ipq international pharmaceutical quality

MONTHLY UPDATE - JANUARY/ FEBRUARY 2015

CMC/REVIEW & GMP/INSPECTION

• Allotrope Analytical Lab Data Standardization Effort Gaining Momentum with Better Analytical and ControlProcesses at Stake....................................................................................................................................................................................3

• Allotrope’s Vision of the Laboratory of the Future Aligns Closely with FDA’s Regulatory Objectives, SeniorIndustry Players Maintain...................................................................................................................................................................11

GMP/INSPECTION

• Comment Review, Public Meetings, Supply Chain Pilot to Follow 2014 Bolus of FDA DQSA Track & TraceGuidances...............................................................................................................................................................................................15

UNITED STATES

UPDATES IN BRIEF - p. 45

U.S CMC: • Commissioner Hamburg • CDER 2015 guidances • FDA guidance database • GDUFA comments • OGD Director Uhl • Biosimilar licensing • Biosimilar filgrastim • Biosimilar infliximab • OBP reshaping • Regulatory science symposium • USP elemental impuritiesU.S GMP: • Combination CGMPs • Compounding advisory meeting • Compounding guidances • Ipca import alert • Ranbaxy lawsuit • Med Prep indictment

EUROPE CMC: • Etanercept biosimilar • Generics assessment sharing • ICH Q3D • Searchable Eudralex • Type II variations • Electronic applications • Biosimilar plans • MHRA leadershipEUROPE GMP: • Annex 1 revision • GMP Chapters 3 & 5 • Drug ID • MHRA Orange/Green Guides • MHRA Wockhardt ban • MRHA on special manufacturers • China integrity findings • Verification organization

INTERNATIONAL CMC: • Nigeria lab accreditation • India pre-submission meetings • India on bioequivalence • Japan insulin biosimilar • Chinese Pharmacopeia lab • CFDA leader • IPEC change guide • Medicines Australia paper • Biosimilar naming in Australia INTERNATIONAL GMP: • Australian supply guidance • Canada Sri Krishna quarantine • CFDA inspections • GMP enforce-ment in India

INTERNATIONAL

CMC/REVIEW

• Asian Agencies Report on Progress in Addressing Emerging Regulatory Challenges at CASSS Biotech CMCStrategy Forum in Japan.......................................................................................................................................................................19

• Global Excipient Databases Are Advancing That Will Fill Content and Functionality Gaps in Existing RegulatoryEfforts and Further Industry/Regulator Communication.............................................................................................................33

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INTERNATIONAL PHARMACEUTICAL QUALITYInside the Global Regulatory Dialogue

VOL. 6, NO. 1

FDA WARNING LETTERS AND RECALLS POSTED IN JANUARY AND FEBRUARY - p. 51

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EDITOR’s NOTE: Welcome to IPQ’s “Monthly Update” on key CMC/GMP developments in the US, Europe, and internationally. The IPQ family of publications includes “The News in Depth” and”Updates in Brief” on our website as they occur, “Weekly News Alerts” sent via e-mail, and the “Monthly Update.” IPQ’s suite of offerings support our mission of helping readers understand, engage in and respond to the dialogue and developments around evolving and harmonizing the regulation of drug and biologic quality and manufacturing. Subscribers and license holders to IPQ have access to all of these sources of cutting-edge news and in-depth analysis as well as to the full IPQ archives. Visit IPQpubs.com for further information.

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MONTHLY UPDATE - JANUARY/ FEBRUARY 2015MONTHLY UPDATE - JANUARY/ FEBRUARY 2015 MONTHLY UPDATE - JANUARY/ FEBRUARY 2015

JANUARY/FEBRUARY 2015 � ......... ....

INSIDE THE GLOBAL REGULATORY DIALOGUE™

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Allotrope Analytical Lab Data Standardization Effort Gaining Momentum with Better Analytical and Control Processes at Stake

UNITED STATES

The industry-based Allotrope Foundation is picking up momentum in its ambitious effort to create a framework for standardizing and sharing lab data, with more effective analytical and manufacturing control processes at stake.

The drivers for the standardized data format that Allotrope is seeking to create include reduced lab data errors and waste, improved efficiency of data archiving and retrieval, analysts time savings, and better communications within and between labs and between pharma companies and their suppliers.

Allotrope – a “pre-collaboration consortium” of several major pharma companies and their vendors – has been moving rapidly forward with proof-of-concept applications. These have been confirming the feasibility of the consortium’s approach to producing a standardized format that captures analytical data and the associated metadata in a way that is instrument and vendor “agnostic” and allows lab systems to communicate.

The goal is to create an “interoperable, open-source laboratory information framework” that will provide significant industry-wide financial and innovative technical benefits in the lab data and information management arena.

The consortium is actively seeking additional companies to join in creating the framework. Allotrope members have: ● the ability to influence the scope, pace and direction of the work ● a potentially greater understanding of their internal needs relating to the collection, formatting and transmittal of data, and ● early insight on and an opportunity to leverage the deliverables.

Upcoming cross-industry workshops, open to all stakeholders, will take place on April 24, 2015 in Cambridge, MA, and on September 16, 2015, in Chicago, IL (see www.allotrope.org for more information on the workshops).

Allotrope Chartered by IQ Consortium

Allotrope grew out of a working group that was established by the International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium) in 2011 to focus on developing a common format for generating, storing, retrieving, transmitting, analyzing and archiving pharmaceutical analytical lab data and the reports generated from that data.

The IQ working group began with the problem statement that the absence of a common format impedes data exchange, data archiving, data re-analysis, custom data analysis, and data conversion from older to newer versions of software or between different software applications (IPQ “Monthly Update” June 2012, pp. 31-38).

At an Allotrope Foundation “cross-industry workshop” held in October 2014 at the Chicago law office of Drinker, Biddle and Reath – which is acting as the secretariat of the foundation – Amgen Analytical Research and Development Executive Director Janet Cheetham explained to IPQ that the working group format was not ideal for the project under consideration.

The working group members felt that a different, separate structure was needed to “fully explore the opportunity, to be focused on the outcome, and to really have the time commitment to manage all that is involved to make it happen,” Cheetham explained.

The response to the IQ group’s concerns was the formation of the Allotrope Foundation. The foundation structure was designed to facilitate company collaboration and allow the identification and engagement of Osthus, a Germany-based software firm that provides expert capabilities in the areas of coding, technical and project leadership regarding data standards, and systems integration.

Shared Resources and Iterative Development Key

Key to the ability of Allotrope to move quickly in accomplishing its goals, Cheetham explained, has been: ● using an iterative development model ● sharing resources such that no one company has excessive time commitments, and ● having an aggressive time frame for completion with a focus on a common goal.

“Because the foundation in its first iteration has a lifetime of three development years,” Cheetham commented, “it means it is not distracted. Staying focused on scope and on execution against the aspiration is a critical component – not just of the mission and the operational model of how we work together, but also getting as far as we are getting as quickly as we are.”

For example, implementation of the first proof

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of concept project – a virtual machine around instrument integration of HPLCs – required a “very small resource for a very small period of time” to put in place, initially at Amgen and then at Eisai, she said.

“I think for these projects it is very important, in times when resources are critically sparse for all of us, that we are able to do this adjunct iterative development in a way that does not represent a huge resource cost and burden to the company.”

Using an iterative development model – a “learn by doing” approach – allows company participation with a minimum of resources. Using this model, goals can be accomplished “within weeks rather than months.”

Another important component is the diversity of subject matter experts that the foundation “crowd-sources” from the individual companies, she pointed out. “We have a very dedicated core group that works through the overall framework strategy. But at any one time we can quickly reach out to others in a very focused way.”

While the projects are taking place across multiple companies, geographies, and disciplines, “the team works as a collective

unit,” Cheetham commented.

The agility and rapid progress that Allotrope is displaying, the Amgen official maintained, is driven in part by the members’ recognition of the need for the data standards as well as the other benefits that may be realized.

Common Format Facilitates Data Mining

The difficulty of mining data across multiple systems that do not talk to each other and the business implications of missing or erroneous data are among the problems that the Allotrope effort aims to help solve.

In a presentation at the annual IFPAC conference on process technologies in late January in Arlington, Virginia, Boehringer Ingelheim Highly Distinguished Research Fellow Terry Tougas delved into the problems that Allotrope is working to solve, the solutions being proposed, and the foundation’s goals and accomplishments. [His complete remarks at IFPAC are included below.]

The problem, Tougas summarized, is that we have all of these computerized analytical systems, but they use different formats and standards and cannot talk to each other.

AMGEN’S JANET CHEETHAM ON THE NEED FOR THE ALLOTROPE FRAMEWORK

Addressing the Allotrope meeting in Chicago in October, Amgen Analytical Research and Development Ex-ecutive Director Janet Cheetham gave her perspective on the need for the work Allotrope is doing and the costs of not doing it.

Well, what is the cost of not doing this? The cost of not doing this is multiple. The cost is losing talent from our industries because they are going to go to those places where they can work in the way that they want to. Our staff are mobile. They want to be able to take their creative ideas and they want to implement them today. They do not want to wait until tomorrow.

We have a society that is impatient to derive different ways of doing things. And yet the barrier to doing it is ‘well, if you want to implement that new technology, I will see you in two or three months. This is the price for doing it. By the way, if you want to do validation, come back in a year.’ And so immediately people then stop trying those types of things.

The other thing that I think is really important about the cost of not doing it now is at some point we will have to do this. Look at what happened with standards coming in the safety and pharmacovigilance arena. So the standards will come, because at some point they will be required.

There are two options: ● One is to be part of shaping and enabling them and having them work for us. ● The other is simply to wait for them to come in the mail and then understand how much it is going to cost you to implement them, and how much productivity it is going to take out of your business. Then you are stuck.

There is an urgency and an opportunity through working together to keep ourselves focused on the future. How far that future goes is really up to us collectively as a group, to kind of continue to crowd source…and brainstorm around common problems, common issues, and come up with solutions that will work for all of us, and being able to get them faster. Working together, we can get there faster, and we can get there with a better outcome.




“Practically every single instrument has its own native file format that you cannot do much with other than through that system,” he commented. The goal is to “fix the root cause” and produce one standard format that can be used across multiple systems and vendors – the “allotrope data format” (ADF). He likened the advantages of a common format to the mp3 standard for music or the jpeg format for images.

“That is the kind of structure that we are talking about,” Tougas explained: “A file that contains the ‘raw data’ as well as the relevant metadata that goes along with it so that you can do something with that file, whether you are doing something in the system that created it or some other system” – for example, one that has better analytical capabilities.

“I am a photographer,” he commented. “So I like to take those jpegs and pull them into Lightroom or something else and manipulate them. I can do that because there are standard file formats. That is the meat of the huge things we are proposing.”

When files are in myriad formats and spread across multiple systems, the potential for lost or erroneous data creates business as well as compliance risks.

“We spend a lot of money getting information,” Tougas

emphasized, “and a lot of times we cannot find it again once we are done with it. Or, even worse, a lot of times – and I think there is good solid information on this – we repeat experiments that we have done before because it is easier to do that than to find the original data.”

Allotrope is also working to create a standard vocabulary to enable efficient searching and retrieval of data.

Data entry needs to be standardized and controlled, for example by using a pull-down menu of agreed-to terms, Tougas commented, stressing that a word search through a data archive would be facilitated if common terms were used.

Allotrope sees its efforts resulting in improved regulatory compliance and data integrity by: ● allowing for the automated creation of documents and reports ● eliminating data errors that can happen from transcription ● ensuring that information requested during regulatory inspections is available rapidly ● decreasing the chance of lost data, and ● facilitating instrument validation. [Editor’s Note: HowAllotrope’s efforts will support regulatory compliance is explored further on pp. 11-14.]

BI’S TERRY TOUGAS ON THE ALLOTROPE PROJECT AND ITS GOALS

In a presentation at the annual IFPAC conference in late January in Arlington, Virginia, Boehringer-Ingelheim Highly Distinguished Research Fellow Terry Tougas explained how the consortium works, the problems that Allotrope is working to solve, the solutions being proposed, and the foundation’s goals and accomplish-ments.

Let me first of all describe what the composition of this foundation is: It is a consortium. It is what we are referring to these days as a ‘consortium of pharmaceutical companies in a pre-collaboration space.’

It is really composed primarily of a set of pharmaceutical companies. The current members are those listed here (see box at right). So you can see that it is a pretty good group of the industry.

Because it is a consortium of pharmaceutical companies we need to keep ourselves out of trouble. That means that we need to have at least some legal support. In our case this comes from Drinker, Biddle and Reath, which is a law firm here in DC. The unique part of that particular law firm is that they also provide us with a lot of what I would call project management support in this effort.

As I will describe for us here, this is really about data management and data standardization. The




consortium has engaged a software development firm, Osthus, who we have been working with very closely and has been an integral part of this whole effort.

The last piece of this that is also critically important is what we call our partner network: This is really the vendors of the analytical instrumentation that we have been trying to engage. These are, at the moment, the formal members of that network. There are a few more on the way, we hope. I think they are getting close to joining. So again, this is a network that spans not only the end users of the analytical instrumentation, but the vendors that supply it to us.

As far as the foundation is concerned, it actually grew out of a working group that started in the IQ Consortium, the co-sponsor of this session. It got to a point where we really needed to break this effort out as its own separate entity because of its size and the scope of the effort itself.

The Problem

So what is the problem that we are trying to solve here? It is really around the fact that we have all of these analytical systems. They are all computerized. But in essence, nobody talks to anybody else, in that we have all of these different formats and standards.

It is really around this notion that, number one, it is hard to find data based on sort of intuitive starting points and search criteria. It is hard to share and compare and integrate data from different labs and instruments because of all the different file formats. It is hard to analyze or mine a collection of data across different systems. And we have difficulty understanding and interpreting data later because of the context that is incomplete and inconsistent.

There are also other efficiency opportunities there as well. For example, we require our analysts to spend a lot of time entering information that is really inefficient and a waste of time, and often involves paper or some other media that is not conducive. That is really in a nutshell kind of the problem that we are trying to solve.

I think if you think about this, although this is from the perspective of the analytical laboratory, I think a lot of these things you can begin to translate into the process analytical world. It is not that far removed in terms of these pain points.

You may have your own list that is a little bit different from this (see box below). But I think this list sort of captures what certainly we see are many of the pain points that are associated with the fact that our systems do not talk to each other and are not standardized. It is on the documentation preparation side. It is on the archiving and data management side. It is on just the sheer opportunities there are for human errors in terms of data entry.

Certainly the notion of extracting data and the silos that are created by the instruments, and the fact that software does not communicate well with each other [are issues]. Certainly there are pain points around the exchange of data.

And then finally, the regulatory compliance effort is certainly huge with the way that we do this today. The efforts that we put into validating instruments today, and will have to do it again two years later when there is a major update in the software, is to me one of the big pain points that this effort potentially solves.

Looking at the root cause of the problem – incompatible, incomplete software, no standard file formats, and inconsistent metadata – those three elements are really what drives a lot of our efforts.

The absence of standards in the current laboratory environment are often spread over multiple sources. So again, this idea of no standard for file format: Practically every single instrument has its own native file format that you cannot do much with other than through that system.

On the metadata side of it, within a company, among companies, there is a not a lot of standardization of the terms we use. We might use IR fingerprinting to describe a test one time, and IR the next time. And when we start to get into searching, that becomes problematic. That is the bit about the language and library piece of this.




And then finally, it is this notion that it is very hard to exchange information between different platforms. In essence, there is a brick wall between most things. We have an application or something coming out of one system, and I would like to get it into another system or application, but to do that I have to build some kind of decoder to get from one to the other. I cannot do that for the hundreds of systems we have operating. So I have to do that conversion, that transcription in some way. And it just becomes completely impractical from an IT perspective to generate all these translators.

The Proposed Solution

So this really then starts to describe what Allotrope sees as the solution to this problem. Again here are our causes and our effects. What we would argue is that rather than try to band-aid all of these effects by doing things like pre-translators, that we really ought to fix the root causes, which are around these three major areas: ● having some kind of reusable software components that can talk to each other ● having some kind of an open document data standard, and ● finally having some kind of open metadata repository or library of terms.

We see that as then opening up the possibility of reaping these benefits that are truly economic and time benefits to all of us. We want to be able to do things like: ● automate the creation of documents and reports ● eliminate data errors that can happen from transcription ● improve the whole compliance effort, because you can get things quickly in front of an inspector, and ● not lose data in the system somewhere.

So what are we creating and what does it all have (see box on the next page)?

With respect to that first box, what we really envision is the ‘allotrope data format’ – that is what the ‘adf’ stands for. The concept is a standard file format that can capture analytical data as well as the metadata that goes along with it.

I think the best analogy or couple of analogies here are in our private lives. Think about something like an mp3 for music, or a jpeg for images. That is the kind of structure that we are talking about – a file that contains the ‘raw data’ as well as the relevant metadata that goes along with it, so that you can do something with that file, whether you are doing something that in the system that created it or some other system that you like to use that is better at doing whatever, like analyzing.

I am a photographer. So I like to take those jpegs and pull them into Lightroom or something else and manipulate them. I can do that because there are standard file formats. That is the meat of the huge things we are proposing.

Common Costs & Limitations in Data Lifecyclewith downstream effects well beyond the ‘analytical lab’

Document Preparation

• Difficulty finding data• Copy/paste• Transcribe/convert• Difficulty combining

multiple sources

Extracting Knowledge &Value from Data

• Impeded speed toanswer/decision

• Data silos• Constrained innovation• Limited data mining &

analytics

Limited Data Exchange

• Disparatedata fileformats

• Manual transcriptions• Added cost & complexity

to CROs, CMOs,partnerships

Data Management &Archiving Cost & Complexity

• Searching/Finding data ishard

• Data format conversion• Data migration• Maintenance and/or

unavailability of legacysystems

Errors

• Manual text entry ortranscription

• Manual calculations• Missing, inaccurate

metadata• Need to reprocess data

Regulatory ComplianceEffort

• Instrument & so�warevalidation

• SOPs• System documentation• Supporting

questions/investigations




We need to control vocabulary. Again, I think this is sort of obvious. We need to set up systems where not only do you standardize the nomenclature that you are using, but you enforce it in some way. In other words, you do not have analysts typing in that description. They have to pull it from a list and they can only pull those terms.

Then finally some sort of a toolkit: We call this a toolkit, but essentially it is applications that can be reused in different environments that are agnostic to the particular vendor system that will allow you to do this exchange of information between those applications.

These are the kinds of unit operations that we typically deal with in the laboratory (see “process steps” in box on the next page).

Now it is a little different for you guys when we talk about process analytical technology, but many of these boxes exist in that world as well – they are just in a slightly different form.

To illustrate what we are talking about coming in: At each of these steps we are generating information – metadata or data itself, once you get to the later steps here. So that is the piece here that really relates to this standard file format and the metadata connected with it. That is the toolkit. It enables interoperability between systems and requests.

Rather than call this an exercise in creating a standard, we have talked about it in the context of a framework. Because it is not really just one standard, it is multiple pieces.

Accomplishments and Goals

I am going to spend a few minutes talking about what our goals are and where we are with this. We have estimated three years to complete this from the start of the real work. Year one the goal was to establish the technical feasibility of all these concepts. And basically that is what we have done in 2014. We have concentrated on projects that we have

What is Allotrope Creating?

