CMC/REVIEW - International Pharmaceutical Quality...quality attributes and how they are mitigated – with hyperlinks to the detailed information in Module 3. This would provide “a

MONTHLY UPDATE - AUGUST/SEPTEMBER 2014

CMC/REVIEW

• New CMC Submission Approach Needed to Foster Transparency and Continuous Improvement, PhRMATeam Says; Embedding Control Strategy as Regulatory Commitment in QOS Proposed...................................3

UNITED STATES

UPDATES IN BRIEF - p. 44

U.S CMC: • Purple Book • PDUFA V MAPPs • CDER CMC Course • USP Particulate Chapters • ANDA RTR Guidance• Fast Track Guidance • BLA Reg RemovalsU.S GMP: •Recall Reg Comment • Dispute Guidance • Hospira Heparin Recall • USP and Online Pharmacies • Compounding Warning Letters

EUROPE CMC: • EDQM on CEPs • CEP Forms • EMA on NIR • EMA Variations Guideline • Ph. Eur. Inhalation Methods EUROPE GMP: • EU GMP Chapters • EMA Cocrystals Paper

INTERNATIONAL CMC: • PDA Changes Initiative • Generics in the Caribbean • Biosimilar Infliximab • eCTDs in Thailand•China/Taiwan Recognition • Review Speed in CanadaINTERNATIONAL GMP: • Rx360 Traceability Initiative • Brazil Track/Trace Guidance • India Barcoding Implementation

INTERNATIONAL

CMC/REVIEW

• Amgen “Analytics of the Future” Initiative Develops MS-based “Multi-Attribute Methodology” toStreamline Biotech Development and QC Testing.....................................................................................................21

GMP/INSPECTION

• Transparent Discussions, Long-term Relationships and Global Event Monitoring Mark Amgen’s SupplyOversight Program............................................................................................................................................................34

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INTERNATIONAL PHARMACEUTICAL QUALITYInside the Global Regulatory Dialogue

VOL. 5, NO. 7

• Guides on FDA’s Generic Drug Review Process Continue Apace in July; EU Pilot Pursues Generic DrugReview Streamlining Internationally.............................................................................................................................18

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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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New CMC Submission Approach Needed to Foster Transparency and Continuous Improvement, PhRMA Team Says; Embedding Control Strategy as Regulatory Commitment in QOS Proposed

A working group of prominent CMC experts across the member companies of the Pharmaceutical Research and Manufacturers of America (PhRMA) has formulated a proposal for a more performance and risk-based regulatory approach to CMC submissions that would better accommodate post-approval manufacturing and control improvements.

The proposal is emerging from an intensive review by a PhRMA Limited Duration Key Issues Team (LDKIT) focused on the problems in the current CMC review paradigm that have prevented industry’s quality by design (QbD) efforts from achieving the promise of regulatory flexibility throughout the product life-cycle.

Pharma’s LDKITs are set up under its Technical Development and Operations Committee (TDOC) to explore particular front-burner regulatory issues and develop a consensus proposal for addressing them.

The CMC process LDKIT has honed in on the problems with the structure, content and function of the marketing application itself as needing to be addressed to reach a more continuous improvement-based manufacturing paradigm.

The key to improving the review process, the team maintains, is building a “comprehensive” control strategy into the quality overall summary (QOS) that will define the regulatory commitment and determine, in turn, how the post-approval CMC regulatory oversight is handled.

PhRMA Proposal Aired at PQRI Conference

The PhRMA LDKIT took the occasion of a conference cosponsored by the Product Quality Research Institute (PQRI) and FDA in mid-September in Bethesda, Maryland to outline the proposal in anticipation of having the full proposal ready to present to FDA this fall.

The team’s thinking was explained by Pfizer Global CMC VP Roger Nosal at a session focused on the “current practice and future directions [of] life cycle management and post-approval changes.”

Nosal delved into the problems that the current CMC filing approach create for both industry and FDA and the benefits that would flow from evolving it along more risk and

performance-based lines. [Nosal’s full remarks at the PQLI session are provided below].

The structure of Module 3 in the ICH Common Technical Document (CTD), he pointed out, is not amenable to effectively conveying the narrative of a comprehensive and integrated control strategy founded on QbD through which the regulatory commitments could be clearly defined and justified and confidence increased in the applicant’s ability to handle lifecycle change management.

The PhRMA team is proposing that the control strategy be built into the Module 2 QOS, serving as the regulatory commitment. It would convey the enhanced process understanding and product knowledge – identifying the risks to the critical quality attributes and how they are mitigated – with hyperlinks to the detailed information inModule 3.

