years. This includes project management, engineering and operational tasks within a phar-maceutical engineering company and a pharmaceutical company.

Oliver possesses extensive OSD project experience and has worked with feasibility and front-end studies as well as with con-ceptual design, detailed design to construction, troubleshooting and de-bottlenecking. He currently works in the process technology consulting group and offers consultancy services pertaining to OSD and containment. He is responsible for establishing the global OSD design guide that sets the global NNE standard for OSD facility design.

Morten AllesøSenior Consultant, PhD Morten has 7 years of experience in the pharmaceuticals industry and is a dedicated, results-driven oral solid dosage (OSD) expert with a Master’s degree in phar-maceutical sciences and a PhD in process analytical technology (PAT) for pharmaceutical applications.

Morten has practical experience of implementing Quality-by-De-sign (QbD) methodology in the development of new solid dose form products in order to improve effectiveness (“right the first time”) and efficiency (e.g. reducing time spent on early for-mulation development) and also in troubleshooting and improving performance of commercial tablet production.

Line Lundsberg-NielsenGlobal Technology Partner

Line Lundsberg-Nielsen is a physicist and has worked in the pharmaceutical industry for 20 years. She has a wide experience from both R&D and Manufactur-ing been working with science and risk based approaches such as Quality by Design, Process Analytical Technology and Process Validation.

Line has practical experience from developing, implementing and getting regulatory approval of a control strategy for an OSD based on PAT including NIR and with full Real Time Release Testing of the product. She is familiar with the regulatory pro-cesses used for CMC approval in both FDA and EMA and for lifecycle maintenance.