Metadatarepository

Allotrope Foundation FrameworkReusable Software

Components

Open Document Standard

Open Metadata

Repository

Application 1 Application 2New

Instrument

Instrument

.drdd .etc.etc

.etc

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.etc

.etc

.e.tccsv

.mz ML

.etc

.etc

.tbl.etc

.dat

.HDF

.raw

.DAML

.LCD

.XML.jdx

.irf .pdid.asc.cdf.frx

.adf

The set of standardsusedbased on our requirements

With the Metadata Repository

The core of thecontrolled vocabulary

A toolkit that enables use of the standards & metadata in so�ware

development

Project Test InstrumentAF 0012354 IR Fingerprinting QC Lab #33B 380 FT-IRAE0012764 Bulk & Tapped Density ASTM Standard Seive #6

AF 12989 NMR Characteriza�on AM500Tapped & Bulk Density Sieve XXX

AF0045674 Caractérisation RMN Nouvelle DRX600AF-0034558 IR iS10 FT-IR

Project Test InstrumentAF0012354 IR Fingerprinting 380 FTIR/-SN/145453AF0012764 Bulk and Tapped Density ASTM Sieve-SN/3452AF0012989 NMR Characterization AM500-SN/0034578AF0013142 Bulk and Tapped Density ASTM Sieve-SN/09783AF0045674 NMR Characterization DRX600-SN/10234567AF0034558 IR Fingerprinting iS10 FTIR/-SN/341980




called proof of concept [PoC] applications.

One of these was the instrument software integration PoC, where we demonstrated that we can create those toolbox pieces that are vendor agnostic. We have created files, in this case, that have instructions to control the instrument, and it really does not matter whether it is Agilent, Waters, or what brand of LC.

The next one captures the contextual workflow metadata. We have essentially created that mechanism. We see this as the first example of a mechanism to control the vocabulary for context, and feed that context through the workflow and capture it in a data file. So we have what I would call a prototype data standard format and demonstrated the ability to do that.

The last piece, the archive PoC, is the first example of an archive based on these open standards where the metadata can be extracted from the files and automatically assigned a retention time.

Year one we are done with at this point. It got done essentially ahead of schedule. We are about three months ahead of schedule in terms of completing the feasibility studies.

The second phase of it, which is where we are today, is really the member companies creating internal pilot projects to leverage the framework. The idea is that we want to develop this framework and standard, not as one big entity that everybody spends ten years trying to decide on, but rather by iteratively doing it by actually doing projects, seeing the results, seeing how well they work, and incorporating the aspects of that.

In this case, we are involved in a number of these pilot projects that have to conform to the standard idea of what we are talking about with this framework, but they are allowed to go and actually implement these things. The companies work with us and our software designer to actually implement the project. Most of that project will be available to all of the members of the consortium. There obviously will still be some elements that may be proprietary to that arrangement of companies or individual companies, but the agreements that are reached ahead of time are that most of that work becomes exchangeable among the entire foundation.

The Basic Analytical Workflow and Data Flow Standardized

Store,ArchiveData

Request ReportSearch

& ReuseData

Stored Data

Data &Metadata

Process Step

Legend

Standard data file format & metadata

Control Inst.Acquire

DataProcess

DataAnalyze

Data

More automated repor�ng,Interoperability Powerful searching

Method Data Instructions Data Data Data Results

Plan Analysis

Prepare Samples

SubmitSamples

Control Inst.Acquire

Data

Process Data

AnalyzeData

Report Results


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We expect real projects will accelerate the development of the framework through 2016. By then the intent is to really be able to talk about this as a real framework at that point.

So in terms of what you guys are probably interested in, we have more recently gotten started on that. The kick-off of considering process analytical chemistry came with a meeting in October of last year where we had thirty-three attendees representing member companies – the partner network – and a couple of folks that were interested in it from the outside, really to explore the possibility of proof of concepts that relate to process analytical chemistry.

Out of that, at this point there are two projects that have been initiated that are basically still, I think, in the development stage. Project one is a Pfizer project that deals with what is called ‘early integration’ – merging offline analytical data with online data, aligning timestamps to pull out visualization, etc. The second project initiated by GSK is around design space verification. This, as I understand it, is kind of a toolkit to enable design space types of experiments and information.

Closing Thoughts

So I guess this is where I sort of put out the sales pitch: The train is moving. We would love to have more people involved, both vendors and companies. That is the message I want you to take back from this slide.

Then just a couple of comments here on what we call community engagement. The partner network that I talked about earlier was actually formed in early 2014. It is designed to gain input from the vendors. There is a certain autonomy there that we are allowing such that they meet almost as a subgroup within our organization. They have their own part of the website. They are well involved in the scoping of these projects and we really encourage the vendors. This is critical to it as well.

We are, in essence, coming to the vendors and saying that we collectively as customers need this fix, but we cannot do without the cooperation of the vendors. I think as you sort of look at this problem, you begin to realize that there are economic advantages for the vendors to solve these problems as well.

We have also been very concerned with regulatory aspects of this. We spent a lot of time thinking about, in particular, what FDA has said on the topic of data standards and data strategies. We have had some discussions in at least two meetings with FDA on the topics. They are well aware of what we are doing in Allotrope. They are not what I would call directly involved in the effort, but they certainly are well aware of it and understand what we are trying to do (see the story on pp. 11-14).

The potential value of our analytical data is decreased by the problems of access and complexity we face. I think what we mean by that is we spend a lot of money getting that information, and a lot of times we cannot find it again once we are done with it. Or, even worse, a lot of times – and I think there is good solid information on this – we repeat experiments that we have done before because it is easier to do that than to find the original data.

There is a value there that we are really trying to preserve and build on with this effort. Again, the next time you cannot find data, or you might have to find someone else who understands what was done, and sort of face this effort of trying to locate things that are inaccessible because of the nature of your systems, we would like you to really think that at least we have got a better proposal here for how to do something about this.

It is not an easy task, but we think we have a viable solution to this. We think this is a tractable solution. The shared costs…in building this framework [are] significantly lower than doing it on your own. I think this is a prime example of the concept of pre-competitive collaboration. It does none of us a real benefit to try to do this on our own. This is something that has to get solved across the entire industry and regulatory environment for it really to work and to make it economically feasible to attack this problem.

I think we have an excellent group of companies that are really enthusiastic about this, and we encourage more to join. We certainly have a really powerful collection of industry experts in this area that are attacking this. It is a large effort under way.

4th

INTERNATIONAL SYMPOSIUM ON HIGHER ORDER STRUCTURE OF PROTEIN THERAPEUTICS

Symposium Co-Chairs:Linda Narhi, Amgen, Inc.Jamie Moore, Genentech, a Member of the Roche Group

ABSTRACT SUBMISSION DEADLINE:January 16, 2015 oral presentationMarch 13, 2015 poster presentation

April 13-15, 2015 Courtyard Boston DowntownBoston, MA

SCANto browseCASSS forprogram

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Allotrope’s Vision of the Laboratory of the Future Aligns Closely with FDA’s Regulatory Objectives, Senior Industry Players MaintainThe effort of the Allotrope Foundation to create a common lab data format that is instrument and vendor “agnostic,” allowing for more efficient and compliant analytical and manufacturing control processes, aligns closely with FDA’s lab regulatory objectives, senior industry players involved are stressing.

How the foundation’s effort to create a framework in which analytical data can be readily communicated aligns with the concerns on FDA’s front burner in its review of lab data and practices has been explained by its members at recent public forums.

At an Allotrope “cross-industry workshop” held in October 2014 at the Chicago law office of Drinker, Biddle and Reath, which is acting as the secretariat of the foundation, Bristol-Myers Squibb (BMS) Associate Director of Cheminformatics Dana Vanderwall discussed the alignment of the Allotrope effort with the data standards vision of FDA’s Center for Drug Evaluation and Research (CDER).

He referenced a data standards “vision document” on the CDER website and pointed out that what Allotrope is striving for “fits very much within the long-term vision that FDA has articulated.”

The 2012 CDER “Data Standards Strategy” white paper states that “the vision for CDER’s data standards program is to create an environment where regulatory data and submission information are based on common standards, are available electronically, and available to support advanced analytics to better inform regulatory decisions to improve public health” (link provided below).

Also included in the paper is a discussion of some key elements of data standards, including exchange transport format, analysis, and terminology – areas where the Allotrope effort is “directly aligned with the direction that FDA is headed,” Vanderwall maintained.

He further noted that while the agency has put resources into a number of these areas regarding standards, “when it comes specifically to CMC, there is sort of a note that that is not currently prioritized due to resource limitations.”

The BMS exec commented that the timing of the Allotrope project and the alignment with CDER’s data standards vision creates a “unique opportunity.”

“The desire is there,” he asserted. “There is alignment with the vision. And there is an opportunity to actually feed into

that directly as opposed to getting it in the mail.”

Vanderwall explained that there are “ongoing conversations” with the agency. “At this point they have a strong interest in staying engaged. It is a matter of helping them find the opportunities and the resources to engage more deeply.”

Industry/Regulator “Win-Win”

Allotrope sees its efforts resulting in improved regulatory compliance and data integrity by: ● allowing for the automated creation of documents and reports ● eliminating data errors that can happen from transcription ● ensuring that information requested during regulatory inspections is available rapidly ● decreasing the chance of lost data, and ● facilitating instrument validation.

At the October Allotrope workshop, Amgen Analytical Research and Development Executive Director Janet Cheetham noted that findings of data integrity in FDA 483s and warning letters creates “a common sense of urgency” in needing to address the problem and “very good alignment in the dialogue around how this will, for any individual company, reduce the compliance risk, or the cost of being compliant.”

The Amgen lab expert maintained that with standards and a framework in place it is “easier and more efficient” to develop an audit or inspection program than in the current system, which has multiple standards and “no consistency in the meta-data and how it ends up being published in your regulatory filings and used in your manufacturing sites and operations. So there is a win-win.”

FDA and Industry Lab “Pain Points” Overlap

Also emphasizing the relationship between the Allotrope Foundation effort and improved regulatory compliance was Boehringer Ingelheim Distinguished Research Fellow Terry Tougas in a presentation he gave on Allotrope at the IFPAC annual conference on process technology in late January. [Editor’s Note: Tougas’ full remarks at the conference are provided on pp. 5-10.]

“The efforts that we put into validating instruments today, and will have to do again two years later when there is a major update in the software, is to me one of the big pain points that this effort potentially solves.”

Incompatible and incomplete software, lack of


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standard file formats, and inconsistent metadata are “root causes” of a lot the lab compliance issues, Tougas said, and “the three elements are really what drives a lot of” Allotrope’s efforts.

The current “pain points” for both industry and FDA in analytical labs “are associated with the fact that our systems do not talk to each other and are not standardized. It is on the documentation preparation side. It is on the archiving and data management side. It is on just the sheer opportunities there are for human errors in terms of data entry.” In turn, the “pain points” in the analytical lab translate into the process analytical world, he stressed to the IFPAC attendees.

The shared costs in finding the solutions cooperatively “are significantly lower than doing it on your own,” the BI official affirmed, and speak to the value of pre-competitive collaboration.

“It does none of us a real benefit to try to do this on our own. This is something that has to get solved across the entire industry and regulatory environment for it really to work and to make it economically feasible to attack this problem.”

Common Data Standards Empower Lab Operations

Allotrope members are exploring how common standards can enable a more fully automated laboratory environment in which the various instruments, analysts, and the data they produce are linked. The result envisioned is a more

seamless GMP environment that addresses concerns that are dominating FDA’s analytical lab agenda.

At the Chicago workshop, GSK Analytical Scientist James Roberts previewed a “laboratory of the future” pilot that his firm plans to put in place in 2015, which will use the Allotrope framework “in a real lab” (see Roberts’ remarks below).

Using a combination of barcodes, employee identification badges, and a computer system that contains specifications and the relevant procedures, the ultimate goal is that all product, sample, analyst, and method information will be interlinked to create a seamless and compliant set of analytical data with an audit trail.

“We obviously are not going to start at that level,” Roberts commented, “but we are going to progress starting with a balance. I think the first thing that we want to do is get the metadata at the balance correct, get that really robust, and then publish it to a website or something for analytics.”

“If we can scale that balance solution to a hundred or a thousand balances in the company, then we can really start to get analytics information about our entire portfolio without doing any automation downstream – just by capturing that metadata at the balance.”

GSK’S JAMES ROBERTS ON THE LABORATORY OF THE FUTURE

DOWNLOAD FROM THE STORY:

• FDA Data Standards Strategy white paper

At the Allotrope meeting in Chicago in October 2014, GSK Analytical Scientist James Roberts described a GMP “laboratory of the future” initiative that is being piloted at his firm, using the Allotrope framework.

The concept here is to start using the Allotrope framework in a real lab. So we are setting up lab space for the balance and an HPLC stack. The first workflow we want to tackle is drug substance stability testing.

We take the idea of a woman in a museum who has on a headset device. And if you have ever been to a museum, you can walk up to a painting and maybe scan a barcode or type in a number and it describes the painting for you. It says, ‘oh that was a nice painting. Walk down the hallway and turn left and you will see this sculpture.’ It knows the objects, the things around the environment, and it knows how to guide you through a process. This is a pattern that we want to apply next year using a framework.

The idea is that as a user I would have some stability samples from stability chambers. If it is a drug substance, it is a powder in a bottle with a barcode. So I use a barcode scanner and it says, ‘hey, I know what that is,’ and then I would swipe my badge. It says, ‘hey James, I know who you are. Why are you here?’

I push one button and I tell it about the purpose of my experiment. Let’s say it is a twelve-month time point. It says, ‘oh, that is a GMP activity, and you are going to have to type in your password.’ I type in my password and it says, ‘okay, put your drug substance vial on position number three on the carousel,’ and you walk away.

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At this point the balance knows everything it needs to know about how to prepare the sample, because the barcode connects to a batch ID, which connects to a compound, which connects to a project. And for that project we are going to use a dashboard.

The compound is attached to a specification. The specification has an analytical method that is associated with it. It is the analytical method that tells the balance the weight range for the samples, so it knows the upper and the lower limit, and it prepares the samples. It also knows the target concentration. So it prepares a gravimetric solution from my samples – not volumetric. That is an important distinction.

And when the vials are ready to go, you have a barcode at the bottom of them and the user gets notified and they walk to the HPLC stack and scan that barcode. The HPLC stack says, ‘I know what that is because the balance told me what it was.’ So it knows the method, how to run it, and how to process the results, because it knows where the impurities should be if that is known or cited. It knows the peak labels and the retention times where things should land. It knows that if I am running purity, maybe I don’t integrate peaks of less than 0.5%.

Then the data is ready for review by a scientist who needs to go in and confirm that everything is right. A manager or someone would probably need to peer review it. They review it and push a button that says, ‘yes, this is approved,’ and it moves along the reference architecture into the data repository with the retention schedule attached to it. So the retention of that record is automated.

As it moves into the data repository, there is an ingestion process. And as the file is ingested into the repository, all that cool metadata pops out and gets published to a client, like a dashboard.

So what does it know? It knows the project. It knows the phase of development. It knows it was a 12-month stability time point. It knows that I ran the experiment. It has an audit trail with timestamps that are captured along the way at every granular event. It knows that the quality is assured along the way because all of the SOPs that right now we keep on paper are actually built into the system. So that quality is checked in real-time as the work proceeds.

In fact, it will stop you and prevent you from making an error if it does not like what you are doing. For example, it would not let me run that kind of a sample on an HPLC that was not qualified. That is the concept of the work that we are starting next year.

We obviously are not going to start at that level. But we are going to progress starting with a balance. I think the first thing that we want to do is get the metadata at the balance correct – get that really robust, and then publish it to a website or something for analytics.

If we can scale that balance solution to a hundred or a thousand balances in the company, then we can really start to get analytics information about our entire portfolio without doing any automation downstream – just by capturing that metadata at the balance.

You start asking yourself, how do you deploy something to all of those balances? And how do you make progress through interim development? Our model is we are using agile development at Osthus, and within GSK our target is to use a very iterative development and learning cycle. [Editor’s Note: For more information on the Allotrope effort and the role of software developer Osthus, see the story on pp. 3-10.]

If you have these conversations in-house, and you say, ‘oh, we want to learn by doing and we want to test our hypotheses and do continuous improvement,’ everybody is like, ‘oh yeah! That is great. We have to do this. That is motherhood and apple pie.’ But then if you say, ‘actually what that means is that we want to deploy a new GMP-compliant capability that the scientists can use every two weeks,’ at first blush that can freak people out.

We have actually had these conversations in-house, and we have done a lot of studying and discussions with Osthus. This guy, Matt Frank, is a software engineer at GSK, and he is crazy passionate about something called ‘continuous delivery,’ which is a software paradigm where all of the documentation that we know is required for compliance systems is actually automated. It is actually done every day during the creation of software.




For the validation geeks, as you are gathering your requirements and connecting those to unit tests and you are running unit tests and regression tests and system tests, all of that stuff is automated. When we get a new result or a new version of the framework from Osthus in Germany, then we can automate the deployment of that on our lab PC.

That is the concept. That is how we want to work next year. And that is the particular problem, space, and pain point for us. Stability testing is not the most cutting edge science kind of thing, but we do a lot of it and it is not the most efficient process.

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Comment Review, Public Meetings, Supply Chain Pilot to Follow 2014 Bolus of FDA DQSA Track & Trace Guidances

In the wake of having issued a series of guidances in the latter part of 2014 to enable implementation of the 2013 Drug Supply Chain Security Act (DSCSA), FDA is now concentrating on: ● reviewing the comments and finalizing the guidances ● issuing required regulations ● scheduling public meetings ● performing a supply chain pilot program, and ● developing a licensing program for the various trading partners in the supply chain.

Four draft and two final guidances have been released since mid-2014 to support the track and trace provisions of DSCSA, which is the second component (Title II) of the Drug Quality and Safety Act (DQSA). Five of the guidances were required by the law, and one – on national uniform standards and federal preemption – was not, but was prompted by stakeholder requests for clarification on the topic.

At a meeting on DQSA implementation in December, co-sponsored by the Food and Drug Law Institute (FDLI) and the University of Maryland Schools of Law and Pharmacy, FDA Center for Drug Evaluation and Research (CDER) Office of Compliance Deputy Director Ilisa Bernstein reviewed DSCSA’s implementation status and the agency’s upcoming plans.

Also in focus at the meeting, held at the Washington, DC office of the law firm Arnold and Porter, was the Compounding Quality Act (CQA), which is Title I of DQSA. [Editor’s Note: A review will follow later in IPQ of the discussions at the FDLI meeting on the challenges that are presenting themselves in implementing CQA. See IPQ “Monthly Update” July 2014, pp. 11-19 for more insights on the background and regulatory implementation challenges of DSCSA from a leading CDER official involved.]

Supply Chain Partner Engagement Needed

Bernstein commented at the December FDLI meeting that while the agency is doing its part to implement DSCSA, trading partners will need to engage with each other to find solutions specific to their businesses.

She explained that the agency has been getting “a lot of very specific questions” regarding standardization of data and documentation practices. However, she said, “the supply chain and trading partners need to be able to work some of these things out through business relationships and contracts if it is outside the parameters of the law.”