This would provide “a really good scaffold for substantiating how a science- and risk-based approach delivers the quality [and] establish a good baseline for simplifying” post-approval change regulation, Nosal maintained.

The “comprehensive QOS” would contain five key elements, he explained: ● the target product profile ● the quality target profile describing quality attributes and control limits ● a summary of the comprehensive control strategy marking the regulatory commitments ● a summary of the data and risk-assessments justifying the control strategy, with reference to

PhRMA LDKIT Members

Member Company Member Company

Dan Bollinger Takeda John Lepore Merck

Xavier Castell Takeda Rick Lit Amgen

Andrew Chang Novo Nordisk Steve Mason Amgen

Graham Cook Pfizer Moheb Nasr GSK

Frank Diana Endo Roger Nosal Pfizer

Jeff Ferguson Lilly Mark Rosolowsky BMS

Georges France Novartis Tom Schultz J & J

Betsy Fritschel J & J Steve Tyler AbbVie

John Groskoph Pfizer Jim Webb BI

Nirdosh Jagota Roche-Genentech Diane Zezza Novartis

Bob Kelly Bayer

UNITED STATES




the various CTD module elements, and ● a post-approval change management plan.

The post-approval change management plan surfaced as a concept during FDA’s QbD drug and biotech pilots and again in the context of dealing with the CMC issues around breakthrough therapies. The concept was most comprehensively delineated by Genentech in what it termed a “Post-approval Lifecycle Management” (PALM) plan (see IPQ “Monthly Update” Sept. 2013, pp. 12-23).

The LDKIT proposal to FDA will include a broad description of what a plan might look like, referencing examples from different companies including Genentech’s PALM. Nosal explains that the PALM example is compelling in that it addresses post-approval changes from a GMP/PQS as well as review perspective – a broader vantage point than other participants in the FDA pilots had taken.

From Stick to Carrot

The Pfizer official explained how the approach would shift the regulatory framework from punitive reaction toward incentives to provide what the regulator needs upfront to be confident in the ability of the applicant to assure lifecycle quality.

The QOS approach would allow applicants to “tell a compelling story” and “align very nicely” with the substance of the QbR inquiry on the generic drug review side, Nosal maintained (see IPQ “Monthly Update” June 2013, pp. 21-35).

There has been “a lot of discussion in PhRMA about what this might look like,” he commented. “We haven’t been very receptive to filling out a template, because we have to fill out templates already for a lot of markets around the world. But we do recognize the value of the question-based review in the review of our submissions, and we do think that the questions that are in the question-based review are the same ones we use when we are preparing our submissions…for innovator products.”

While the PhRMA team feels that the QbR approach can provide reviewers with a helpful checklist in determining that the applications contain the appropriate elements and are consistently reviewed, it is concerned about the significant amount of extra administrative work involved in filling out a QbR template and that it doesn’t accommodate telling a coherent and compelling story that reveals the logic behind the decision making as the QbD process unfolds.

Building on the QbD and QbR experience to date, “we actually are in a perfect position right now” to improve the process for “effectively conveying enhanced process understanding and product

knowledge,” the Pfizer official maintained at the PQLI session.

He expressed comfort with looking at generic and innovator products together “because the same rules apply. You have to provide a robust control strategy. If you do you are going to be fine, and if you don’t you are going to have to put more controls in place and you are going to have to justify them.”

A key to the success of the effort will be integrating the review and inspection functions, he added. “In order for this to work appropriately, we have to make sure the two are integrated so that the confidence is there.”

Noting the challenges involved in the ICH effort to craft a lifecycle management guideline Q12, Nosal explained that the team’s goal is developing a CMC filing approach that would provide a stronger foundation for the international harmonization activities and reduction in the current continuous improvement roadblocks companies face globally.

ICH has been drafting a concept paper on Q12 and is focusing on putting together the guideline team. Q12 will be discussed further at the November ICH meeting in Portugal.

Nosal commented to IPQ that support has been expressed for the PhRMA team’s comprehensive QOS approach by some key regulators in Europe and Japan – noting that the idea grew out of the current Japanese application format and regulatory commitment approach and resembles the “expert report” concept developed in Europe.

Asked about the international unfolding of the LDKIT proposal if it gets traction at FDA, Nosal explained that while he “tends to be an optimist” when putting together policy initiatives like this, he has been concerned about the direction that other countries around the world are taking, reflecting economic and political factors that “are not easy to change.” The focus is on bolstering their internal pharmaceutical industry and R&D, he noted, and they are not as receptive to taking direction from multinational companies and other regulatory agencies.