The compliance official went on to explain FDA’s upcoming plans regarding: ● license registration ● product identifiers

and serialization ● a supply chain pilot, and ● public meetings.

License registration for manufacturers and repackagers will begin to take place in a new agency system called “CDER Direct.”

The current system is based on a standardized process called structured product labeling (SPL). “It is highly complex,” Bernstein commented, “and a lot of companies find that it is difficult to do – especially small businesses.”

The CDER Direct system circumvents the complexity of SPL by creating an interface where information can be entered in a standard format, which the system then converts to SPL.

“What this does is it creates a really easy system hopefully, once people start using it, for reporting the licensing to FDA,” Bernstein commented. “We have already started using CDER Direct for other registration and reporting as well to FDA.”

With product serialization requirements looming in the next three years, the agency is beginning to plan for that transition.

Under the law, FDA is required to issue guidance on waivers, exemptions, and exceptions, as well as grandfathering, when there are products in the market place that have unique identifiers and serialization and others that do not.

“How does the supply chain handle that?” Bernstein asked. She noted that the agency will be seeking stakeholder input on the guidance that it is developing in this area.

Under DSCSA, a pilot is required in coordination with stakeholders to explore and evaluate methods to enhance the safety and security of the supply chain.

Bernstein explained that the agency is beginning to put some thought into the pilot and will be working on it “sometime in the near future.” The pilot is expected to be put into place and completed over the next six years.

“We have a couple of years to work on that,” she pointed out, “but it does take time to organize the pilot, develop the protocol, implement it, and evaluate it. We recognize that is time-consuming. Right now we are focusing on the guidances and standards that we need to get out.”

Also required under DSCSA are “no less than” five public meetings, as well as an assessment for small businesses.

http://www.ipqpubs.com/issues/ipq-monthly-update-july-2014/





The agency is working to figure out the timing of the meetings, the content of which are specified by the law. “They build on each other,” Bernstein noted, “so that one public meeting will help inform another public meeting that further informs the standards that we establish.”

She noted that in addition to setting up meetings and developing standards and guidance, CDER also needs to develop the infrastructure within the agency to support the new licensing programs for wholesale drug distributors and third-party logistics providers (3PLs), including an inspection component.

“All of these little pieces actually end up being big pieces – big resource-intensive pieces for FDA,” Bernstein commented.

Also in progress is a proposed rule for the 3PL and wholesale distributor standards, required to be issued by November 2015.

Final Guidances Cover UFI and Product Tracing

The final CDER guidances released this year that support DSCSA implementation were a guidance for industry on “Specification of the Unique Facility Identifier System for Drug Establishment Registration” and a Compliance Policy Guide (CPG) on product tracing requirements.

The final guidance on specifying the UFI was released on November 4. No changes were made to the draft released in September 2013 (see IPQ “Monthly Update” January 2014, pp. 13-20).

The guidance addresses the FDA Safety and Innovation Act (FDASIA) requirements for defining the UFI system for registration of domestic and foreign drug establishments. It notes that at this time, FDA’s preferred UFI for a drug establishment is the Data Universal Numbering System (DUNS) number, assigned and managed by Dun and Bradstreet. FDA has been using the DUNS number for registering drug establishments since the implementation of electronic drug registration and listing.

The five-page guidance includes an introduction, a background section covering FDASIA and the scope of the guidance, and specification of the UFI system.

The CPG on product tracing requirements, which is just over two pages, was released on December 23, and extends the period of time for industry compliance with some of the requirements.

It is intended for trading partners – manufacturers, wholesale distributors, and repackagers – who must provide and capture certain product tracing information as required by DSCSA.

“Some trading partners,” the final guidance states, “have expressed concern that unforeseen complications with the exchange of the required information may result in disruptions in the supply chain, and ultimately could impact patients’ access to needed prescription drugs.” In response, FDA “does not intend to take action against trading partners who do not, prior to May 1, 2015, provide or capture the product tracing information required by DSCSA.”

The extension, however, does not apply to other requirements, “such as verification related to suspect and illegitimate product – including quarantine, investigation, notification and recordkeeping – and requirements related to engaging in transactions only with authorized trading partners.”

Four Draft Guidances Issued on DSCSA

The draft guidances on DSCSA implementation issued in 2014 cover identifying suspect product, licensing standards, exchanging supply chain information, and annual reporting requirements (see box below).

The draft on identification of suspect product and notification, released in June, is intended to aid trading partners, such as manufacturers, repackagers, wholesale distributors, and dispensers, in identifying a suspect product and sending notifications regarding an illegitimate product.

Beginning on January 1, 2015, a trading partner who determines that a product in its possession or control is an illegitimate product must notify FDA and certain immediate trading partners under DSCSA.

DSCSA Draft Guidances Issued in 2014The following draft guidances on implementing DSCSA were issued in the later part of 2014, each with a 60-day comment period (the release dates are noted in parentheses):

● Identification of Suspect Product and Notification (June11)

● The Effect of Section 585 of the FD&C Act on Drug Prod-uct Tracing and Wholesale Drug Distributor and Third-Party Logistics Provider Licensing Standards and Requirements: Questions and Answers (October 8)

● DSCSA Standards for the Interoperable Exchange of In-formation for Tracing of Certain Human, Finished, Prescrip-tion Drugs: How to Exchange Product Tracing Information (November 27)

● Annual Reporting by Prescription Drug Wholesale Dis-tributors and Third-Party Logistics Providers (December 8)

http://www.ipqpubs.com/issues/ipq-monthly-update-january-2014/

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Appended to the draft guidance is the FDA form 3911, which needs to be used for reporting illegitimate products.

Along with the discussion of suspect product identification and agency notification, the guidance identifies specific scenarios that could significantly increase the risk of a suspect product entering the pharmaceutical distribution supply chain.

Federal Preemption Draws Comments

Next out of the pipeline, in October, was a draft Q&A intended to assist industry and state and local governments in understanding the effects of the “Uniform National Policy” section (585) of the DSCSA.

Section 585 establishes a federal system for tracing prescription drug products through the pharmaceutical distribution supply chain and requires trading partners to pass, receive, and maintain certain product and distribution information. It also sets forth a uniform national policy preempting states from establishing or continuing certain standards and requirements.

The nine-page draft includes introduction and background sections, and Q&A on three topics: ● product tracing ● wholesale drug distributor standards and licensing, and ● third-party logistics provider standards and licensing.

Many of the seventeen comments that the agency received on the draft voiced general support for FDA establishing a national standard.

For example, Pentec Health, which provides home health care for dialysis patients, applauded FDA “for its clarification in the draft guidance of the DSCSA’s preemption of state laws and regulations that are, inter alia, inconsistent with or otherwise covered by the DSCSA. Given the complex network of rules and regulations governing prescription drugs, including individual states’ pedigree laws, establishing a single system for tracking and tracing prescription drugs across the country is a sensible and valuable reform.”

Similarly, the California State Board of Pharmacy commented that it “strongly supports” the draft guidance and believes it “accurately conveys the effects of section 585 (Uniform National Policy).”

On the other hand, concern was expressed in the comments with how the preemption of state laws is worded and its possible misinterpretation.

For example, the Pharmaceutical Distribution Security Alliance (PDSA) – a multi-stakeholder coalition that represents more than 30 companies, including manufac-turers, repackagers, wholesale distributors, third party

logistics providers (3PLs) and pharmacies – maintained that the guidance “mischaracterizes” the preemptive scope of section 585(b).

“Section 585(b) was intended to preempt state requirements that exceed federal standards, yet the guidance inaccurately characterizes the federal standards as only minimum standards for licensure,” PDSA states. “We ask the agency to clarify that states must not exceed or otherwise deviate from the federal standards that will be developed.”

The coalition quotes section 583(b), which states that the licensing standards established by the DSCSA are “for the purpose of ensuring uniformity with respect to [the federal licensing] standards.” PDSA maintains that “uniformity simply does not exist unless all states are required to utilize identical standards.”

Comments were also received expressing confusion regarding the state and federal licensing requirements for 3PLs and requesting additional clarification.

Product Tracing and Annual Reporting Addressed

Rounding out the set of 2014 DSCSA draft guidances were one on the exchange of product tracing information, released on November 27, and another on annual reporting by wholesale distributors and 3PLs, released on December 8.

The eight-page draft covering exchange of product tracing information addresses the DSCSA requirements for exchanging transaction information, history, and a statement covering product tracing information for certain prescription drugs.

This requirement went into effect on January 1, 2015, for manufacturers, repackagers, and wholesale distributors, and will be effective on July 1, 2015, for dispensers. The guidance proposes initial standards for the interoperable exchange of the product tracing information related to each transaction.

The draft on annual reporting by prescription drug wholesale distributors and third-party logistics providers under DSCSA includes sections on: ● who must report ● what should be reported ● when to report ● how to report, and ● public availability of information.

Beginning November 27, 2014, 3PLs were required to report certain information to FDA, including state licensure information for each facility and the name and address for each.

[Editor’s Note: As of February 10, the only comments which




FDA had posted on the four draft guidances that were issued in 2014 were those on the uniform national policy guidance. IPQ will provide an analysis of the comments on the other DSCSA draft guidances issued in 2014 when they become available.]

DOWNLOADS FROM THE STORY: FDA Final Guidances • Specification of the Unique Facility Identifier System for

Drug Establishment Registration Guidance for Industry• Product Tracing Requirements – Compliance Policy

FDA Draft Guidances • Identification of Suspect Product and Notification• The Effect of Section �� of the FD&C Act on Drug Product Tracing and Wholesale Drug Distributor and Third-Party Logistics Provider Licensing Standards and Requirements: Questions and Answers• DSCSA Standards for the Interoperable Exchange of Information for Tracing of Certain Human, Finished, Prescription Drugs: How to Exchange Product Tracing Information• Annual Reporting by Prescription Drug Wholesale Dis-

tributors and Third-Party Logistics Providers

IPQ wishes to thank the following sponsors:

For subscription and sponsorship information visit IPQpubs.comor contact Wayne Rhodes — [email protected], Tel: �0�-��1-��0.

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http://www.ipqpubs.com/wp-content/uploads/2015/02/Draft-guidance-interoperable-data-exchange.pdf

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The event will bring together thought leaders, health product regulators, life science industry practitioners and academics to explore the role that Knowledge Management can play in ensuring the delivery of safe and effective products to patients.

The ICH Q10 Guideline developed by EU, US and Japan recognized the importance of Knowledge Management by describing it as an enabler to the Pharmaceutical Quality System. Yet both industry and regulators have struggled with how to realize the full potential of the available knowledge and get it flowing through the lifecycle to the benefit of the patient. We are delighted to have speakers from all three ICH regions in Dublin Castle to discuss and debate the future for Knowledge Management for the life science sector.

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Ed Hoffman: Integrating Knowledge Management and Risk Management: Lessons from NASA

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Jean Louis Robert: Moderated Panel & Audience Discussion on outcomes from the KM sessions with ICH Q12 Team Members

Yasuhiro Kishioka: Moderated Panel & Audience Discussion on outcomes from the KM sessions with ICH Q12 Team Members

Emer Cooke: The Future of Regulatory Science

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Asian medicines agencies are joining those in the US and Europe in seeking to address the emerging regulatory challenges posed by: ● new classes of products such as cell-based regenerative medicines and engineered antibodies ● accelerated approval pathways ● biosimilars ● international convergence, and ● validation lifecycle management.

Regulators from Asia provided insights on their agencies’ strategies for dealing with these pressing issues and the progress they have made to date at the CMC Strategy Forum Japan, held in Tokyo in December 2014.

Sponsored by CASSS with the support of Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) as well as the Japan Pharmaceutical Manufacturers Association (JPMA) and the U.S. FDA, the forum provided the opportunity for regulator and industry experts from Asia to compare notes with those from the US and Europe on where viable solutions and harmonization pathways lie and the hurdles that have to be crossed to achieve them.

In their presentations, the various regulators discussed how their staffing, product classification and review processes are changing to deal with the new challenges, and the coordination, integration and streamlining efforts that are being pursued.

They also highlighted the regional and global organizations that they and their agencies are involved with, and the impact the organization working groups are having on their ability to handle the new review and inspection demands.

In a summary of the discussions at the two-day forum presented at its conclusion, industry consultant Nadine Ritter pointed out that “all speakers were acutely aware” of the increased filing and inspection workload and decreasing review timelines, which are “putting massive pressure on CMC reviews.” [Ritter’s full summary is included below.]

All of the agencies, she noted, reported that they are looking at: ● staff expansion ● assignment flexibility ● streamlining and simplifying their internal reviews and inspections, and ● coordinating and integrating reviews and inspections toreduce redundancies and maximize their efficiency.

A universal theme was the need to work with other global health authorities and industry groups to find ways

to “increase communications, share experiences, align philosophies, harmonize policies and leverage information.” On the other hand, the regulators also emphasized that industry needs to be aware of the legal constraints the agencies operate under in pursuing the convergence efforts.

The new classes of products are “requiring an adaptation of our traditional well-characterized models – balanced with the risks and benefits of patient safety and product availability,” Ritter summarized.

She highlighted a key point made in one of the presentations that “regulators are the spokespersons for the patient population, and the need for the data that they have to have” to perform that role must be respected by industry accordingly.

At risk for industry, Ritter stressed, is the large negative impact of a prominent product failure.“ We have a lot of quiet successes in biotech,” the industry consultant commented. “We have done amazing things in the last 30 years that the public really does not appreciate so much. But it only takes one loud product failure – one really spectacular patient population to be hurt – and it can bring parts of our business to a crashing halt.”

Cell-based Product Regulation Follows Biologics Models

The diversity of the number and types of cell-based regenerative medicine products makes addressing them as a product class difficult.

There was general agreement in the discussion at the forum among the US, European, and Asian industry and regulatory participants that while aspects of these products have to be dealt with on an individual basis, there are some common principles that can be extended from other complex biological products.

Because the cell-based products are heterogeneous mixtures like antibodies, the degree and control of that heterogeneity is important and needs to be demonstrated using appropriate analytical tools. Product characterization and control strategies that ensure the defined target product profile is met consistently for each batch of these complex and frequently very labile biological materials are also critical.

In discussing risk to the patient, participants asserted that

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risk mitigation plans should be in place for each product and its intended use, including: ● the traceability of the source material ● the chain of custody of the process material, with an emphasis on where it was made and the patient that gets it, and ● long-term safety follow-up for post-market surveillance. [Editor’s Note: The current advanced therapy regulatory landscape in the US, Europe, and Asia, and related harmonization efforts will be reviewed in the March IPQ “Monthly Update.”]

Engineered Antibodies Can Use Conventional CMC Strategies

A new class of antibodies – for example, those that have been engineered to contain modified glycosylation patterns resulting in reduced levels of antibody-dependent cell-mediated cytotoxicity (ADCC) – requires sophisticated manufacturing technologies, but can successfully use conventional CMC strategies, workshop participants agreed.

The general consensus was that structure/function relationships of these antibodies can, for the most part, be characterized using tools similar to those used for conventional antibodies. For the stability-indicating methods, it is important to demonstrate that the method is capable of detecting structural differences as well as functional changes.

At the workshop, Roche Diagnostics’ Elisabeth Kirchisner gave a presentation on GAZYVA (obinutuzumab), the first approved glycoengineered antibody, which is used for treating chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, and diffuse large B-cell lymphoma.

Kirchisner explained that “a full quality-by-design (QbD) approach was used for technical development of obinutuzumab,” which was granted both orphan drug and breakthrough status in the US, and approved by FDA in late 2013. Approval in the EU followed in 2014.

The manufacturing technology is based on the co-expression of the antibody with glycosylation-modifying enzymes during cell culture, which leads to a modified glycosylation pattern with reduced levels of core-fucosylation. The increased level of afucosylation results in an increase in ADCC.

Biosimilar Regulations Progressing in Asia

A discussion of the status of biosimilar regulations in Asian countries revealed that while there has been some harmonization of the CMC requirements in the Common Technical Document (CTD) Module 3, agency policies on

the use of non-national clinical trial data and reference drugs are highly diverse.

In addition, the types and amounts of analytical comparison required with the reference drug also varies, but in some cases can be overcome by the use of three-way bridging studies comparing analytical and/or clinical data with that of the reference drug.

Jeewon Joung, representing Korea’s Ministry of Food and Drug Safety (MFDS), explained that while some Asian countries, such as Malaysia, have used the EU biosimilar guidelines as models, the Asia-Pacific Economic Cooperation (APEC) Regulatory Harmonization Steering Committee (RHSC) has settled on the WHO biosimilar guidelines as its model for regulatory convergence in the APEC countries.

APEC is proposing that the convergence effort take place under the auspices of the International Coalition of Medicines Regulatory Authorities (ICMRA), a body sanctioned by WHO in 2013 (see box below for the depiction presented by Joung).

Serving a central role in the effort will be the International Pharmaceutical Regulators Forum (IPRF), which grew out of ICH, and Korea’s MFDS.

The effort, Joung said, is intended to “aim for efficient and timely global development and access to biotherapeutics, including biosimilars.”

Also presenting at the session, Malaysia Ministry of Health Head Of Biotech Product Registration Arpah Abas discussed the issues her agency has been seeing that have caused non-approvals of biosimilar applications.

Application deficiencies her agency has seen include: ●

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insufficient data on process ● insufficient characterization of product ● inadequate specifications ● deficient strategy for analytics ● no justification for the choice of the reference product ● poorly designed technical studies ● inadequate immunogenicity assessment, and ● prescribing and product labeling problems.

In her summary of the forum discussions, Ritter commented that the deficiencies cited by Abas comprised “a laundry list that is probably something you would see similarly in other regulatory bodies as well.”

During the discussion period at the biosimilars session, a question was raised regarding whether current regulatory frameworks would allow approval of biosimilar vaccines.

Japan’s PMDA responded that it would be dealt with on a case-by-case basis. EU and FDA regulators concurred that a biosimilar vaccine approval would be covered by their current regulations. However, under the Malaysian system, vaccines are not covered.

The Korean and Taiwan regulators commented that their agencies would consider a biosimilar vaccine if the product was well-characterized and therapeutic rather than prophylactic.

APEC Leads Asian Regulatory Convergence

There was general agreement at the workshop on the benefits of convergence of regulatory filing requirements across regions and agencies for both industry and regulators. Asian agency involvement with international harmonization and coordination efforts was a focal point at the conference.

It was noted in the discussions how challenging it has been to produce and get agreement on centralized procedures across the EU member states and the greater difficulty of achieving mutual recognition across Asian countries, which have unique jurisdictional requirements and are not linked legally in the way the countries in the EU are.

The most prominent and broadest-based efforts on regulatory harmonization and convergence of biotherapeutic regulations taking place across Asia are being spearheaded by APEC. [Editor’s Note: IPQ’s March “Monthly Update” will include more on APEC’s current efforts on regulatory convergence. See also IPQ “Monthly Update” May 2013, pp. 45-47. For a review of APEC’s work on global supply chains, see IPQ “Monthly Update” July 2014, pp. 20-29.]

In her summary of the regulatory harmonization discussion, Ritter commented on the important role that ICH Q12 on product lifecycle will play (see IPQ “Monthly Update” December 2014, pp. 28-41).