PhRMA Proposal Reflects Concerns Voiced by Moheb Nasr

The concepts that are being embedded into the LDKIT proposal are reflective of concerns about the CMC review process that have been forcefully enunciated over the past few years by one of its prominent members, Moheb Nasr – both during the latter part of his tenure as Director ofCDER’s Office of New Drug Quality Assessment (ONDQA), where he had played a key role in the agency’s efforts to

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advance QbD, and after he left FDA to head up global CMC strategy for GlaxoSmithKline (GSK) in the fall of 2011.

At the June 2012 DIA annual meeting, Nasr reaffirmed the case he made while ONDQA director and a member of the ICH Q8-10 Implementation Working Group (IWG) that agreement around the control strategy filing expectations could provide a risk- and science-based platform for a unified global CMC application and post-approval change regulatory approach that would foster QbD and continuous improvement (see IPQ “Monthly Update” October 2012, pp. 27-33 and June 2011, pp. 20-33).

Drawing on his experience with CMC policy setting at FDA, with the development and implementation of the ICH Q8-10 guidelines, and subsequently with GSK, Nasr explained the challenges industry and regulators face in advancing the new paradigm and where the pathway forward may lie.

What is needed, Nasr stressed, is for industry to become more transparent about its QbD knowledge base in applications, so that the agency has the confidence to allow the self-regulation of manufacturing changes and the application review process can serve as a springboard rather than a roadblock for continuous improvement.

“The current system is not only challenging for industry but also for regulators,” he maintained. “It is very complex, costly and resource-intensive. I think what bothers me the most as a scientist is that it discourages transparency in the regulatory filing…. It hampers innovation and continuous improvement [and] is responsible, at some level, for drug shortages.”

Meanwhile, he stressed, “CMC lifecycle management is becoming increasingly critical.” Drivers for making manufacturing changes include: ● manufacturing efficiency ● security of supply ● response to regulatory developments ● advances in technology ● increase in product and process knowledge, and ● the commitment to making continual improvements.

The key lies in clarifying for industry what information provided in the application is considered a regulatory commitment, Nasr maintained. “Without that, we will never have regulatory transparency. There will always be a desire to put in as little information as possible. Is this the right approach? I hope not.”

“What is needed now more than ever before,” he affirmed, “is bold leadership to meet the 21st century expectations – not to make minor changes on 25-year-old guidances.”

Foreshadowing the current LDKIT proposal, Nasr suggested that the issue of what information to file could be solved, in part, by focusing attention in the application on the firm’s control strategy.

The control strategy, he noted, “is the key regulatory part of the filing to assure quality, safety and efficacy, and should serve as the primary regulatory commitment.” Additional information “needs to be there for transparency and to share the science,” Nasr said, “but it should be there as supportive information intended to facilitate the review, assure fitness for use, and robustness of the control strategy.”

Focusing on the control strategy, in turn, he maintained, could provide a path toward greater regulatory flexibility in making manufacturing changes and foster innovation and continuous improvement.

PQRI Conference Draws Broad CDER Support

The PQRI conference drew wide attendance from across CDER’s CMC and compliance offices, with more than 100 agency personnel participating.

The level of FDA participation was reflective of its need for industry support in ironing out the variety of issues that are now on the table in CDER’s effort to create a quality regulatory process that better reflects the advancements in science and technology, risk management, and QbD.

PQRI was established with FDA backing in the mid-1990s to support the regulatory research and development needs of CDER’s new Office of Pharmaceutical Science (OPS), which was led from its 1995 inception through 2000 by Roger Williams. Williams left OPS to assume the helm at USP – a position he held through the spring of 2014.

The institute is guided by a steering committee composed of representatives from its sponsoring organizations, which include CDER, Health Canada, USP, the American Association of Pharmaceutical Scientists (AAPS), and the Consumer Healthcare Products Association (CHPA). PDA has recently rejoined PQRI. AAPS provides administrative support for the institute.

Through its working groups and technical committees, PQRI tackles specific scientific research projects to support the review process in ensuring drug product quality, safety and performance (see box on p. 6).

Industry’s inability to deploy technology advancements and learnings post-approval due to the current CMC review processes across agencies was a dominant theme at the PQRI conference as well as at the PDA/FDA conference held a week earlier.

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The dialogue at the two conferences around how to advance the regulatory initiatives underway for breakthrough therapies, drug shortages, quality metrics, global harmonization, generic user fee implementation and quality by design all threw the problems in the current CMC review and post-approval change paradigm into strong relief.

[Editor’s Note: More on the current regulatory/industry dialogue around the post-approval change issues and their relationship to drug shortages, in particular, will be provided in an upcoming IPQ story.]