ICH Q12 “is going to include things on review and inspections, which is that integrated approach that we were talking about. This is good because we want to drive better global harmonization and the better use of comparability protocols for post-market changes.”

Validation Terminology Needs Harmonizing

Dominating the discussion on validation lifecycle management at the CASSS workshop were concerns regarding the differences in terminology used in different regions and the impact that misunderstandings and translation errors can cause.

In her summary of the discussion, Ritter commented on the importance of understanding the various terms, such as validation, verification, continued versus continuous validation, and evaluation.

“This is not a trivial thing,” she stressed, “because it materially affects how much data you collect, when you collect it, what reviewers are expecting to see, and how they are interpreting what you are claiming by the set of data that you are generating for them. That is even complicated by the fact that we have different languages that have different translation subtleties associated with them.”

Ritter pointed to the assertion during the workshop by Germany Federal Institute for Drugs and Medical Devices (BfArM) Biotech and Biologics Inspections Head Brigitte Brake that harmonizing the terminology in this area would be valuable to both industry and regulators. “The use of common language,” Brake maintained, “will facilitate acceptability of the PV data package in different regions of the world.”

Ritter also commented that “we really should be harmonizing this terminology and making it a lot more clear so that for this extraordinarily expensive and labor intensive activity, we know exactly what regulators need to see and when they need to see it, so that we can be sure we generate the set of data that is expected.” [Editor’s Note: For a discussion of the similarities and differences regarding process validation terminology in US and EU guidances, see IPQ “Monthly Update” May 2012, pp. 44-45.]

CPV Case Study Highlighted

Also presented at the workshop was a case study developed by the BioPhorum Operations Group (BPOG), whose mem-bership includes 20 major biotech companies, on general approaches to implementing continuous process verification (CPV). The case study provides specific recommendations on the content of a CPV protocol and the associated rationale (a link to the case study is provided below).

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The cross-company effort was compiled in response to FDA’s 2011 process validation guidance, explained Pfizer Global CMC Biologics and Devices Research Fellow Stefanie Pluschkell, presenting on behalf of the BPOG’s CPV team.

BPOG was formed in 2008 and consists primarily of experts from biopharmaceutical drug substance operations, who meet and work together at face-to-face meetings in the US and Europe, and in regular teleconferences via web meetings. The group, Pluschkell said, “has established best practice on a wide variety of quality, engineering, and organizational topics considered central to the challenge of mastering effective biotech drug substance operations.”

The purpose of the CPV case study, she noted, is to: ● provide a new business process for the industry● leverage collective experience and expertise ●include realistic examples in a case study format, and ● provide groundwork for further useful discussion on implementation.

There are “very few” articles written by actual practitioners, Pluschkell asserted, and “most of the literature covers only some aspects of the topic.”

Included is a “comprehensive industry example,” which was based on the CMC Biotech Working Group 2009 A-MAb case study to leverage the industry work and familiarity with A-MAb. She noted, however, that the CPV case study does not include concepts associated with design space implementation, as in A-MAb.


• BioPhorum CPV Case Study

SUMMARY OF DECEMBER BIOTECH CMC STRATEGY FORUM JAPAN

The following is a summary of the presentations and discussions at the December biotech CMC Strategy Forum in Tokyo, provided by Global Biotech Experts’ Nadine Ritter at the conclusion of the forum. The sessions at the two-day forum, which included presentations by industry and regulator experts from Asia, North America and Europe, and panel discussions, addressed: ● recent trends in the regulation of biophar-maceutical products and practices ● breakthrough products and accelerated approval ● biosimilars ● inter-national regulatory convergence ● cell-based products for regenerative medicines, ● antibody engineering, and ● the process validation lifecycle.

We heard from nine global regulatory authorities [Japan, U.S., Finland, Malaysia, Korea, Taiwan, Portugal, and Germany, with Health Canada not presenting but contributing to the discussions]. It was a fantastic representation certainly of the Asian countries and then some very notable representatives from some European and Western countries that have been leaders in some of the thoughts on biotech product regulation over the years and will be going into the future.

We had a very good set of case studies that were provided to us by industry on cell therapies, cell-based products, and a variety of antibody products. I am not going to summarize those because of time. But I will pull out some salient points that came out in the discussions. The same thing is true for the research projects that we saw that came from some fantastic laboratories. I will summarize only the pieces that are related to the discussions.

A great deal of discussion was held on the industry perspectives that were contributed by the speakers and the panel members. Those points and discussions will show up in the answers to the questions that were posed both ahead of the forum and during the discussions.

Recent Trends in Biopharmaceutical Product Regulation

These are the highest of the high points from the regulatory bodies that I captured. I grouped the first set under individual regulatory agencies.

Japan’s PMDA

Japan’s PDMA plans to significantly increase its staff size in the next few years.

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It strongly supports the QbD initiatives that are going on. They were a pilot program observer.

The agency launched a “forerunner” package priority review known as ‘Sakigake” and a rapid authorization program for off-label unapproved drugs that have an unmet medical need.

Also new is a regenerative medicine program that has arisen under the revised Pharmaceutical Affairs Law – PAL – and the pharmaceutical medical device act.

An update was provided on its science board considerations that affect the topics that we have been dealing with for biotech and biologic products.

PMDA has recently revised its process validation standards to be more in alignment with ICH and PIC/S and product lifecycle strategies, although there are still some points that are being assessed. We heard that Japan’s perspectives on process validation are highly risk-driven for what they are going to decide to do. PMDA is now a member of PIC/S. We will talk about the global harmonization efforts – that was a major topic.

US FDA – CDER Office of Biotechnology Products (OBP)

One of the big things for those of us on that side of the pond is the reorganization of CDER that will better align the research, review, and inspection activities under one Office of Pharmaceutical Quality (OPQ). It actually is not a new approach for biotech products to have an integrated review and inspection system. They currently have a document internally – a MAPP – that describes the split of those activities within the discussion of the dossier.

OBP remains intact, but it will go from having two divisions – monoclonal antibodies and all of the therapeutic products – to four divisions that will allow them more flexibility in assigning resources.

The agency did define a sponsor meeting plan for biosimilar programs that matches to what we have for conventional product end-of-phase-2 meetings, pre-IND meetings, etc. They outlined statistical discussions that they have had for assessing analytical similarity, and promised that the guideline on interchangeability might be due sometime in 2015.

Finland/EMA

The Finnish regulator – as did many others – wore multiple hats during his presentation. In addition to representing FIMEA, [Niklas Ekman] also represented some things from EMA and the Biologics Working Party [BWP].

The big news for us, I think, is that there is going to be a single clinical trial assessment pathway and that we will be utilizing an EMA portal, which he gave us a great deal of information about. Some of it was a bit scary – like if the portal crashes, you are suddenly approved….

It is a two-part assessment, but it has incredibly aggressive timelines. I had to look twice at the timeline to make sure it was saying ‘days’ instead of ‘weeks.’ I do not know how they are going to do it. Although with biotech products you can petition for a 50-day extension, and I suspect everyone will, with that kind of aggressiveness.

There is a tremendous emphasis on increasing the public transparency of the systems, including information regarding the experts who are involved in the assessments, the clinical trial programs, and the market authorization decision details, to try to improve information that goes to the agencies.

FIMEA has adaptive licensing for clinical plans. The CMC seems mostly the same, although the clinical side of it is more affected.

I was interested in the ‘valley of death’ concept for novice sponsors and the ‘baby medicines welfare clinic.’ That does not sound like what you think it means. It sounds like something that would involve pacifiers and bottles. But it is to provide regulatory support to companies that otherwise would crash and burn – that need some additional assistance to make better decisions.




Malaysia

They gave us a very spirited discussion on their activities, and also gave us a very good overview of the ASEAN [Association of Southeast Asian Nations] activities.

The CMC review of vaccine therapeutics and regenerative medicine products are all conducted by one group.

It has a biosimilar guidance that came out in 2008. It was emphasized that it has a very strong CMC package requirement and strong risk management plans with a lot of post-market surveillance. It was emphasized that they do not allow any quality shortcuts that could possibly compromise patient safety.

There is a big concern over safety risks of what are called ‘bio-copies.’ There was a paper that came out not long ago on the risk of some of those bio-copies to patient health. That is not a trivial concern as you will see later – what that can do to public opinion about these products.

Sponsors are allowed to choose the reference product for biosimilar products so long as it has a complete dossier and there is a sufficient duration/scope of commercial use of that reference product.

For cell and tissue products, there are tiered levels of review for high vs. low-risk product types.

Right now, gene therapy products are only getting licensed in Malaysia if they have been previously approved by a benchmark agency like US FDA, EMA, or Health Canada.

Korea

I am not sure Korea ever goes to sleep – there are so many things Korea is doing. I am impressed not only by the Korean regulatory strategy, but also all of the additional international organizations and the driving force that they seem to be in some of these global harmonization efforts.

They provided a summary of the Asia-Pacific Economic Cooperation [APEC] regulatory harmonization steering committee activities. There are nine roadmaps for pharmaceutical products. Vaccines, blood products, and cell and gene therapy products are in a separate area from the nine roadmaps.

There is a biotherapeutics global initiative goal to have the guidance documents from WHO and ICH rolled into APEC nations by 2020. They see a gap between the countries that have been harmonized with those international regulations vs. those that are not. They see quite a lot of disparity in practices when that situation occurs. A big problem is that there are no common languages that allow shared principles among those regional entities.

In 2015, a meeting is going to be held at which they are going to have discussions about convergence on a couple of different issues. A couple of key topics might be post-approval changes, immunogenicity assessments for biotherapeutics and biosimilars, and what degree of acceptance there may be for using foreign clinical trial data for biosimilar products.

It was also highlighted that there is a Singapore Center of Excellence that has been established that takes up issues of CMC questions for lifecycle management and post-approval changes.

Taiwan

Taiwan weighed in on the regulatory framework of Taiwan FDA and IMPRO [Integrated Medicinal Products Review Office], and highlighted the good review practices that guide them for looking at efficiency, quality, consistency, clarity and transparency in their review practices.

Taiwan has a tiered review classification system. Everybody seems to have a review classification system that allows some accelerated products and some regular products. After hearing all of the discussions today, I am not sure we are ever going to have regular products again. Everybody is going to be accelerated, priority, or abbreviated, as far as I can see.

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The agency likes to adopt best practices from many international organizations. They gave us a list of the organizations that they benchmark against in adopting their own internal practices. It has its own guidances on biosimilars.

The Taiwanese regulator Churn-Shiouh Gau who presented sees a translational gap from basic research to clinical development. It was brought up that there is a big disconnect between the academicians and the medical profession and the way they look at some of these products, especially some of the new products like advanced therapies, vs. those of us who have been for a long time on the development side, who know what it takes to get something through a regulatory review process for quality, safety, and ultimately, for efficacy.

For a biosimilar, it requires that the reference product be from Taiwan unless a justification for why it is not can be made.

Taiwan is now a PIC/S member.

Portugal

We had some wonderful discussions with Portugal’s INFARMED. [Margarida Ferreira] also represented EMA’s Committee for Advanced Therapies [CAT], which was a predominant focus of her presentation.

Margarida enlightened us about the centralized market authorization of advanced therapies and medical products from the EU member states in terms of the GMP provisions, the risk assessments, and post-market surveillance.

She gave us a 2014 status report on the Committee for Advanced Therapies, where they were looking at classifications that will be harmonized for these types of products and clarifying data requirements and marketing authorizations across member states.

Margarida talked about the goals to streamline the marketing authorization procedures and link certification procedures to the marketing authorization procedures and what incentives there are for academics and non-profits to be able to develop some of these, and also discussed some of the fees for post-market obligations.

Germany

Brigitte Brake talked about BfArM’s activities and her activities in the EMA and the BWP as well.

She came in at the end of the session today talking about the comparison of different guidance documents for process validation and the differences in dossier elements vs. inspection practices between FDA and EMA guidances for process validation.

Brigitte talked about process validation and continuous process verification, which we later learned is causing a tremendous amount of terminology problems in the industry. In fact, she mentioned that we should harmonize terminology about these things to facilitate the acceptability of our process validation packages in different regions in the world.

Common Themes: Internal Agency Activities

Even though there were some differences as I just pointed out, there were some common themes that came out from all of the regulators who spoke. There is a set of internal activities that they are all undertaking, and they followed similar themes:

We had outstanding organizational overviews of the regional health authorities.

We heard fantastic details in all of the regulators’ slides about: ● what their planned changes to their staff sizes are ● how they are going to arrange their product assignments ● what types of products they approve, and ● how they have changed over the years in the number and type of biotech products and cell products that they have approved. Each of them gave us phenomenal insights into their recent history and future plans.




Each outlined and compared the logistical pathways within their agencies and even between agencies for classifications of our products because they want to be able to have efforts that coordinate, integrate, and streamline those processes. Nobody wants to do any more work than they have to on either side of the table.

Many of them explained the history and gave us the current status and expected near-future elements of their regulations and guidance documents.

Everyone gave us a tremendous list of resources or links or provided us complete citations so that we could follow up after this meeting to get their drafts or guidance documents so that we can understand in great detail the policies and practices that apply to us and apply to them for our types of products.

Common Themes: External Activities

Most of our agency speakers adopted a second hat, like APEC or EMA or CAT, to share with us what their other work has been for regional or global organizations that they and their authorities are participating in.

They gave us a comprehensive view of the structure and function of the working groups that are having a major positive impact on our ability to get our products approved. Each gave us detailed updates on the status of those organizations with key upcoming activities and encouraged participation in discussions and dialogue at meetings such as this to be able to bring information to those agencies and have those thoughts be added to the discussions.

All speakers were acutely aware of the CMC review and inspection scenario that is happening now where we are generating and they are getting an increased number of filings and inspections, which is putting massive pressure on CMC reviews. The clinical timelines for breakthrough products or biosimilar products may be compressed, but the CMC timelines have to remain about the same, because you simply cannot compress things so much. So we end up with a situation where the CMC is on the critical path, and that is a tough thing to do on both sides of the table.

Also discussed were emerging new product classes that are requiring an adaptation of our traditional well-characterized models balanced with the risks and benefits of patient safety and product availability. We do not want to cause problems for patients. But if we do not get products to them, we will never solve those problems either.

Uniformly the regulatory bodies said that they are looking at staff expansion, assignment flexibility, streamlining and simplifying their internal review and inspection processes, and coordinating and integrating review and inspection activities to reduce redundancies and to maximize their efficiency.

Their external activities are to continue to work with other global health authorities and industries looking for ways to – and these are the same terms I heard over and over again – increase communications, share experiences, alignphilosophies, harmonize policies, leverage information, etc. We got all of these wonderful concepts. But every one of them said that we have to remember, as industry, that they have to work within the legal constraints of their individual statutory and regional requirements. So while it is a strong desire to want to be as coordinated and convergent as possible, it is very true that each of these agencies has its own constraints that it must honor. And we must be respectful of that.

Breakthrough Products and Accelerated Approval

I am not going to read this slide to you in terms of time (see box on p. 27).

One thing that I wanted to point out, regardless of whether it was a breakthrough product or a biosimilar product, again and again talked about was the need to front-load the CMC studies. Regulators have to make decisions based on data. And if we do not provide them with the data, they cannot make the decisions that we need for them to make.

We heard a couple of times about the quality of the dossier itself: Having the data is important. But if you make it difficult for them to sort through it and review it then you are going to end up with more questions. It is going to slow down the review cycle. And as [FDA Molecular and Developmental Immunology Laboratory Chief Margie Shapiro] once said in a fabulous presentation on pet peeves, ‘a grumpy reviewer is not a benevolent reviewer.’ It can certainly




slow down the review to have the information not put in a proper manner that can be reviewed quickly.

From industry, we heard the exact same kinds of situations where having CMC on the critical path is now becoming a problem. The good news is that we have these rapid review capabilities. The bad news is that the CMC is now the gating item. Where we used to be able to hide under the clinical timelines, we are now being pushed to get more data faster and try to get our cases in front of the regulatory bodies as quickly as possible.

We had some terrific case studies today on how some companies are implementing this to their maximum efficiency. It did have some surprises. Some things were not so surprising – for example, establishing cross-functional teams. That is a wonderful thing to do anyway.

But the idea of how many people it takes to do things more quickly – we had one report that it could even require quadrupling CMC staff to be able to get the information in a parallel path as quickly as possible.

There were lots of other heads-ups on things like trying to minimize process and test method transfers to minimize disconnects and save time.

There was an idea that if you are going to get a product approval faster it means that the pre-approval inspection will come faster, so it is better to get a parallel system going on to remediate any gaps in the quality systems at the manufacturing and testing facilities. That one is frequently left out. So I was glad to see that one picked up by [Genentech’s Earl Dye].

We saw two different approaches to QbD from the industry perspective: On the one hand, the thought was that QbD is not going to be all that useful for accelerated products because you do not have the time or the energy or the people to get that really sound process design space data set that you need. However, we did see some examples where a firm did use QbD very successfully. Senior folks put together a QbD package at Roche, and it was a really nice way to approach it. So it is going to probably depend a great deal upon individual companies, their experiences, and their timelines, as to whether QbD will be useful to them in a preapproval mode or in a post-approval mode.

We talked at the end today about platform analytical methodology – not just platform process technology. I think we just scratched the surface on that today. Maybe that can be the subject of future discussions, because there is a lot of rich information there that we can continue to discuss, including how to use the data that we get.

Whether it is the regulators or industry, both had the same challenges with limited batches being made for accelerated products, which means that we have a limited amount of information to establish specification ranges or process consistency. Obviously we have limited real-time stability data as is required for biotech products. And then the whole concept of process validation vs. continuous process verification was an issue.

Regulatory Considerations for Accelerated Approval Pathways

● Each agency has different designations for accelerated approval based onunmet medical needs, orphan drugs, off-label use or drugs in national interest

● None will compromise quality, safety and efficacy for the sake of expediency;all require a risk assessment/risk mitigation plan (quality parameters should not be on the edge of safety limits)

● Emphasized need to significantly ‘front load’ the CMC studies for process andproduct characterization to allow detailed evaluation of each dossier sooner than for standard product review

● Cannot make decisions on assumptions; must have data to support conclu-sions and to review risk assessments and risk mitigation plans

● May exercise discretion in some CMC elements within regulatory/compendialrequirements and balancing risks/benefits to patients

● Might place strong emphasis on post approval activities (risk-based decisionson pre vs post approval requirements)

● The quality of the dossier can have a major impact on efficiency of review – if itis poor quality it could trigger more questions from reviewers requiring more data to be submitted which will slow down the review process (and annoy reviewer!)

The following are the considerations for breakthrough and accelerated pathway approvals provided by regulators at the CASSS Japan CMC Strategy Forum as summarized by Nadine Ritter:




The bottom line is that everybody said communicate earlier and more frequently. You do not want to make erroneous CMC assumptions. You do not want to do too much. You do not want to do too little. You want to achieve successful reviews.

Health authorities cannot compromise their responsibilities. I think one of the comments that [BfArM’s Brigitte Brake] made was that quality parameters should not be ‘on the edge of safety limits.’

Regulators are taking risks for patients. I saw one other slide that said the regulators are the spokesperson for the patient population. So respect the regulators’ need for the data that they have to have.

I have a comment that came out of the issue we talked about regarding problems with bio-copies and the issues with gene therapy trials a long time ago: We have a lot of quiet successes in biotech. We have done amazing things in the last 30 years that the public really does not appreciate so much. But it only takes one loud product failure – one really spectacular patient population to be hurt – and it can bring parts of our business to a crashing halt.

If you do not know, if you have not seen what happened to the gene therapy trials in the late 90s and early 2000s, gene therapies took a major hit because of one failure. The PRCA issues were causing problems. We can have a lot of quiet successes, but it only takes one failure for the public to not have any of these products. So we do not want that to happen.

Now in terms of some detailed things, these are the questions [in bold] that I pulled out of the panel discussions that I have tried to populate with key answers:

● In some of the regulatory jurisdictions, evaluation of marketing applications could be streamlined if youhave benchmark agencies. If you have breakthrough-type product approaches and accelerated approval, how will their reliance on less well-developed data be accommodated?

The comments from regulators were that it would be hard to accept benchmark approval if it was highly accelerated because that, by definition, means it may have limited pre-approval CMC data available in the dossier.

But even if the CMC module is OK, a regulatory body could still have questions on the suitability of a product in that particular regional population. It is not a given. It is not going to be a slam dunk necessarily just because you have a good CMC module. There are other considerations, including political experiences with the product in the licensed area versus the patients that are going to be in the new target area.

They could base reviewer expectations on the current CMC guidance for the particular types of products, like the guidance for plant-derived products or other types of products from the benchmark agency. But every health agency retains the right to make the final decisions on a case-by-case basis, which is why they encourage communication early and often so that you can outline the detail of the strategy and get their concurrence.

● What regulatory frameworks and pathways are available for the potential accelerated new products?What are the advantages and disadvantages?

We had a really interesting conversation today: Why can’t we just treat every product like a breakthrough product where real process and test capabilities are only demonstrated after commercialization? The response from the regulators is pretty clear: They can only work within the framework of the regulations that they have been given to enforce.

But on the other hand, there is nothing stopping industry from planning their programs like they will be breakthrough therapies. In other words, go ahead and add staff and increase your data collection capabilities. And you may even choose to use minimalist approaches for simple formulations or limited shelf-life or a very narrow design space. But in the end, your commercially approved product or process will be constrained by the data you have given them.

How much do you want to get up front versus how much do you want to get in the end? That is a decision that a business has to make for itself. And as Earl Dye pointed out, it is a Catch-22, because when you have to do a lot of




CMC work up front, you have got to put a lot of investment in it, then the product fails you have lost it all. So that does not benefit anybody.

I think that [Genentech CMC Regulatory Director Kathy Francissen] made a good point about trying to strategically and scientifically understand the molecule, leveraging everything you possibly know about it and its predecessors to get the highest possible chance of success, and then prioritizing those within your company for possible breakthrough status so that if it is successful as a breakthrough product you are ready to go. That is probably the smartest thing to do.

Biosimilars

● What is the level of current activity and the future landscape for biosimilars?

Regionally there are highly diverse policies on non-national clinical trial data. Most of it is driven by either statutory constraints and/or population pharmacogenomic questions. That is the clinical side of it.

Actually, we have a lot of harmonization on Module 3 CMC requirements, with the exception of which reference drug you choose. Having the information to fill out characterization and process design and reference standards for your own is pretty similar from region to region by following the ICH Module 3 guidance document.

The type and nature and the amount of analytical comparison that you have to make to the reference drug can differ pretty widely, as does which reference drugs are legally allowed. We have known that for quite a while.

When you have to use one particular type of drug, frequently three-way bridging strategies are possible. We started this discussion. We did not finish it. But I would say to check to see whether your regulatory authority is talking about the three-way bridging strategy as being only analytical head to head, only clinical head to head, or both analytical and clinical head to head. It does vary from region to region. You do not want to make the mistake of doing the wrong study, because it is not an easy study to do.

We also learned that over the last couple of years we have had an increased learning curve, both on the regulatory and on the industry side from global biosimilars, and that this is feeding into both new guidances as well as looking back and updating early guidances for biosimilars based upon experiences.

I thought that the case study that was presented by the Malaysian regulatory authority was really interesting. She listed the typical problems that have been causing non-approvals of biosimilars in Malaysia. I suspect it is very similar to what happens in other health authorities in Asia, which is: ● insufficient data on process ● insufficient characterization of product ● inadequate specifications ● deficient strategy for analytics ● no justification for your choice of the reference product ● poorly designed technical studies ● not assessing immunogenicity adequately enough, and ● prescribing problems and product labeling problems.

That is a laundry list that is probably something you would see similarly in other regulatory bodies as well. I thought it was a nice list to put up here for everybody to benchmark off of.

International Regulatory Convergence

● What is the state of international regulatory convergence and, in particular, how does the picture for Asia differ from the global picture?

We saw that regulatory actions vary across global agencies, especially for CMC of new product classes, and also post-approval notification procedures, where you have got to make a change to a method or to a process. The regional requirements for reporting vary quite a lot.

There is no doubt that it would be beneficial on both the industry and regulatory sides to find a process that is within the jurisdictional requirements of each region to make it coordinated as possible for global industries.




We heard that most Asian authorities are heavily involved with key international harmonization and coordination organizations. We did see that it is a challenge to even think that we could get one uniform global guidance for accelerated and breakthrough products, because there are so many things that can happen regionally that can affect it.

Getting a central approval procedure for regular products – for example, among the ASEAN countries, which was a question that was asked – would require some kind of mutual recognition process among the countries. But the countries in the ASEAN organization are not legally linked the way they are in the EU. Look how long it took the EU just to get a harmonized process for clinical trials.

It was thrilling to see that ICH Q1� has made it to a concept paper now, because that is the document that is going to give us some guidance about product life-cycle. It is going to include things on review and inspections, which is that integrated approach that we were talking about. This is good because we want to drive better global harmonization for post-approval changes and the better use of comparability protocols for post-market changes.

We did hear that many health authorities that we are dealing with are now members of PIC/S for globally coordinated GMP practices. Hopefully the ultimate goal is to reduce redundant inspections for commercial products, because regulatory agencies just do not have staff hanging around to go out and inspect. If they can mutually recognize each other’s findings against a common set of GMP standards, that is going to make our lives easier as well, because we do not have a bunch of people sitting around just waiting to get inspected.

Cell-Based Products for Regenerative Medicines

● What strategy can be employed for evaluation and control for cell-based products for regenerative medicines? What is the role of specification?

We certainly heard very clearly that the current EU system for regenerative medicine is based on pretty much the same principles as for biotech therapeutics, which starts with characterization of the product and evolves into divining whatever the control strategy is going to be to assure that your defined target product profile is met consistently for each batch of this extraordinarily complex and probably highly labile biological material.

There need to be sufficient and appropriate analytical tools to let you molecularly define or cellularly define a regenerative medicine’s product profile. It is going to be different from a purified protein, but it still has a profile. From these you would select a subset of release and stability tests that you are going to use for quality control testing of that complex material.

When you make a change, such as getting another set of cells, or generating another stock, then you have to use similar analytical characterization tools to be sure that that change that you have made has not somehow negatively affected or shifted the product quality consistency that you are depending upon that you know has been safe and efficacious with the previous batches of that material.

The real take home message for us is that this is just another type of heterogeneous material. We have been dealing with heterogeneous proteins since the beginning of well-characterized biotech products. We are just applying those analytics and those control mechanisms to something that is even more complex.

It is not impossible, you just have to remember what the goal is: You still want to make sure that you have a defined degree of heterogeneity that is controlled and consistent so that you can be sure that you are maintaining safety and not having any contaminations that could possibly negatively affect the patient.

We had a quick overview of what some of the types of regenerative medicine products would be. And this is actually extremely diverse, from skin to cartilage to allogenic and autologous materials, stem cells, and I am sure the list is just going to continue to increase as we go along.

Points to consider for the type of product and its elements: They were risk-based approaches for each of those. But the dossier should contain justifications for decisions that you have made for each of them with the supporting data




that justifies your conclusion.

You should be putting this together as a part of an overall risk mitigation plan – that is risk to the patients – for the product type and its intended use, including things like: ● the traceability of the source material ● the chain of custody of the process material and where it was made and the patient that gets it, and ● whatever long-term safety follow-up there is for post-market surveillance for patients. These products are very limited in their distribution and in their use.

● For regenerative medicines can we overcome legal differences among countries and regions?

We had a wonderfully spirited debate about this yesterday. And what we revealed is that there were quite substantial differences in the current status and CMC expectations for regenerative medicines. But the bottom line to me, these are my words – ‘first do no harm.’

One of the comments that was made by [INFARMED’s Margarida Ferreira] is that if the cell population is supposed to be chondrocites, and it ends up 50% fibroblasts, you could end up with something that you are not intending, like scar tissue. Depending upon the risk for that particular patient population, scar tissue on a 95% burn victim might not be bad, because there might not be anything else that person has going for them. But if you are using it to repair a highly flexible element, then scar tissue could actually negate the thing it is supposed to fix.

You have to think about: What are the characteristics? What is the control? What is the consistency of the product for its intended use? What is the risk/benefit to the patient population? But again, you do not want a lot of quiet successes to be wiped out by one spectacular failure in the patient populations.

Antibody Engineering

● What are the biological and structural features characteristic to engineered antibodies? Compared to conventional monoclonal antibodies, are there any additional CMC issues to be considered for their approval?

We certainly saw the most magnificent presentations about all these molecular entities that can be generated, some wonderfully strategic ways to sort through them, and some very targeted design considerations. This clearly is going to be a class of molecules that we are going to be expanding. I have no doubt about it.

When it comes to their CMC, when they get out of the academic mode and go into development mode, and they go into the clinic, the CMC strategies are pretty conventional. In terms of the structure/function relationship characterization for biospecific antibodies, it is pretty much the same strategy and almost the same tools that you would use for a conventional monoclonal antibody.

You apply the analytics as appropriate. If you want to look at the stability-indicating capabilities of those methods, you would do certain studies to be sure that they were capable of detecting structural differences as well as functional changes. If the mechanism of action involves two different epitope-binding-domains, then you have got to assess the ability to measure those two different epitope-binding-domains.

We did have this wonderful conversation – thank you [Roche Biologics Regulatory Policy Head Thomas Schreitmueller] for bringing it up for us – about whether you define CQAs as something they mean for the product or if they are just something that is just a checkbox or a requirement. I would like to think it is more than a checkbox for a compendial requirement for some of these general characteristics. It was brought up, and I had not thought about it before.

I have to admit that this is a really interesting thing: Appearance is the most prominent product characteristic that anybody sees. Literally speaking, no one is going to call in and complain because they have an oxidation, they are going to call because it is yellow. It is not like that it is a trivial parameter.

As was mentioned by one of the regulators, if your specifications say the product can be red, blue, or sparkly, it can be red, or blue or sparkly. But if it says colorless, it had better be colorless.




A question came up: When do you remove product testing for something like a process residual critical quality attribute? Several different points were made about that. But pretty much universally the answer was when you can show sufficient batch consistency.

I am not sure I got this, Stephanie [Pluschkell], so correct me if I am wrong: I heard you say something about continuous process verification meaning thirty DS [drug substance] batches. And that was not before you removed the spec, I hope. That was a part of the CTD, right? [Pluschkell]: Thirty batches before you can truly do statistical process control.

Okay, thank you very much. Because I know that in the A-MAb case study when they talked about relieving some of the specification tests for things like process residuals and host cell proteins, buried in there in a little clause, it said that would be done after 20 or 30 batches are made for consistency. That seemed a little bit much to me, but I was not sure.

In any event, whenever it is that you are allowed to have regulatory relief from some of those process residuals, if you make a process change or something else occurs, then it is very likely that you are going to have to re-introduce those tests until you can show control over the process again.

Process Validation Lifecycle

We had a great discussion today about validation lifecycle. I apologize if I did not do justice to it, because literally as you were speaking, I was writing it. I apologize in advance if I missed a key topic. But this is what I heard at least: That the terminology can have an incredible effect on how we have to plan strategies.

And just listening to discussions – I do not normally get involved in process validation personally – but now I have a major appreciation for what some of the differences are in terms of validation versus verification, continued versus continuous validation, and evaluation. This is not a trivial thing, because it materially affects how much data you collect, when you collect it, what reviewers are expecting to see, and how they are interpreting what you are claiming by the set of data that you are generating for them. That is even complicated by the fact that we have different languages that have different translation subtleties associated with them.

I think Brigitte [Brake’s] original comment early on is that we really should be harmonizing this terminology and making it a lot more clear, so that for this extraordinarily expensive and labor intensive activity we know exactly what regulators need to see and when they need to see it, so that we can be sure we generate the set of data that is expected.

We did see that different regulatory bodies are at different stages of adopting the lifecycle approach. And ICH Q12 is going to help that as well.

[Kowid Ho] was very provocative. He threw up a slide postulating where things could go in the Module 3 for process validation and continuous process verification. That was a great slide that stimulated a lot of debate. But the ultimate question would be, how much of the information in the dossier would be legally binding? The conventional interpretation by most people would be ‘all of it.’

The caution there was to really give considerations to what that means in terms of what you put in the dossier for continuous process verification. Stephanie pointed out the fact that that is actually kind of an internal process that you are using to your own benefit to be able to understand what is going on with your own process. Any changes outside of the approved ranges would be managed according to your post approval change guidance anyway with appropriate regulatory communication.

The final piece of information I have, and I would certainly plan to look at myself, is the [Industry Group BioPhorum Operations Group (BPOG)] case study, a white paper on the details of how to execute and design continued process verification, which is available online.

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Global Excipient Databases Are Advancing That Will Fill Content and Functionality Gaps in Existing Regulatory Efforts and Further Industry/Regulator CommunicationFDA is working with industry, academia, and other regulators globally on major information management initiatives intended to help industry and regulators communicate about pharmaceutical excipients and fill gaps in existing regulatory database efforts, such as the agency’s Inactive Ingredients Database (IID).

While a collaboration between FDA and the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) on the agency’s IID has been fruitful (see IPQ “Monthly Update” Nov./Dec. 2013, pp. 16-27), the accuracy and content challenges that remain point to the need to develop a more in-depth and global approach to help resolve them.

The advancing projects that FDA is participating in include:

● a “Global Ingredient Archive System” (GInAS), beingdeveloped with broad international participation, that would identify, organize, and catalogue all pharmaceutical ingredients in line with ISO standard 11238 on the identification of medicinal products (IDMP)

● a “spectral library,” with USP participation, aimed atcreating a more coherent approach for authentication of materials, including APIs, glass, poisons, packaging materials, and excipients. The library will contain “fingerprint” spectra of confirmed materials that can be used for comparison with pharma company testing results (see IPQ “Monthly Update” December 2012, pp. 20-26). And,

● an “Excipients Knowledge Base,” spearheaded bythe academic consortium, the National Institute for Pharmaceutical Technology and Education (NIPTE), that is focused on cataloguing and comparing excipient properties.

GInAS Implements ISO Standard

A proposal for a monitoring system under the GInAS designation took shape at a meeting hosted by USP and the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) in February 2013.

The meeting followed in the wake of the completion in 2012 of ISO 11238, which had broad regulatory participation, including FDA. ISO 11238 describes standards for

exchanging information on regulated medical products and ingredients to better ensure the safety and availability of medicines globally.

Researchers at the National Institutes of Health (NIH) have developed software implementing the proposed standard and are providing this as a practical tool for stakeholders and researchers.

The GInAS project is being pursued in an international collaboration involving NCATS, Canadian, Dutch, German, Swiss, and US regulators, and the US and European pharmacopeias. Other organizations such as IPEC, Kew Gardens, and the World Health Organization (WHO), are sharing their expertise on the project.

The aim is to develop and deploy a global pharmaceutical substance identification and information system that can be shared among the global health community and used to improve health care delivery, the proper use of medications, and the management of risks involved in their use.

Included in the database will be information regar-ding definitions, analytics (spectra, chromatograms, specifications), manufacturing, and biological components, such as on metabolites, metabolic enzymes, and transporters. Health Canada is hosting a prototype database using software developed by NCATS.

The system is being designed to encompass all substances in marketed medicinal products and active substances in clinical research and to be used by regulators, companies and other interested parties. It is envisioned that a consortium of regulators and other international organizations will manage and govern the repository.

IPEC-Americas Weighs in on GInAS

At a GInAS update meeting held at USP headquarters in Rockville, Maryland, in June 2014, Colorcon Regulatory Affairs Director Dave Schoneker, who serves as IPEC-Americas Maker & Distributor Relations Committee vice chair, highlighted IPEC’s support for the database project and some of the issues that present themselves in implementation (Schoneker’s complete remarks at the GInAS meeting are included below).

Noting the potential for GInAS to house safety references, spectral identification, and elemental impurity information, Schoneker characterized

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the effort as having “big benefits for the excipient industry as well as the pharmaceutical industry and regulators around the world.”

Industry involvement, he maintained, is needed to help ensure that the excipient data in GInAS is correct and to help define a mechanism to address excipient formulation and/or processing differences and how they will be reflected in the database when the same excipient is made by multiple manufacturers. Also desired by IPEC is a process for updating GInAS data found to be incorrect.

In discussing industry’s need to be involved in determining what goes into the database, Schoneker cautioned that the inclusion, for example, of a particular impurity, could reveal to a firm’s competition what manufacturing routes or catalysts are being used in its process.

He also pointed out: ● the unique requirements for specified substances ● the need for data confidentiality, such as the use of non-published safety data and compositional impurity information, and ● some changes that IPEC feels would be needed in the SRS/UNII nomenclature rules as related to certain excipients to allow the GInAS approach to work.

Spectral Library Will Empower Monograph Modernization

Some of the same concerns that IPEC has with the GInAS effort also extend to USP’s spectral library initiative – specifically, the need for confidentiality of data that has the potential to reveal trade secrets.

While the spectral library is envisioned as being made publicly available, the project team is considering limited access to excipient clients where security or intellectual property (IP) issues may be a concern.

The USP/FDA project, which began in 2007, is incorporating the capabilities of CDER’s Forensic Chemistry Center (FCC) in Cincinnati in creating a library of spectral “fingerprints” (ibid.). The GInAS database has the potential to house the spectral data.

The forensics center is using multiple, orthogonal analytical technologies including gas chromatography-mass spectrometry (GC-MS), near infrared spectroscopy (NIR), NMR, SRD/SRF and Raman technology to gather spectral information for material and contaminant identification.

While the challenges in developing a spectral library are many, FDA is working with USP to develop a road map to identify the challenges and propose solutions.

The spectral library effort and how it relates

to FDA’s concerns with the drug supply chain were discussed at the GInAS June meeting by CDER Office of Drug Security, Integrity and Recalls (ODSIR) Consumer Safety Officer Steve Wolfgang (his complete remarks at the meeting are provided below).

Wolfgang pointed out the current weaknesses in the pharmaceutical excipient supply chain, the importance of correctly identifying incoming materials, and how the USP/FDA spectral library project may be used to address the weaknesses.

Excipients are in scope for the library “based on the premise that the excipient supply chain needs some help,” Wolfgang commented – specifically to enable users of excipients to be sure that when they buy an excipient they are getting “the genuine article.” He expressed concern regarding “the infiltration of unsuitable excipients” into the pharma supply chain, and, in particular, the failure of the end user to be able to recognize when that has happened.