OPS Staffers Affirm FDA Openness to Change

Preceding Nosal to the podium at the PQRI post-approval change session were two FDA OPS officials, Geoffrey Wu and Daniel Peng. They focused on where the agency is now in regulating post-approval changes and how scientific advances are opening up pathways to improve the process.

Their presentations reflected OPS familiarity with and openness to the concepts in the PhRMA proposal.

During 2012 and 2013, the LDKIT had submitted a

whitepaper to CDER on the “implementation and application of quality by design” and a follow-up paper on “regulatory commitments and post-approval change management.”

Before the PQRI meeting, Nosal had also forwarded to CDER a copy of his presentation, the outline of which provided the basis for a third white paper focused on how a comprehensive QOS incorporating the control strategy regulatory commitments would provide a new risk-based review and life-cycle management paradigm.

The PhRMA group will be discussing the third white paper and the overall proposal with CDER’s Lawrence Yu and his OPS staff in October.

The levers for reducing the post-approval change burden, Wu noted at the PQRI session, include: ● the ability to collect a significant body of relevant information in a short period of time ● better product and process design and design space understanding ● enhanced process monitoring and control capabilities ● higher process capability ● more consistent and predictable product quality, and ● the ability of better metrics and surveillance techniques to identify how well firms are handling change management.

PQRI Organization ChartBoard of Directors

Anthony DeStefano, Chair; Louis Yu (Perrigo), Treasurer; Vinod Shah; Rachael Roehrig; Margaret Szymczak

Steering Commi�eeRachael Roehrig, Chair; Margaret Szymczak, Vice-Chair; John Punzi, (CHPA); Lynn Van Campen,

(AAPS); Dave Schoneker (Colorcon, represen�ng IPEC-Americas); Lawrence Yu, (FDA); Anita DiFranco (Health Canada); Kevin Hool, (USP)

Execu�ve SecretaryVicki Penn

Development Tech. Commi�eeReggie Saraceno (Boehringer-

Ingelheim) Chair

Biopharmaceu�cs Technical Commi�ee

Erika S�ppler (USP), Chair

Manufacturing Tech. Commi�ee

Jean Poulos (Aceto), Chair

Container-Closure Work Group

Dan Malinowski (Pfizer), Chair

Stability Shelf Life Work GroupRobert Capen (Merck), Nate Pa�erson (Alexza), Co-Chairs

PODP Work GroupDiane Paskiet (West), Chair

BCS Guidance Work GroupErika S�ppler, Chair

BCS III Work GroupAlan Parr (GSK), Chair

Sequen�al Design Work GroupAlan Parr, Chair

Excipient Variability Work Group

Larry Block (Duquesne University), Chair

Elemental Impuri�es Workshop

Dave Schoneker, Chair

In progressIn development




Firms doing better risk profiling of critical parameters and attributes during product development and found to be in good standing through product and facility surveillance incorporating quality metrics should have more post-approval flexibility, Wu said.

Accumulated process and product knowledge expands the ability to understand the risks and should result in a lower burden on low-risk areas in accord with the principle espoused in FDA’s April 2014 annual report (AR) guidance, he added.

A related tack would be to enhance the evaluation of annual reports, including standardizing data submissions, allowing for data mining, and employing automated risk analysis to facilitate the regulatory review. Cross linking the AR review with the quality surveillance platform would also enhance the ability to get a more complete picture of a firm’s post-approval performance.

Regulatory Commitment is Key, OPS’ Peng Concurs

Wu’s OPS colleague Peng addressed more specifically the issue of defining regulatory commitments and the related concepts that were embedded in the PhRMA papers.

Peng agreed with the PhRMA team’s assertion that clarity around these commitments promotes more knowledge-rich submissions and allows for narrowing the post-approval regulatory focus to high risk areas, which, in turn, fosters innovation and continuous improvement.

He went on to pose the questions that flow from the LDKIT’s definition of regulatory commitment (RC) as “a specific description of how a company intends to manufacture and control the drug product that is defined in the dossier, and that is subject to a regulatory action if changed after approval.”

The OPS official’s questions highlight the issues that the PhRMA LDKIT is seeking to address in its proposal, as Nosal went on at the session to explain.

A first question is how much detail should be provided related to the commitment, Peng said – suggesting that the focus should be on process and product high-risk areas and failure modes.

Also at issue is where to draw the line between supportive information and commitments. Peng queried on what the proposed model says about the importance of the supportive information and whether supportive information would need to be submitted if there were changes to the RC.

Further at issue in the PhRMA RC definition, Peng said, is

what the expectations are for the description of the drug substance and drug product manufacturing processes. Related questions include: ● what process parameters and ranges should be included ● whether the master batch record is one of the RC elements, and ● whether all changes to a batch record need to be reported to FDA.