Contributing to the elevated risk of undetected adulteration is the lack of specificity of ID tests – a concern that has been expressed in a series ofletters since 2010 to USP by FDA’s Monograph Modernization Task Group [MMTG] (see IPQ “Monthly Update” July 2014, pp. 30-43).

Noting that the monograph modernization efforts by the US, European, and Japanese pharmacopeias have been in progress for many years, Wolfgang, who has participated in the efforts, characterized the task of updating the “outdated and non-specific” ID tests as “extremely difficult.” He commented that the spectral library project could be a “possible solution.”

NIPTE/FDA/UMD Project Targets Better Formulations

The NIPTE/FDA/UMD project is focusing on excipient properties and the comparison of critical material attributes and variability of individual excipients over time and between vendors. The ability to compare excipient parameters and perform data-mining is intended to improve understanding of product design and to enable better product formulation.

The database is already functional and is being populated with information from the literature and from excipient makers and users (a link to the current database is provided below). It is intended to facilitate better formulations by aggregating data over time from the literature, vendors, and pharma firms, then analyzing it and looking for patterns.

At the Generic Pharmaceutical Association (GPhA) Fall Technical Conference, held in late October






2014 in Bethesda, MD, UMD School of Pharmacy professor and NIPTE executive committee member Stephen Hoag commented on the potential power of the database in allowing for a linking of the “supplier’s data to the user’s data and how that affects performance.”

As an example, he pointed out that when a change is made in an excipient manufacturing process, it could be detected in the database and monitored by the user to determine if that change had an effect on the product formulation.

Data mining will also allow users to see the range of variability in excipients, both over time from the same vendor and between vendors.

Hoag explained that sources of variability in excipients can be either random or intentional, and as such, cataloguing them is “very important.”

Intentional variability is introduced by the supplier within monograph limits to create different grades or introduce properties that better enable formulation – for example, for microcrystalline cellulose, the particle size, moisture content, and bulk density are varied.

Hoag maintained that it is important for excipient users to have a tool that will separate the random lot-to-lot from intentional variability and categorize the two types – one of the intended purposes of the NIPTE/FDA/UMD database.

The UMD professor also stressed the importance of the database as a platform for sharing data in a neutral system and in providing a mechanism for interaction and feedback between excipient makers and users.

IID Concerns Include Generic Drug Review Impact

On the IID front, in September and December 2014, IPEC and FDA continued their series of meetings to discuss the challenges in improving the accuracy of the content and the functionality of the IID. The Generic Pharmaceutical Association (GPhA) has also been participating in the

meetings.

Among the high priority items under discussion at the meetings have been safety evaluations for excipient families, including polymers, and acceptable levels in generic drugs, as well as conflicts and actions needed to resolve current issues in FDA guidances that IPEC-Americas and GPhA feel need “immediate attention.”

FDA was tasked at the December meeting with making a decision on the family approach by the next quarterly meeting, scheduled for late February, 2015.

GPhA’s concerns are reflective of the impact that the IID database continues to have on the generic drug review process.

For example, if the limit listed in the database for an excipient is exceeded without the generic drug manufacturer supplying extensive supporting documentation, the application will be classified as “refuse to receive,” and may lose its “first to file” status. When that happens, the result is a potentially large financial penalty for exceeding an excipient level in an oral product that may be well below the threshold for the same material used in a food product.

Many of the challenges previously on the table – including the family approach and the lack of accuracy of the information in the database, which continues to be used to make regulatory decisions – remain unresolved, pointing to the importance of the broader-based GInAS and NIPTE efforts.


• NIPTE/FDA/UMD Excipients Knowledge Base

Story Continues on Next Page

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COLORCON’S DAVE SCHONEKER ON EXCIPIENT DATA IN GINAS

At the June 2014 GInAS meeting, Colorcon’s Dave Schoneker, who serves as IPEC-Americas Maker & Dis-tributor Relations Committee Vice Chair, provided an excipient industry view on the GInAS project. In his remarks, Schoneker focused on: ● the possible use of GInAS for safety references, spectral identification, and elemental impurity information ● the industry correctness assessment of GInAS data ● information/data handling sourced from multiple excipient manufacturers ● the possible misuse of GInAS data ● the inclu-sion of specified substances ● data confidentiality ● some changes that IPEC feels would be needed in some of the SRS/UNII nomenclature rules as they related to certain excipients, and ● a process for updating GInAS data that is found to be incorrect.

I will talk a little bit about some of the things we have been discussing over the last two days. I will try to sum it up in terms of IPEC’s perspective on the excipient part of the story.

Industry Involvement

I think that IPEC-Americas certainly is supportive of the development of a global database like GInAS. I think the key thing from industry’s perspective would be to have one place to go – not multiple versions of this in different countries with slight differences. You are not going to get a lot of participation from industry with that kind of approach.

Overall, the concept is something that I think has big benefits for the excipient industry as well as the pharmaceutical industry and regulators around the world. We think it would be very helpful to compile and standardize this kind of substance information for regulators and industry. But there are some key points that we think are going to be important to getting industry involved.

One of those would be that the manufacturer of the substance should be involved in entering information about their materials, especially as you get to specified substances. For regular substances, it is more general. But as you start getting to specified substances, we think that the manufacturer of the substance being talked about needs to be part of the reviewing cycle prior to putting information in the database. Again, I think that is not inconsistent with some of the things I have been hearing.

So the types of data that we think could be considered in addition to some of the standardized information that we talked about that we would have an interest in exploring would be safety data and toxicology summary information related to the safety of the excipient and the excipient family. I am going to talk about each one of these in more detail.

Excipients are used by everybody. Most of them are food additives or similar to food additives. They are very safe materials. Many times you can eat them in large quantities in the food industry…but in the pharmaceutical arena we have all these things where we worry about a silly milligram here or there. In fact, in many cases, the actual safety data that supports its use is never looked at, as opposed to looking at some list of precedence issues. That is something that we feel there needs to be improvement in, especially globally, for us to really survive in the future.

The spectral library identification project that [FDA’s] Steve Wolfgang talked about [see Wolfgang’s remarks below]: We think there is some real potential there. And then finally the elemental impurity concentrations – typical concentrations that might exist for certain materials – I think is going to be especially important with all the impetus now in ICH Q3D as it goes to Step 4, which I understand didn’t happen this month but should happen before September. [Editor’s Note: The ICH Q3D guideline reached Step 4 of the ICH process in December 2014. For more on the implementation challenges that the guideline presents, see IPQ “Monthly Update” October 2014, p. 23-31.]

This is going to be an area with excipients that is going to be a lot more complex than anybody understands. It is not necessarily the limits and everything else, it is going to be the testing. The testing in these matrices from the work that we have been doing in industry is much more complex than anybody thought it was. We thought it was going to be pretty complex, but it is going to be a lot worse. It is going to be really important how we implement those controls and how we think about risk assessment as a tool as opposed to just doing a bunch of testing that does not make a lot of sense. We think there is a place for that as well.

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Some of the defining properties and specifications that you might be interested in getting into the database might be difficult to acquire for a number of different reasons. One of the big ones that I already talked about and you will see throughout the rest of the presentation is the issue of different levels of confidentiality. Again, as we mentioned, maybe there are some ways of dealing with that. That is going to be a critical piece to all of this.

Safety Assessments

Let’s talk about safety assessments for a minute. There has been huge confusion within the FDA about this issue that has created a monster for the generic drug industry. It relates to the IID and the way that the SRS system has driven the nomenclature that goes into the IID, which the Office of Generic Drugs uses essentially as a bible for ‘refuse to receive’ [RTR] decisions on a drug application coming through.

They are looking at the level of a particular excipient. And if anybody exceeds that level and there is not a safety justification with all kinds of data, it gets a refuse to file. There have been many circumstances with huge implications, like people losing first-to-file status, and everything else, over something crazy. I will give an example in a minute. The real key here is that where the understanding has to be is that many of these excipients are families of excipients.

We talked a lot about polymers. This is a key area. A polymer family does not have toxicology data on each and every grade. It has toxicology data that spans the entire family. It has one set of toxicology data. And it doesn’t matter if you are looking at this or that viscosity grade, you are going to have the same exact tox data and the same ADI [allowable daily intake]. There is a one-to-one relationship between a UNII code and a specific grade of material, which, as we all know, is important.

The important thing that we think about as we structure how safety data can go into a database like this, and especially with the IID connection that is out there, is the safety data for the family has to represent a one-to-many relationship. There must be a connection of that safety data and whatever the highest level of use is that we are going to say is okay for one grade. And that highest level for use has to be acceptable for all of those grades.

Hypromellose Example

Now what I am talking about here is an example that has created a monster. This is one of our favorite examples that we have used in previous talks – the hypromellose nomenclature issue. But the problem with the connection to the IID has been that in the IID we had this generic term called ‘hypromelloses.’ We had a whole bunch of listings for hypromelloses, and in the IID it had a unique code for the generic name. We had maximum potency levels listed, and you will see the top one is 670 mgs. For years, 670 mg is what everybody used for all the grades. It was an acceptable level for high-grade hypromellose from an IID referencing standpoint.

Now with the new nomenclature coming in, and all new applications being put in the system with the new nomenclature that gets into the substitution type, the viscosity type, etc. – if you do a search based on hypromellose 2910, you will see a bunch of the specifics [showing the variation].

But I am just going to use one common example here, and that is hypromellose 2910 5 MPA S. You will see that the maximum potency level is 2.02 milligrams. Now this particular grade of hypromellose is the most used grade in film coatings in tens of thousands of drug products all over the world, and it is also a material that is used in the food industry and you can eat it by the pound. But we have 2.02 milligrams, and we actually have OGD reviewers refusing to file drug applications because somebody wants to use four milligrams. That is a real life case study where I got involved. Meanwhile, 670 was always there for some generic listing that somebody got approval for.

If you look from a nomenclature standpoint in the IID currently, and go under hydroxpropylmethyl cellulose E5, you will also see that it is listed at 9 milligrams. So when you are a drug company, you know, which one do I use? This is a very confusing thing if they put in hydroxypropylmethyl cellulose they get nine, and look at the specific grade they get two, and if they look at the general grade they get 670. At the end of the day, the safety data would support eating it by the pound. This is all in oral applications that I am looking at. It does not make sense.




How do we get the safety data to cover the family both from a GInAS perspective, and even more importantly from a regulatory decision making perspective, as far as excipient safety?

If we look at hypromellose, there are many grades – many different viscosity grades, different substitution grades – and there have been many studies out there that have demonstrated that there is absolutely no difference in toxicology depending on the methoxy or hydroxy or propoxy compound. Viscosity has not been specified by JECFA [Joint FAO/WHO Expert Committee on Food Additives] on the food side as a factor related to safety. CFSAN also concluded that for cellulose and cellulose derivatives – this pretty much covers all of this family of materials – on the food side was there is no safety effect derived from the change in viscosity.

Meanwhile we have OGD reviewers refusing to file an application for four milligrams of hypromellose – a lot of wasted time. So hopefully some of the efforts that we are doing at GInAS can tie in with decision making at various levels in the regulatory community – ideally in a global way – to solve problems like this. Frankly, this is a waste of time, a waste of resources, and frankly all we hear today from regulators around the world is, ‘we are going to use risk assessment.’ What is risk assessment about that? In fact, they are going to refuse a four milligram type of thing. So we have to use the safety data to look at the maximum level of use and accept that – not look for how we can justify small levels of use.

Just expanding on this: This is just if we look at a couple of different listings, and this comes from the IID as well, some different grades of hypromellose, different viscosities, and different substitution types. The UNII codes are listed there, and you see the maximum potencies are all over the place. The bottom line is that the same safety data supports all of it. It should not be any different.

If we get into other cellulosics – you got ethylcellulose, sodium CMC, methylcellulose – each one of them have family-based safety data that cover much higher levels than any of the levels that have prior use. So the ADI needs to be driving these decisions. On the food side, that is what drives the decision, not some precedence of use level because somebody just happened to use it in a drug that high. We need to get the thinking process changed in that area.

Industry would probably be willing to supply safety data on excipient families, which could be included in GInAS, where that data is published. And in many cases, there is published data. We are actually already working on a template with the Office of Generic Drugs here in the U.S. as to how summary safety information could be supplied to support a family approach on this.

However, when it comes to non-published safety data, again we run into some confidentiality issues, because many times the company has spent millions of dollars on that and it is not in the public domain. They do not want to necessarily have that data out there without it being referenced in some confidential manner. And again, the type of guarantee there is that the information is also not accessible under freedom of information [FOI].

Spectral Library and Elemental Impurities

Now with the spectral library: Steve [Wolfgang] has talked a lot about this. Excipients from various manufacturers may have different spectral profiles due to the compositional differences from different raw material sources and from different manufacturing processes. We have been working, as I mentioned, with FDA on this project, and we would be interested in working with the GInAS group as well as Steve’s group – the group working on it within FDA and USP – to define how this library could be incorporated in the GInAS database with manufacturing involved and expand thescope somewhat.

To move on to elemental impurity data: We have collaborated very closely with the FDA’s research labs in St. Louis, trying to get an understanding of what levels of elemental impurities of all these 28 different metals might actually exist in some commonly used materials, especially mineral-derived materials where there is a higher likelihood of some elemental impurities being there.

We put together a blinded supplier study, where we supplied a lot of samples to FDA where the supplier was not identified. They have done a tremendous amount of analysis at the laboratory. [Dow Corning’s Kathy Ulman] and I have both been involved with FDA’s Jon Kaufman on this, and I know there is a publication that is going to be coming




out soon where this data is going to get published to start giving people an idea of what levels might we see or not see of some of these metals.

In most cases, most of these materials have never been tested at these levels for many of these elements. And FDA has certainly indicated an interest in finding an appropriate mechanism for making both the data that they are putting together as well as industry data come together into some sort of format that would allow companies to assess the risk of what they should be putting their resources towards in terms of testing. You can’t test everything for 28 metals – that is just not reasonable or necessary.

There are other industry groups that have begun to compile typical elemental impurity data on both excipients and APIs. A template is currently being developed by a group in the U.K. to standardize how this information could be put together related to sample preparation, analytical methods, and how the data could be compiled and shared, because it is going to be critical with elemental impurities. The test methodology is going to be key to the results, more so than we have seen in many cases. All of that is going to have to be a data set. Otherwise, the results will not be comparable.

Elemental impurity data again could be uploaded into GInAS, but it is going to be important that it is going to be represented simply as something that is typical of what might occur at some manufacturers, because it is going to be a limited dataset at best. What we do know is that these materials might be quite different, not only from manufacturer to manufacturer, but even from batch to batch – for example, if you consider something that comes from a mine.

The level of a metal depends on where you are digging in the mine. And what it was last month and for the last hundred batches might have absolutely nothing to do with what you are going to see in the next batch that you get. There is no predictability in that situation. But at least it might target what types of metals you might want to control at a higher level than other metals that you don’t have to control as much.

It is going to be really key that the data not be used to represent any type of a specification or established range – that would be the nail in the coffin. Nobody would provide any data if it got represented in some manner in that way. It only can represent likely concentrations based on some current available material or data.

So traceability confidentiality of the supplier and data for each substance is critical here. Again, we have put together a blinding mechanism at the first stage. But companies may be interested in supplying their data into something like GInAS if there is a way to maintain that confidentiality of whose material had what level. People aren’t going to want to put that out there with their name on it necessarily if they have got a little bit of this element that might trigger some attention in terms of a competitive threat.

And so we are considering right now – and I will say considering, because it is not established yet if or how we would do such a thing – the design and implementation of some mechanism where suppliers could submit the data through IPEC for a vetting and blinding and a subsequent uploading into something like GInAS, utilizing appropriate legal ways of keeping that blinded from even all other IPEC members. However, there are some issues around how we would fund such a thing and how it would be administered. Those would have to be resolved before we set up something like that. But it is not that much different from what we have been talking about with GInAS.

Correctness Assessment

Correctness assessment of data: The substance data and information that gets uploaded to GInAS, we believe, should be assessed for accuracy by the substance manufacturers prior to publicizing it in GInAS. That should take place through some sort of a standardized process where the manufacturers are involved, and it should be something where the process takes place well before publicizing it in the GInAS database.

If the information is found to be incorrect that somebody has dug up and wants to be put in the database or whatever, there needs to be a process for correcting that through a simple mechanism prior to publishing it in the first place. Because if it gets out there and it is wrong, it has already created a problem. And if we fix it, it is too late. It could kill somebody’s business. It could do a lot of damage if it is not correct.




Data from Multiple Manufacturers

Handling information from multiple manufacturers: We need to define a mechanism to address excipient formulation and/or processing differences, which can be significant between manufacturers of the same substance. As I think I mentioned earlier, the type and level of additives and residual processing aids can vary quite significantly between manufacturers and can have a major impact on the functionality of the excipient. It can have an impact on the stability of the drug, and many other things, and many times that is information that has not been accessible to anyone at this point.

There is actually a project we have underway at IPEC. We will be going to FDA later this year to have a whole discussion about how to handle the issues related to additives and processing aids. It is a very controversial topic. To get companies to talk about it in the right way, there has to be mechanism of somehow grandfathering the past and finding the right way to have this conversation in a quality-by-design arena. That is where we need to have that discussion. But if that discussion is going to result in somebody being threatened because that material was there all along, that is going to be a problem. We have to find a way around that. We will be talking to FDA more about that later this year. We do have to ensure strict confidentiality around all this type of information, as we have been saying.

Possible Misuse of GInAS Data

So, the possible misuse of GInAS information: Again, we have alluded to some of this. Publicizing compositional and impurity information: It may be information that a regulator might not think there is any big deal. But it may be that that particular impurity is what gives away to the competition exactly what you are doing in the process, or what catalyst you are using.

Think of it in terms of Coca Cola: If there is something that is going to give away the magic ingredient in Coca Cola for some small bit of business that you don’t care about, there is no way you are going to continue doing that business. I think that is the way it is with a lot of excipient companies, if there is anything they have to provide in the pharmaceutical arena that might affect their competitiveness in the food world or the industrial world. That is business that is, in many cases, just nice to have, excess business, but is something that is not a target. And we have to recognize that….

Specified Substances

Specified substances: In this case there are a number of different issues. The first one I will talk about has to do with mixtures. There are many different kinds of mixtures out there – whether it be compositional mixtures of a standardized excipient, whether it be a formulated system, whether it be co-processed excipients. There are a lot of things where percentages and mixture levels come into play.

Specified substances may be a good place to put that kind of information, because right now that information is held within drug master files. But when it comes to the global aspect, many times it is more difficult to try to supply this information through a customer, who is going to be the user, and then get it to the regulatory agencies that need it.

This is specifically a problem in Europe, where there is no drug master file, and the only mechanism we have in Europe to get this information to a regulator is to provide it to a customer. Well, if it is confidential information and you don’t trust the customer because they have given your information away before, now you have a problem. Either you give it to them, or they cannot use the product. And so you are in a Catch-22….

The IP protection needs to be at the same level as we have for drug master files. The bottom line is if that kind of appropriate IP protection is not there, than industry is probably not going to be willing to assist in providing much of this information going forward.