RC/Control Strategy/PQS Relationships Explored

Also warranting consideration, Peng maintained, is the relationship between the scope of the regulatory commitment and control strategy.

ICH Q10 defines the control strategy in the context of the quality system as “a planned set of controls, derived from current product and process understanding, that assures process performance and product quality.” The guideline adds that the controls “can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.”

With this Q10 explanation in mind, of concern is how a change in the control strategy would impact the regulatory commitment, Peng pointed out.

Another area of concern in focusing on the PhRMA definition of regulatory commitment, he said, is where it is contained in the quality CTD and avoiding the “unintended consequences” of having elements of it in the various sections – a concern that the QOS proposal enunciated by Nosal addresses.

Questions also arise on changing the regulatory commitment, such as: ● when and how often it should be updated ● how the changes should be communicated ● what supporting information is needed, and ● what documentation is needed for the changes made within the internal quality system.

Peng suggested that the scientific considerations for managing RC changes include assessing how the change could affect the process and product and the effectiveness of the control strategy in addressing the product-specific failure modes. He suggested the need to design and execute an evaluation plan to assess the effects of the change on the product and process, and stressed the value of a formal risk assessment in doing so.

The OPS official went on to explore the relationship between the regulatory commitment and the pharmaceutical quality system (PQS), noting the implications of a paradigm shift that would recognize a “culture of quality.”




In a quality culture-based paradigm, manufacturers would take full responsibility for the quality of the products, with manufacturing changes evaluated under an applicant’s PQS, Peng said. The focus would be on meeting patients’ expectations, with the regulators’ expectations considered a minimal approach. Companies would strive for continual improvement and have a management and organization commitment to prioritizing quality and ensuring that each person in the organization understands and embraces their respective roles.

Establishing, Justifying, Placing, and Assessing RC at Issue

Delving further into the considerations in making the regulatory commitment central to the CMC review process, Peng pointed out that the RC and risk categories would likely be proposed by the applicant and subject to agency assessment.

A science and risk-based approach based on product and process understanding would be desired for establishing the RC, he asserted.

The approach, Peng suggested, could entail high risk parameters being identified and controlled and a justification provided for why other parameters are low risk. At issue would be how the control strategy overall would be justified and supported, and how it would be formatted, hyperlinked and placed in the application.

In his opinion, the summary should be concise – “short and sweet” – with a focus on the clinically relevant risks.

The OPS official suggested that some of the strategies that could be deployed to reduce the filing category of changes to the regulatory commitment/control strategy include: ● a comparability protocol ● testing and/or sampling beyond standard release testing and/or compendial standards ● using modern technologies which significantly increase the detectability of failure modes – for example, LC/MS for a new drug substance supplier, PAT for adaptive process control, and IVIVC for dissolution testing, and ● demonstrating that the process is in a state of statistical control and capable – for example, meeting a particular Cpk and confidence level.

Peng cited some additional questions that warrant discussion in the regulatory commitment context, such as whether the RC would be included in all new applications and how the concept could be applied to legacy products. Related to these would be whether applicants with or without a filled RC could continue to utilize “traditional” approaches to reporting changes.

Peng closed his remarks by affirming that the regulatory commitment is a “great concept” that could significantly reduce post-approval change filings and one that FDA scientists are discussing and working on, although the definition/terminology has not officially gelled yet.

Noting that guidance on lifecycle management is under consideration in ICH, and that the regulatory commitment could be an important element in it, he urged the attendees to “stay tuned.”

PFIZER’S ROGER NOSAL ON PHRMA PROPOSAL FOR IMPROVING CMC REVIEW PARADIGM

At the FDA/PQRI conference on evolving product quality, Pfizer Global CMC VP Roger Nosal discussed the problems with the current CMC review and post-approval change process and the proposal that is emerging through PhRMA’s Limited Duration Key Initiative Team (LDKIT) to address them. Nosal followed FDA Office of Generic Drugs Senior CMC Reviewer/QbD Liaison Daniel Peng to the podium at the session and refer-ences some of Peng’s comments related to opportunities for using QbD as a lever for easing post-approval change filing burdens.

My presentation is essentially designed to talk about what we have learned about quality by design, what we have learned about control strategies, what we have learned about risk management over the last 10 to 15 years.

I will start out by saying that back in 2003, 2004, when the industry pursued quality by design, we thought a lot about the process of developing products. We didn’t think as much about what would happen post-approval.