Nomenclature Rules

Now let’s switch gears to the SRS/UNII nomenclature rules, which I know are coming over to GInAS. There are some




areas and examples that I want to bring up...because some of them need to get fixed, and they need to get fixed now. Prior to when we would go forward too far with GInAS, we feel it would be important to get these things addressed because they are creating a lot of confusion.

I am going to talk about two examples: Polyethylene oxide – and I was glad to see Kathy Ulman use that as an example in her presentation yesterday – is a very commonly used polymer material, and the nomenclature got changed in the SRS system to call it polyethylene glycol. I am going to show an example here of why that is not an acceptable nomenclature for this material.

Aluminum lakes was changed to be a multiple material of aluminum oxide and associated dye. Again, not an appropriate representation of that material. I will talk a little bit more about that.

If we look at polyethylene oxide vs. polyethylene glycol, which is what it is called now, it is not just a molecular weight difference. If you look at the two charts at the bottom, they show you the molecular weights of what we would consider to be polyethylene glycol, and then up where polyethylene oxide is, is a huge difference in molecular weight. Polyethylene oxide is in a different physical state, it is a different molecular weight, it is a different manufacturing process, and a completely different impurity profile. So there is nothing the same between polyethylene oxide and polyethylene glycol except the repeating unit. So the repeating unit is what drove the nomenclature. But that is the only thing that is the same. Anybody using this material knows that.

Updating Incorrect Information

I am just using this as an example of where we need to have a way to correct for these things as we go forward. And in this case it shows an overview of the manufacturing processes, which are quite different. In the right corner, it actually shows some of the safety data for polyethylene oxide that again supports this….

The point I am trying make for both of these is that you have scientific rules based on just chemistry, and then you have other regulatory rules that sometimes take precedence, and this is an example with the lakes. The 21 CFR tells you

that you have to call it FD&C blue number two, aluminum lake. That is the name that you are forced to call it.

Even in your compositional labeling, if somebody put in ‘aluminum oxide and dye,’ that is incorrect. Regardless of what you want to say about the connection, it is a unique entity, and it is regulated and certified that way.

All I am saying in this particular case, is that representing it as aluminum oxide and dye is misrepresentation of the true material being used. I understand the reasons why it got that way. But as we go forward we need to have a mechanism so that this does not happen and find out afterwards. We need to have a mechanism to ask whether it is some sort of exception to the rule. The rules have to be basically in the situation where if there are other things that would dictate a different way to call it, like a regulation, well that needs to take a priority over the chemistry or something.

I was just using these as two examples because they highlight some of the issues we need to think about going forward with other materials as we make it more global. I can tell you these two examples have created a huge amount of confusion in the industry, and even with regulators who do not understand all this stuff.

Some simple mechanisms for corrections could be utilized. Again, this process we need has to be simple, standardized, and allow for quick changes. I think IPEC members would like to be actively involved in the development of the database, and we welcome discussions with your implementation team and how we can develop acceptable resolutions to some of the concerns that have been identified here.

Story Continues on Next Page




CDER’S STEVE WOLFGANG ON THE FDA/USP SPECTRAL LIBRARY FOR EXCIPIENTS

At the GInAS meeting, CDER Office of Drug Security, Integrity and Recalls Consumer Safety Officer Steve Wolfgang discussed the current weaknesses in the pharmaceutical excipient supply chain, the importance of correctly identifying incoming materials, and how the FDA/USP “spectral library” project may be used to address the weaknesses.

I am with FDA. I have been with FDA for about 10 years. I started out in industry for about 15 years on the manufacturing side. With FDA, now I am in the CDER Office of Compliance, in the Office of Drug Security, Integrity and Recalls, which was created about three or four years ago specifically to address issues in pharmaceutical supply chains both upstream and downstream. My area of expertise being upstream, that is where I tend to focus.

Excipient Supply Chain Weaknesses

In looking at where some of the weaknesses are in the pharmaceutical supply chain, we think back to some of the adulteration incidents. What we found is that, in general, obviously globalization is part of it. And because of globalization – we don’t have the exact figures or numbers like 40% or 80% – but I am just going to say that a significant portion ofsupply chain ingredients come from outside the US. And a large share of that is used in foreign manufacturing sites. So we do not really see all of the ingredients coming into the US.

The other thing specifically about excipients that I have learned over the years in the manufacturing industry is that there is a very fine line between what people call an excipient and what was manufactured as an industrial grade chemical. What you want to realize there is that somebody is making ingredients for pharmaceutical use and they are also making them for other markets in the same building, on the same equipment, often times using the same manufacturing process.

Another important consideration for globalization is that there are many intermediaries that make up the typical supply chain. And the more global the supply chain, the more intermediaries there possibly are.

With that, you often times see that people who are using the ingredients may know the people that are selling them directly to them. But they do not have that level of personal interaction, and often times that is what it takes. They

may think that the person that is selling it to them is actually making the ingredient, when in fact they are not. With the possibility of having multiple transactions of ownership, transfers between hands, and transportation across long distances with different carriers, you have a lot of potential things that can go wrong, whether intentionally or unintentionally.

Identifying Excipients

What we have been considering as part of a spectral library for excipients is based on the premise that the excipient supply chain needs some help, but specifically the users of excipients need some help to be able to say that when they buy an excipient that they have the genuine article. This may or may not be as true for the bigger pharmaceutical companies as much it is for the smaller ones, but in general it is a good idea for somebody to be able to say that this excipient is definitely coming from the place I think it is coming from.

As far as the library goes, what I have found in looking at some of the FDA data, as poor as our data systems are, is that certain excipients are very common in drug products. There might be 20 or 30 excipients that tend to show up repeatedly, even though there might be as many as 1200 that are actually being used. The possibility is more about the infiltration of unsuitable excipients and, in particular, the failure of the end user to be able to recognize when that has happened.

Part of the problem there is that the end user has to very heavily rely on ID testing, and basically those are the only tests that are being done often times when shipments arrive. So what they will do is qualify the supplier by testing a few batches. They will check the supplier’s CoA and their findings and see that they agree, and at a certain point




they feel that they have a high enough confidence that they no longer need to test. There are some reasons why that confidence level should not really be that high – being mainly the fact of globalization and that they might not know the supplier that well.

The other thing that is important here is that when a drug is approved, the excipients that are in that drug are approved along with it. We certainly do not approve excipients apart from drugs. So what that says basically is that the whole premise of the drug approval process is that the excipients that were used in making those exhibit batches, which are few, that were presented to FDA, are going to be representative of what is going to happen after this drug gets approved, for 15, 20, or 30 years down the road.

There is a little bit of concern there that the manufacturer will not be able to assess that continuity, particularly in terms of knowing if the people they are buying from are the same people that they have bought from all along, or are the same manufacturers of those ingredients. The reason we are looking at excipients for these libraries is that they are a significant fraction of the product, usually more than the API.

And secondly, excipients often show up in many FDA-regulated products, such as food, cosmetics, animal drugs, or devices. So the interest here in terms of this project is actually falling under what we call ‘the China safety initiative,’ which is more or less an effort at addressing the global supply chain for all FDA-regulated commodities, and, in particular, the ingredients that go into them….

The Spectral Library

[Why participate in the spectral library project?]

For the manufacturers of the excipients, it gives them a chance in their global distribution network to detect somebody falsely claiming to sell legitimate excipients.

For the users, it gives them an opportunity to identify the excipients. And based on the capabilities of the technologies that are out there, what we think is that it might help to be able to tell you if you bought an excipient from one particular supplier or another. In addition to that, there is this concept of a fingerprint: Each time something comes in, we will do a screen on it and compare it to what is in the library, and give you some sort of a rapid screen for any amount that might show up that you might want to investigate.

Everyone who has been involved knows what a struggle it has been to try to modernize excipient monographs. In particular, the ID test modernization has been extremely difficult for us. We have actually formed expert panels to look at some of these specific excipients like povidone, and it comes down to basically a bunch of ID tests that are being done that are really outdated and non-specific.

Lastly, for the regulatory agencies, it gives us an opportunity and a tool for the work that we do to make it less invasive and less time-consuming than it currently is.

So, what we have done with USP as part of the project is we have asked USP to do a global scan. And we have also, ourselves, been involved in the spectral library development since around 2007. We have talked with a lot of the solution providers themselves. They have had discussions around a lot of the observations that have been made.

Basically, the interim software solution providers were hot to trot, so they went right out and started working with the contract manufacturers and built those relationships, and they started developing libraries that were not based on any recognized standards or any protocols dictating sample collection for building libraries – for example, for how many or how long do you have to collect samples before you know you have a very good representation of the excipient that the manufacturer produced?

As a result, the quality robustness is variable. You can talk to the instrument manufacturers and you can gather that some have felt that it is good enough just to be able to identify an excipient. But others are a little bit more progressive in terms of the capabilities of their technologies that might have more discriminatory power and possibly be able to detect very minor, subtle differences that could show up.




The challenges in developing a spectral library are many. We are working with USP right now on developing a road map, which will identify some of the challenges or all of the challenges, and also propose solutions to meet every single one of the challenges.

So here they are: Basically you can see some of the ones that I mentioned before. The big ones that are probably of interest to folks in the room are…managing the equipment and the spectra and metadata on an ongoing basis. All this information is going to be collected by people throughout the world. It basically has to be processed and somehow managed.

In order to get a bunch of people on board with this idea, we have to also assure them that the information will only reside in the library. But we still realize that various people are going to be hesitant to participate based on concerns about security or IT issues. So we have to address those issues, obviously. My feeling is that those issues can be addressed. I look at things like credit cards, which obviously are not impenetrable, but you get the picture that it is possible to develop a secure system….

The other thing that we realize and that we are trying to achieve is collaboration. We definitely want to bring excipient manufacturers on board, laboratories globally, and solution providers, who are very important in helping us get to the point where we can develop standards that are workable for everyone – for the instruments, software creation, and for the algorithms.

And finally, the host for the library: The vision is that it is possibly a web portal, possibly a single access point where [information on] all genuine pharmaceutical excipients is housed.

This is a little bit about excipient candidates that have been thought of: As we have found, excipients used in solid oral dosage forms comprise 80% of excipient production volume. And among those there are four or five categories of excipients that tend to show up all the time, including fillers, binders, lubricants, etc. It turns out when we look at those common excipients, among the ones most widely used the ID test is often non-specific or nonexistent. So therein lies a significant opportunity….

An opportunity for statisticians to share, discuss and collaborate in finding optimal approaches to implement statistical elements within the

FDA PV Guidance

Work alongside FDA representatives and seasoned statisticians to examine and evaluate various statistical approaches supporting the lifecycle

approach to Process Validation

REGISTER TODAY: www.ISPE.org/2015StatisticianForum

Connecting a World of Pharmaceutical Knowledge

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Scheduled Workshops

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March 25

March 26

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Fees

IPEC-Americas Members: 1 workshop - $700 2 workshops - $1190 3 workshops - $1680

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Risk assessment and Quality Risk Management are new components of excipient Quality Systems. Eleven sections of the new excipient GMP Standard require risk assessment.

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Workshop Leaders Learn from individuals involved in the development of the IPEC guidelines; each with over 20 years of experience

Day 1 - Qualification/Validation

Tuesday, March 24, 2015 8:30AM-4:30PM This workshop reviews the requirements for equipment and instrument qualification and process, computer, cleaning and method validation. Also addressed is risk assessment to determine the potential quality effect on the excipient from changes to facilities, operating parameters, equipment/instruments, and packaging materials READ MORE

Day 2 - Quality Risk Management and Risk Assessment

Wednesday, March 25, 2015 8:30AM-4:30PM This workshop reviews the various techniques for evaluation of risk under a Quality Risk Management program. Risk Assessment is a systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. READ MORE

Day 3 - Significant Change

Thursday, March 26, 2015 8:30AM-4:30PM Learn how to identify and evaluate changes involving the manufacture of pharmaceutical excipients that may impact the drug formulation and when it is expected that the pharmaceutical customer will be notified of the change. See how risk assessment facilitates making an informed risk decision. READ MORE

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Updates in Brief

CMC/REVIEW

Commissioner Hamburg Stepping Down

Commissioner Margaret Hamburg, who has served for almost six years, announced that she is stepping down at the end of March. Commissioner Hamburg had previously served at NIH and as New York City’s health commissioner. Stephen Ostroff, FDA’s chief scientist, will hold the position of acting commissioner until it is filled.

CDER Guidances in 2015

In late February, CDER published a list of new and revised draft guidances that it plans to issue in 2015. Quality-related topic areas include: ● biosimilars (4) ● generics (5) ● pharmaceutical quality/CMC (13) ● pharmaceutical quality/cGMP (3) ● procedural, including DQSA implementation – compounding (1), and track & trace (6).

FDA Guidance Database

FDA introduced a new guidance database in early January. The database allows guidance searching based on product type or FDA office and includes whether there is an open comment period, when a guidance was issued, and if it is finalized or a draft.

GDUFA Comment Period Extended

FDA announced in the Federal Register in early February that it was extending the comment period on the agency’s earlier request for comments on what GDUFA implementation topics are still in need of guidance. The extended comment period ends on March 9. For guidances to be issued on GDUFA in 2015 see above.

Kathleen Uhl Named Director of OGD

Kathleen Uhl was named as director of the OGD office in mid-January. She has been serving as acting director of the office since 2013. [See IPQ “Monthly Update” November/December 2013 pp. 2-15 for Uhl’s discussion of OGDs GDUFA goals.]

Comments Requested on Licensing Provisions for Biosimilar Applications

In early February, FDA requested comments on the licensing provisions and interchangeability data required for biosimilar ap-plications. The notice states that biosimilar manufacturers are expected to have the same clinical results and no greater risk than the reference product used.

Biosimilar Filgrastim Recommended for Approval

FDA’s Oncologic Drugs Advisory Committee (ODAC) recommended approval of Sandoz’s biosimilar filgrastim in the US. The product is a biosimilar of Amgen’s Neupogen. Sandoz’s filgrastim would become the first biosimilar approved in the US.

Advisory Meeting on Celltrion’s Infliximab Biosimilar Delayed

A meeting to evaluate Celltrion’s biosimilar infliximab, scheduled for March 17, has been delayed. The product is a biosimilar of J&J’s Remicade and is the first biosimilar mAb filed in the US. No new date has been set. The reason for the delay was given as “information requests pending with the sponsor.”

Biotechnology Office Reshaped under Office of Pharmaceutical Quality

Following its inclusion into the Office of Pharmaceutical Quality (OPQ), CDER’s Office of Biotechnology Products (OBP) will be reshaped. Previously the office had two divisions, one for mAbs and one for other proteins. Now, a central OBP group will evaluate INDs, NDAs, and BLAs and assign theme to an appropriate review team in one of four of the new divisions, which will not be organized by product type.

UNITED STATES

http://www.fda.gov/AboutFDA/CommissionersPage/ucm433094.htm

http://www.ipqpubs.com/wp-content/uploads/2015/03/Guidance-Agenda-2015_022715.pdf

http://www.fda.gov/RegulatoryInformation/Guidances/default.htm

https://www.federalregister.gov/articles/2015/02/06/2015-02401/generic-drug-user-fee-amendments-of-2012-september-2014-public-hearing-on-policy-development

http://www.drugstorenews.com/article/fda-names-acting-director-ogd-director


https://www.federalregister.gov/articles/2015/02/03/2015-02025/agency-information-collection-activities-proposed-collection-comment-request-general-licensing?utm_campaign=subscription+mailing+list&utm_medium=email&utm_source=federalregister.gov

http://www.novartis.com/newsroom/media-releases/en/2015/1885139.shtml




Office of Regulatory Science and Innovation Science Symposium

In late January, FDA announced its 2015 Office of Regulatory Science and Innovation Science Symposium, to be held on April 27. The symposium is designed to increase scientific collaborations with government institutions to improve training and advance regulatory science.

USP Elemental Impurities Timeline

In mid-January, USP announced January 1, 2018 as the date of applicability for its chapters <232> and <2332> on elemental impurities. The new date is in alignment with the implementation date for ICH’s elemental impurities guideline Q3D. [Implementation of ICH Q3D is addressed in IPQ “Monthly Update” October 2014 pp. 23-31.]

GMP/INSPECTION

Draft CGMP Requirements for Combination Products

In late January, FDA released a draft guidance on CGMP requirements for combination products. The guidance is organized into four main sections, covering: • background • general considerations for CGMP compliance • specific information on 21 CFR 4.4(b), and • applications for specific types of combination products. The guidance fleshes out the January 2013 final rule 21 CFR 4 on CGMP requirements for combination products.

Compounding Advisory Committee Meeting

In late February, FDA’s Compounding Advisory Committee held a meeting on implementing the compounding provisions (Title 1) of the Drug Quality and Security Act (DQSA). The first part of the meeting discussed proposed revisions to the list of drugproducts that may not be compounded, while the second part focused on the criteria for developing a list of bulk drug substances that may be used to compound drug products.

Draft Guidances on Compounding

In mid-February, FDA issued five draft guidances on policies for compounding and repackaging. One draft covers whether a company should register as an outsourcing facility, while another discusses regulations around repackaging by outsourcing facilities. A draft on biologics repackaging covers when the agency will not take action against facilities lacking a BLA. The other two guidelines cover adverse event reporting for outsourcing facilities and a draft of a Memorandum of Understanding a state would sign relating to compounded drugs.

Import Alert on Ipca Labs

Ipca Laboratories Ratlam, India plant was placed on FDA’s import alert list in late January. The company announced it would voluntarily halt shipments to the US until the data integrity issues highlighted by FDA were resolved (see IPQ “Monthly Update” July 2014 p. 44) Canada has also placed restrictions on Ipca’s products (see IPQ “Monthly Update” October 2014 p. 41).

Ranbaxy Lawsuit Denied

A lawsuit from Ranbaxy against the FDA to reinstate approvals that were revoked based on FDA’s findings of data integrity breeches (IPQ “Monthly Update” March/April 2014 pp. 19-29) was thrown out by a federal judge in late February. In revoking them, FDA denied Ranbaxy the six month exclusivity it would have received for being “first-to-file” generics.

Med Prep Indictment

An indictment was released in mid-February, charging Med Prep Consulting with violations of the FDCA for introducing adulterated and misbranded drugs into commerce. According to the indictment, Med Prep misrepresented that it had met or exceeded GMP standards and laws for sterile drug manufacture, while failing to meet established GMP standards of cleanliness.

https://www.federalregister.gov/articles/2015/02/27/2015-04123/the-2015-office-of-regulatory-science-and-innovation-science-symposium

http://multibriefs.com/briefs/ipec/EI_Timeline_revised.pdf


http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM429304.pdf

http://www.fda.gov/AdvisoryCommittees/Calendar/ucm431283.htm

http://www.ipqpubs.com/wp-content/uploads/2015/03/OutsourcingRegisterGuidance.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/03/OutsourceRepackageGuidance.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/03/OutsourceRepackageGuidance.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/03/MixingDilutingBiologicGuidance.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/03/OursourcingAdverseEventGuidance.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/03/DraftCompoundingMOUFINAL.pdf




http://www.ipqpubs.com/issues/ipq-monthly-update-marchapril/

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm359060.htm

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Bend Research

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Biogen Idec, Inc.