Part of the reason for that is there were two words that were entered into the lexicon during that time – regulatory flexibility. Nobody really knew what that was. So as a result, a lot of us just assumed that if we did quality by design,…we would naturally be able to do almost anything we wanted post-approval….

In the last two or three years, I have had the privilege of working with the PhRMA LDKIT developing some ideas on how to fix the problems that we encountered when we first embarked on quality by design, and I am going to talk about that.




This was the abstract to this session [see box at right]. What I am going to do here is talk about risk-based regulatory review topics in a very narrow focus on three of them. Those three are: ● regulatory commitments, which Daniel started to talk about ● control strategy, and ● the QOS as a primary review document or preliminary review document.

The reason why I am going to talk about it that way is because one of the things we have been struggling with with quality by design – and in fact we have struggled with this with almost all the regulatory submissions that I have been associated with over the years – is how we tell a compelling story, and what does a compelling story mean so that a regulator can pick it up and say, ‘oh yeah, these guys know what they are doing.’

Three Key Elements of Performance-based Expectations

I could start with post-approval and work backwards, but I would rather basically look at what we should be doing up front to identify how we can make post-approval changes better. And for me, these three elements of [performance-based expectations] are probably the most important ones that we have to worry about in your product’s lifecyle:

The first is confidence of quality. Where did I get this? [FDA Office of New Drug Quality Assessment (ONDQA) Acting Director] Christine Moore and I were having breakfast about four years ago. We were having a debate about flexibility, and how we can get regulatory flexibility. She said to me that the issue for the regulators is confidence in quality through the product life-cycle. So when a regulator picks up a submission and first sees what you put in that submission, they might be able to say, ‘right now, everything looks great. But in five years, you are going to move that product from one site to another. You are going to get starting materials from different places. How am I going to be confident that that quality is going to be the same?’

I think that is something that is tremendously important as a concept – to try to understand how we get post-approval– to try to understand how we get post-approval or life-cycle management going forward.

It depends on – and I am going to focus on this for a good portion of this talk – it depends on our control strategy and what is a good control strategy. It is not just controls. It is, what is the control strategy? Is it comprehensive?

Regulatory commitments: [CDER’s Daniel Peng] already talked about them. The industry has been using the term regulatory commitments for 30 years, if not longer. I don’t think the regulators knew that, but every time we filed a submission, we picked out in the submission what we thought was a commitment and used that as the basis for determining post-approval changes. So it is not a new concept. It is just one we have been more transparent with recently and brought it forward to see if it would resonate….

It has always been predicated on something that I think is rather important – change management and knowledge management – because frankly those two are the basis for what we do. We do risk assessments now, routinely, for all of our products, and we do them in a change management system. And if we have a good robust knowledge management system, we capture them in our knowledge management system.

Now I will admit, on behalf of the industry…we don’t have great knowledge management systems. If I go back 30 years and look at some of the old products that we have, if the person who was most responsible for the manufacturing and development of that product is gone – retired or dead, whatever – we have lost a fairly significant proportion of knowledge.

Abstract of PQLI Session on “Life Cycle Management & Post-Approval Changes (Current Practice – Future Direction)”

Regulatory bodies across the world are placing unprec-edented emphasis on performance of the industry and life-cycle management of drug products, especially in the post-approval phase. This session will focus on these two interrelated aspects. Discussions will be centered around the following topics:

1) How to better manage post-approval CMC changes fol-lowing risk and science-based approaches

2) How to integrate production data (e.g., batch data) into the current regulatory framework (e.g., annual reports), and

3) How to assure product quality and prevent drug short-ages utilizing performance-based regulation.


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But the change management systems have been operating. I think knowledge management is one area that we definitely have to work on in the future. I know FDA has the same problem….That is part of the systemic aspect of what we have to do together, and that helps build confidence in quality at a level that is different from our submission. It is what we do all the time.

Performance criteria: I will talk a little bit about this – I will not talk a lot about it here. It is really how we convey the– I will not talk a lot about it here. It is really how we convey the I will not talk a lot about it here. It is really how we convey the information to establish the confidence in qualty. So how do we put tis submission together? I will tell you right now, the way the CTD is structured...is not very helpful.

So we need an alternative way to do that. We need an alternative way to tell the story. I will talk a little bit about the PhRMA proposal in here. It is a draft proposal, so bear with us – we are trying to figure this out as we go along – that may help facilitate that. And it will also lend some credence to the global harmonization activities that weare all embarking on as well. If any of you attended the ICH session this morning, we are facing a fairly significant challenge and a lot of very complex situations trying to handle the variety of divergent regulatory [requirements].

And then finally, risk-based review: This is more for the regulators. How should the regulators be looking at our submissions with the eye of having some measure of risk and whether or not some of the things we file really warrant the type of scrutiny that they think? I think that this is the 80/20 concept that Daniel was trying to suggest. I am not sure we are there yet, but I think collaboratively between industry and FDA we can figure it out.

The Comprehensive Control Strategy

So improving confidence in quality for me means focusing on control, and robust control is predicated on understanding the risks.

Quality by design ushered in a prospective way of looking at how the risks will have an impact down the road. If you understand the risks well enough, you could build the controls into your process so that you understood how you could manage and mitigate those risks. And if you did that well, then you can make changes later on, and you would have a better understanding of what risks are truly problematic.

The previous speakers today talked about looking at risks from a post-approval perspective. I am suggesting that you probably should be looking at them prospectively, not retrospectively.

The comprehensive control strategy is predicated on two major pieces: ● regulatory commitments –this is a concept that is near and dear to a lot of us in our industry, because it does reflect what we have committed to do, and I will explain what that means in a minute, and ● the pharmaceutical quality system.

I will go even further and say that the control strategy equals regulatory commitments. So for me, and for the PhRMA folks who helped me put this together, the view is that if we identify the regulatory commitments appropriately, they will reflect and represent the control strategy up front. And the baseline systems will make sure that they operate to maintain them. Does that make sense to everybody? I see some nodding heads.

I want to talk a little bit about control. About a year and a half ago I was in a meeting and [EMA Quality Working Party head] Jean-Louis Robert came up to me, and said, ‘Roger, I have been struggling with this notion of control – because you can’t have too many analytical methods in my opinion for some products.’ And I said, ‘Jean-Louis, I think what we are trying to do is shift the paradigm from analytical control to control through the process.’

The whole purpose of quality by design is to design a process that you understand well so that the controls that you put in place to manage that process will be confirmed by the analytical methods – it won’t be controlled by them. That is a bit of a paradigm shift….

So I am proposing going forward that while the analytical methods are part of your regulatory commitments, which become part of your control strategy, they are not what controls the quality of your product. It is the manufacturing process that controls the quality of your product, and the analytical controls are there to confirm it.


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Controlling the critical process parameters: I like the term critical material attributes even though ICH does no. I did file a request to have the ‘critical material attribute’ accepted as a term and I was roundly rejected. But I did feel that it is relevant because materials and processes parameters are different, even in the English language if you look it up in the dictionary. But they will be achieved by understanding the relationship between the input and output parameters. This is just fundamental to what I am talking about.

Every CPP that you identify in your process or as a part of a material attribute represents part of your regulatory commitment. So you are basically ring-fencing your risk and locking it down by understanding and being able to control this.

More Carrots, Less Stick

So I would like to put a plug in for working together. Mary Oates is my colleague at Pfizer. She runs the quality end of the business and I kind of run the CMC end of the business for Pfizer. She and I had a very interesting conversation the other day about where are we going with regulators around the world in terms of whether or not we are going to put forth incentives or whether we are going to look at punitive reactions.

Right now we are more on the punitive action side than the incentive side. And I really think that we need to increase the carrots and reduce the stick. I think Daniel open the door for, as he basically was saying, let’s find out where the appropriate incentives are so that we can adequately and appropriately identify how we can put together the confidence in quality for the regulators so that they don’t have to worry that our products are going to be safe.

That is an incentive-based approach. And if we do have a problem, we should be able to engage with the FDA – much like…the ASAP [Aviation Safety Action Program] FAA approach to the airlines, where if there is a problem, the airlines don’t go hide the problem somewhere, they go talk to the FAA, because they don’t want to be shut down, and certainly they don’t want to put flyers at risk. I think the pharmaceutical industry needs to move in that same direction.

The Comprehensive Quality Overall Summary

So I am going to provide an example here. This is the comprehensive quality overall summary. I don’t know if this will work, but I am going to propose that we could use the comprehensive overall summary in a different way than we are now. Rather than module 3 – although we will still fill out module three in the CTD and put all the things in there that– although we will still fill out module three in the CTD and put all the things in there that we need – that the quality overall summary could tell the story that we want to tell about what our products can do and the control strategy subsequently.

So for me, the quality of the overall summary would be a summary of module three, and would include hyperlinks to data and information in module three as necessary. And it would provide a comprehensive control strategy for the drug product based on the target product profile.

The target product profile has to be comprehensive, which means it also has to include things that sometimes in the past I don’t think we were associating it with – for example, in use. If you give a product that is blue, a blue tablet, for example, it is friendly. And then one day when that product is pink or faded, they won’t take it. Patient compliance is part of the target product profile just as all of the other manifestations of in vitro tests and methods are.