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Myoderm

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EUROPE

CMC/REVIEW

Samsung Etanercept Biosimilar in EMA

In late January, Samsung Bioepis announced that its biosimilar of Amgen’s Enbrel (etanercept), used to treat autoimmune dis-eases, was accepted for review by EMA. Amgen’s patents on Enbrel set to expire in August 2015.

EMA to Share Generics Assessments

EMA announced in mid-January that it would share its assessments of applications for generic drugs with other regulatory agen-cies. The first phase of its “International Generic Drug Regulators Pilot,” started in July 2014, involves the EU, Australia, Canada, Chinese Taipei, and Switzerland. Initially ten applications for generics will be shared.

EMA Guideline on Elemental Impurities

EMA announced that ICH’s Q3D guideline on elemental impurities will come into effect in June 2016 for new applications and December 2017 for products that have already been authorized.

EMA Searchable EudraLex

In late January, EU introduced a downloadable and searchable version of its Eudralex listings on pharma legislation. Eudralex V30 can be used offline and contains pdf versions of all legislation listed online.

EMA Weekly Start Dates for Type II Variations

Starting July 1, EMA will only accept electronic applications for initial marketing authorisations, variations, and renewals for human and veterinary drugs. Next January, applications in Word format will no longer be filable and only eCTD versions of the electronic application will be accepted. These measures are designed to reduce administrative burden, while also improving data quality and consistency.

Biosimilar Working Party Plan

EMA’s Biosimilar Medicinal Products Working Party (BMWP) announced its 2015 work plan in late January. The plan lists meet-ings to be held March 3-4 and October 27-29, activities with external parties, and guidelines that are anticipated to be updated. In the first quarter of 2015 the group anticipates updating the guideline on products containing recombinant human insulin, while guidelines on low-molecular-weight-heparins, recombinant interferon alpha, and recombinant granulocyte-colony stimulating factor are expecting to be updated in the second quarter.

New MHRA Vice-Chair of Human Medicines

MHRA announced Angela Thomas as the new vice-chair of its Commission on Human Medicines (CHM) in mid-January. The CHM advises on matters relating to safety, quality, and efficacy of drugs, as well collecting adverse drug reaction reports. Thomas has been on the CHM since 2005, where she chairs the Clinical Trials, Biologicals & Vaccines Expert Advisory Group.

GMP/INSPECTION

Concept Paper on Revision of GMP Annex 1

A concept paper on revisions to EMA’s GMP Annex 1 on the manufacture of sterile medicinal products was published in early February. The concept paper proposes incorporating changes resulting from the adoption of ICH Q9 and Q10 as well as changes made in other EU GMP chapters.

http://www.samsungbioepis.com/newsroom1/newsroom_0.html

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/01/news_detail_002251.jsp&mid=WC0b01ac058004d5c1

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180284.pdf

http://ec.europa.eu/health/documents/eudralex/cd/index_en.htm


http://www.ema.europa.eu/docs/en_GB/document_library/Work_programme/2009/11/WC500014447.pdf

Jerry

Line

https://www.gov.uk/government/news/new-vice-chair-appointed-to-commission-on-human-medicines

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/02/WC500181863.pdf




Minor Changes to GMP Chapters 3 and 5

Minor changes to EU GMP chapters 3 and 5 were made in late January. Added were transitional arrangements for toxicological evaluation that come into effect in March.

EMA Drug Identification Implementation

EMA announced the establishment of a task force for implementing international standards for the identification of medicinal products (IDMP) in early February. The task force creation follows from the finalization of ISO IDMP standards in 2012. Imple-mentation guidelines are expected to be available in 2016.

New MHRA Orange and Green Guides

MHRA released the latest edition of its Orange Guide (Rules and Guidance for Pharmaceutical Manufacturers and Distribu-tors) and Green Guide (Rules and Guidance for Pharmaceutical Distributors) in early January. The Orange Guide now includes sections on MHRAs: ● Innovation Office • Compliance and Action Group • risk-based inspection program • gold standard for Responsible Persons, and • application and inspection processes.

MHRA Import Ban on Wockhardt Expanded

In January, MHRA expanded its import ban on products coming from Wockhardt’s Chikalthana plant. The plant was found to be non-compliant in 2013 and the scope of the original ban has now been expanded to include APIs that had received a waiver due to their critical status. Wockhardt’s Aurangabad plant had received a warning letter from FDA in July 2013 (see IPQ “Monthly Update” March/April 2014 pp. 19-29).

Revised MHRA GMP Requirements for “Specials” Manufacturers

In late January, MHRA published a revised guidance on the GMP requirements for “specials” manufacturers – those who make product without a marketing authorization, similar to a compounding pharmacy in the U.S. The guidance consists of an introduc-tion, scope, Q&A section, glossary, reference documents, and revision history. An appendix is included listing the updates to the document.

France Finds Data Integrity Issues at China Plant

Inspectors from the French National Agency for Medicines and Health Products Safety found North China Pharmaceutical Group Semisyntech’s Shijiazhuang plant to be non-compliant with GMPs in late January following an inspection in November. Inspec-tors cited manipulation of documents, data integrity in QC, contamination risk, change controls, and documentation manage-ment as the areas of concern.

European Medicines Verification Organisation Established

In mid-February, EFPIA, along with EGA and EAEPC, announced the establishment of the European Medicines Verification Organisation (EMVO). EMVO is designed to provide end-to-end verification of drugs from manufacture, through distribution to patients by creating an infrastructure for complying with EU’s Falsified Medicines Directive.

IPQ’S WEEKLY ALERT KEEPS YOU ON THE CMC/GMP CUTTING EDGE

SIGN UP AT IPQpubs.com

http://ec.europa.eu/health/documents/new_en.htm


https://www.gov.uk/government/news/new-essential-orange-and-green-guides-2015-out-now



https://www.gov.uk/government/publications/guidance-for-specials-manufacturers

http://efpia.eu/mediaroom/231/21/New-Landmark-in-fight-against-counterfeit-medicines-with-establishment-of-the-European-Medicines-Verification-System

http://t.co/o2AnpNK2Ki

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CMC/REVIEW

Nigeria’s Regulatory Agency Receives Lab Accreditation

Nigeria’s National Agency for Food and Drug Administration and Control (NAFDAC) lab received ISO 17025 accreditation in January. This accreditation acknowledges the agency’s ability to implement a quality system designed to improve their ability to consistently produce valid results. Having an accredited lab will allow NAFDAC to better assess drugs and fight counterfeiting.

India Formalizes Pre-Submission Meetings

In late January, the Central Drugs Standard Control Organization (CDSCO) of India announced plans to formalize its pre-submis-sion meetings. Informal pre-submission meetings have been taking place for a few years, but stakeholders had been requesting a better window for technical deliberations with regulators.

India Proposes New Bioequivalence Requirements

In late January, India’s CDSCO released a draft revised checklist for BA/BE studies. A main feature of the guidance is the intro-duction of a uniform format for filing requests for approval of BE studies.

Japan Approves Lily/BI Insulin Biosimilar

Eli Lilly and Boehringer Ingelheim announced that they had received approval for their insulin glargine biosimilar for Japan in mid-January. The product is a biosimilar of Sanofi’s diabetes drug Lantus. The biosimilar received EC approval in September 2014.

Chinese Pharmacopoeia Opens Lab to Build Compendium

A joint lab was opened by The Chinese Pharmacopoeia Commission and Waters in late January. The lab seeks to produce an official compendium covering both western and traditional Chinese medicines.

New CFDA Leader

China’s CFDA announced Bi Jingquan as its new leader in early February. Jingquan, a price management expert, replaces Zhang Yong, who has led the CFDA for two years.

IPEC Significant Change Guide

The IPEC Federation announced the availability of its “Significant Change Guide for Pharmaceutical Excipients” in mid-January. The guide is designed to provide a uniform approach in evaluating how changes to the manufacture and distribution of an excipient will impact a product and whether regulatory authorities or manufacturers should be informed. This is the first guide published by the IPEC Federation, a combination of the regional IPECs.

Medicines Australia Opinion Paper on Regulatory Restructuring

Medicines Australia, a group representing Australia’s pharma industry, released a list of recommendations for the restructuring of the countries regulatory agency, TGA. The group recommends: • increasing sharing activities with overseas agencies • creating multiple approval pathways • providing better IT capabilities, removing unnecessary data requirements for pre-submission, and • removing redundant requirements.

INTERNATIONAL

http://www.cdsco.nic.in/writereaddata/NOTICE15.pdf

http://www.cdsco.nic.in/writereaddata/BABE website 2014 revised document required.pdf

http://multibriefs.com/briefs/ipec/Sig_Change_Press_Release_FINAL.pdf

http://medicinesaustralia.com.au/files/2010/02/20150109-sub-medicines-australia-submission-to-medicines-review-FINAL.pdf




Australia Changes Biosimilar Naming

In late January, Australia’s TGA made changes to its biosimilar naming convention in order to better match those used interna-tionally. The agency’s former naming convention was based on WHO’s INN biosimilar identifier combined with the Australian biological name (ABN). TGA is reviewing its naming policy following a July 2014 WHO draft policy on biological qualifiers. In the interim, TGA will use the ABN without a specific biosimilar identifier.

GMP/INSPECTION

Australian Guidance on Release for Supply

Australia’s TGA issued a guidance on the batch release certification process for marketed medicines. The guidance consists of two parts: ● the general requirements for all manufacturers and sponsors, and ● examples of how the general requirements described in part one can be met for specific areas of manufacture.

Canada Quarantines Products with Sri Krishna APIs

In early January, Health Canada requested the quarantine of products made with APIs from Sri Krishna Pharma’s Hyderabad, India plant. The plant was put on the EU’s non-compliance list following data integrity concerns by inspectors from the Italian Medicines Agency in December (see IPQ “Monthly Update” December 2014 p. 44).

CFDA Plan to Improve Inspections

A plan to improve its regulatory inspections was announced by China’s CFDA in late January. The plan calls for increased inspec-tion capacity, improved training, and better information sharing and coordination.

Drug Controller General of India to Strengthen GMP Enforcement

In late January, the Drug Controller General of India (DCGI) said that they would expand their sample testing program to North Eastern states to better assess drug quality. DCGI had begun testing samples from public healthcare and retail pharmacies to check for quality and efficacy last year in a number of other states.

https://www.tga.gov.au/book/naming-conventions-biosimilars

https://www.tga.gov.au/publication/guidance-release-supply

http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/43209a-eng.php


http://www.sfda.gov.cn/WS01/CL0050/113431.html


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FDA Drug GMP Warning Letters and Recalls Posted in January/February

Warning Letters

ocation Letter Date

Product Type

Areas Cited

United States

Oregon Compound-ing Center dba Creative Compounds

Wilsonville, OR

1/27/2015 Compounded ● Microbial control SOPs ● Environmental Monitoring ●Gowning ● Stability testing ● Conformance to final spec ● Drug approval ● Branding

Cantrell Drug Com-pany

Little Rock, AR

1/21/2015 Compounded ● Microbial control SOPs ● Environmental Monitoring ●Gowning ● Cleaning SOPs

InternationalMicro Labs Verna, India 1/9/2015 Oral Solid ● Data integrity ● Lab records ● “Trial” testing ● Com-

puter controls ● OOS investigation ● FARs submission

Apotex Research Bangalore, India

1/30/2015 Oral Solid ● Data integrity ● “Trial” testing ● Lab records ● Com-puter controls ● Microbial control SOPs ● QC SOPs

Note: The warning letters to Micro Labs and Apotex are lengthy (about ten pages each) and cover a broad range of GMP concerns in addition to the data integrity issues. A common denominator in the two letters was inadequate security controls over lab computers. At Micro labs, investigators pointed to "a lack of basic lab controls to prevent changes to electronically stored data," while at Apotex they discovered "unauthorized folders" on lab computers containing GMP data that lacked "appropriate oversight." FDA asked both firms to conduct a "comprehensive investigation and evaluation" of their recordkeeping practices. Both were also cited for using "trial injections," – a practice that FDA has highlighted in other warning letters issued abroad, including another warning letter to Apotex issued in 2014 regarding a second facility in Bangalore. [For more on FDA’s findings of data integrity-related concerns abroad, including those at Apotex, see IPQ “Monthly Update” March/April 2014, pp. 19-29.]

The following are the drug GMP warning letters posted by FDA during January and February, categorized into U.S. and International. The key concerns that each of the warning letters address and links to the let-ters themselves are provided. Included are notes on salient features of the warning letter with links to IPQ’s related coverage.

Company Name

http://www.ipqpubs.com/wp-content/uploads/2015/02/Warning-Letters-_-Oregon-Compounding-Centers-Inc.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/03/Warning-Letters-_-Cantrell-Drug-Company-1_21_15.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/02/Warning-Letters-_-Micro-Labs-Limited-1_9_15.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/02/Warning-Letters-_-Apotex-Research-Private-Limited-1_30_15.pdf



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Recalls

JANUARYProduct Recaller # of

LotsClass Reason

Compliance with NDA/Monograph RequirementsSupplement caps

One and Zen All II Marketed Without An Approved NDA/ANDA: FDA analysis found this product to contain undeclared dexamethasone and cypro-heptadine which are FDA approved drugs making this product an unapproved drug.

Contamination / Lack of Sterility AssuranceSore throat liquid

Tropichem Research Labs

One II Microbial Contamination of Non Sterile Product; microbial assay reported unacceptable high plate counts and positive for E. Coli

Saline inj Hospira One II Lack of Assurance of Sterility: The product has the potential for solution to leak at the administrative port.

Various compounded products

Walgreens Infusion Services

All II Lack of sterility assurance.

Ribavirin for inhalation solution

Valeant One II Non-Sterility: Valeant’s laboratory observed a positive microbial contamination of Virazole lot 340353F, during testing at the 12 month stability pull.

Foreign ProductHydralazine tabs Par Pharma One II Presence of Foreign Substance: Par Pharmaceutical, Inc. is

recalling one lot of HydrALAZINE Hydrochloride tablets due to the presence of small aluminum particles. GMP/GDP

Ciprofloxacin and lamotrigine tabs

UDL Labs <10 II CGMP Deviations: Pharmaceuticals were produced and distrib-uted with active ingredients not manufactured according to Good Manufacturing PracticesImpurity

Triamcinolone acetonide lotion

Akorn <10 III Failed Impurities/Degradation Specifications: The known impurity went out of specification at 12 months stability point.

Acetaminophen and codeine oral solution

Qualitest Pharma

<10 III Failed Impurities/Degradation Specifications: High out of specifi-cation results for the known impurity p-Aminophenol.

The following is a listing of the drug product recalls included in FDA’s weekly “Enforcement Reports” is-sued during January and February, respectively. Included are the generic names of the products, the dos-age form, the manufacturer, the number of lots involved, FDA’s classification, and the specific reason pro-vided by FDA in the Enforcement Report. The recalls are grouped by the general category of problem that caused them. The categories are: ● compliance with NDA/monograph requirements ● contamination/lack of sterility assurance ● dissolution ● GMP/GDP ● impurity ● labeling/packaging ● foreign product ● particulate ● potency/content uniformity, and ● other spec nonconformance. Within the categories, the recalls are or-ganized by class, with the most serious, Class I recalls at the top.

http://www.accessdata.fda.gov/scripts/enforcement/enforce_rpt-Product-Tabs.cfm?action=select&recall_number=D-0329-2015&w=01072015&lang=eng



http://www.accessdata.fda.gov/scripts/enforcement/enforce_rpt-Event-Detail.cfm?action=detail&id=70118&w=01282015&lang=eng









Labeling/PackagingCough and cold syrup

Jaymac Pharma

One II Labeling: Not Elsewhere Classified: Product is labeled “Dye Free” on front panel but contains Red Dye 40.

Glycopyrrolate inj

SCA Pharma <10 II Labeling: Incorrect or missing Lot and/or Exp Date: Printing error caused an overlap in the “y” and “3” making the actual “Use By 3/2015” date appear to read “Use By8/2015”.

Flouride tooth-paste

3M One III Labeling: Incorrect or Missing Lot and/or Exp. Date - The subject lot is missing the lot number and expiration date stamp on the pri-mary box.

Other Spec NonconformanceGabapentin caps Aurobindo One II Failed Tablet/Capsule Specifications: Complaints of empty cap-

sules received.Gabapentin caps Actavis <10 II Failed Capsule/Tablet Specifications: Actavis has received sev-

eral complaint for clumping and breaking of capsules with some bottles showing popped out bottle bottom (round bottom) and creased labels from one distribution center.

Glutathione inj Right Value Drug Stores

>10 II Incorrect Product Formulation: An incorrect gas was used to remove the oxygen from the vial.

FEBRUARYProduct Recaller # of

LotsClass Reason

Contamination / Lack of Sterility AssuranceDextrose inj Hospira One I Non-Sterility: Confirmed customer complaint of particulate matter

floating within the solution of the primary container, consistent with mold.

Fluconazole inj Baxter One II Lack of Assurance of Sterility: Complaints of leaks due to an incomplete seal at the bag seam.

Erythromycin pledgets

Akorn <10 II Microbial Contamination of Non-Sterile Products: Active Pharma-ceutical Ingredient (API) failed USP microbial tests.

Levetiracetam tabs

Sun Pharma One II Failed Dissolution Specifications: Failure of dissolution test ob-served at the 6 month time point

Foreign ProductLoratadine syrup

Taro Pharma One II Presence of Foreign Substance: Presence of blue plastic floating in loratadine syrup.

GMP/GDPPhosphatidyl choline, sodium deoxycholate, and di alpha tocopheryl inj

AnazaoHealth <10 II Good Manufacturing Practices Deviations: The product has an ac-tive pharmaceutical ingredient from an unapproved source.

ParticulateLidocaine inj Hospira One I Presence of Particulate Matter: Confirmed customer complaint

that orange and black particulates, identified as iron oxide, were found embedded within the glass vial and floating in solution.












http://www.accessdata.fda.gov/scripts/enforcement/enforce_rpt-Product-Tabs.cfm?action=select&recall_number=D0384-2015&w=02182015&lang=eng





Lidocaine inj Hospira One I Presence of particulate matter: A returned customer sample was evaluated and found to have human hair attached to a pinched area of the stopper.

Propofol inj Hospira One II Presence of Particulate Matter: The firm received a complaint of an embedded particulate in the neck of one vial composed primarily of iron.

Other Spec NonconformancePropofol/vancomycin/ ketorolac inj

Hospira <10 I/II Temperature Abuse: Products experienced uncontrolled tempera-ture excursions during transit.

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The opening session of the conference will feature a keynote speaker who was one of the first healthca e professionals deployed to deal with the Ebola crisis in West Africa. This speaker promises to offer insight into how the government deals with outbreaks and what activities need to transpire to quickly approve new medically necessary drug products to curtail potentially pandemic disease outbreaks.

Building from the opening plenary, subsequent plenary sessions will discuss the role of quality and regulatory systems in bringing new products to patients in an effici t and timely manner. The committee also plans to have the FDA speak on each of its Centers Initiatives in relation to the patient as well as having the traditional compliance update session.

You won’t find this le el of direct information exchange with FDA at any other conference!

Want to learn more? On October 1-2, PDA will host fi e courses designed to complement what you learned at the conference.

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• Process Validation and Verific tion:A Lifecycle Approach (October 1-2)

• CMC Regulatory Requirements in DrugApplications (October 2)

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