The comprehensive control strategy for the drug product includes and identifies risks to product quality – those things that are most problematic. It contains all the regulatory commitments and actually equals the regulatory commitments in this case.

It will summarize the results of our risk assessments and our experiments, with hyperlinks to the detail either in module three or, if necessary, reference to our systems where we actually manage change and knowledge, and provide a summary of the development of the product formulation – the P2, for example – that actually provides substantiation for why we developed and why we are registering those commitments….

It also tells a compelling story. What I mean by a compelling story is if you read it, you will be convinced hopefully that this product provides you with the confidence and quality to approve. It satisfies, I hope, the criteria/questions described


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in FDA’s question-based review.

I had a lot of discussion in PhRMA about what this might look like. We haven’t been very receptive to filling out a template, because we have to fill out templates already for a lot of markets around the world. But we do recognize the value of the question-based review in the review of our submissions. And we do think that the questions that are in the question-based review are the same ones we use when we are preparing our submissions. We have already got them in our submissions for innovator products, so we see a lot of value in that. I will show you an example of how I think those could align very nicely in this quality overall summary. Just to parenthetically make a reference to Japan: The PMDA uses the quality overall summary as the place where the application form resides. The application form is their view of what regulatory commitments are, and you make decisions for post-approval changes based on what is in the application. In fact, every five or ten years the government, the PMDA, asks companies to go back and review those application forms and update them, because things get sloppy over time and they want to make sure companies are maintaining those. And those regulatory commitments are very important, because they represent what the company’s commitment is to them in terms of the operation of the process and the control strategies, and they define the control strategy.

So very simplistically, the target product profile: I won’t go into detail here. The slides are available, you can read them. So I will just bounce through them. I don’t want to take up a lot of time on this. The quality target product profile essentially defines the critical quality attributes. You will notice there is one PQS in here. I put in contamination control. Contamination is something that we don’t typically put in our registrations unless it is a sterile product and we are concerned about it. In this case, this is a solid oral dosage form. But contamination is something that we control within our systems. As I mentioned before, change management systems and GMP systems are responsible for that. So it is still something that we have to identify, and we should identify, as part of our quality target product profile.

This is a very busy slide but it is meant to make a point. In a way, you could almost say it is a little bit like an Ishikawa diagram. You have this whole Ishikawa diagram approach to show that this control strategy is really the backbone of what the quality overall summary should be conveying to the regulators (see first box on p. 13).

Product Characteristics Example: Target Product Profile

CRITERIA PRODUCTCHARACTERISTICS

TARGET ATTRIBUTE

TherapeuticIndication

Chronic Hypertension Immediate release

Patient Population Adult & Geriatric Easy to swallowMarkets Global Meet global regulatory

requirementsRoute ofAdministration

Oral BID Opportunity for lifecycle ODor ER formulation

TreatmentDuration

Chronic

Dosage Form(s) 10, 20 & 50-mgTablets

Small & easy to differentiate

Co-Administration Fasted Taste tolerabilityPharmacokineticsClass

BCS 2 (LowSolubility/HighPermeability)

IVIVR Considerations

PackageConfigurations

• Opaque PE Bottles• Opaque ACLAR/FoilBlisters

Easy to open

Storage • Ambient Conditions• Protect from Light

Protective packaging

Handling Keep unused tablets inclosed container

Quality Target Product Profile Example

QTTPATTRIBUTE DRUG PRODUCT CQA CONTROL

Purity Impurity/Degradation Control CQA2

Contamination Control PQS

Quality DP Dissolution CQA1

DP Physical Characteristics CQA3

Patient Compliance - Taste CQA4

Identity Confirmation CQA6

Potency Content Uniformity CQA5

API Assay CQA7


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Control Strategy Linkages Between CQAs and CPPs

QTPP ATTRIBUTE DRUG PRODUCTCQA FUNCTIONAL RELATIONSHIPS CONTROLS

Purity

Impurity Degradation Control

= f (CPP1 CPP2 CPP3)

CPP1 = f (CPP23 CPP24) CPP3 = f (CPP11 CPP17)

CPP1 DP Release & Stability Specification Limit

CPP23 (CMA) Opaque ACLAR Specification Criteria

CPP24 Package Sealing Temperature

CPP2 (CMA) API Chromatography & Specification Limit

CPP3 (CMA) API Specification Limit

CPP11 Step 2 Temperature IPC Limit

CPP17 Step 2 Addition Rate

Contamination N/A PQS Adherence to cGMP

Quality (Biorelevance)

DP Dissolution = f (CPP4 CPP6) CPP4 = f (CPP18)

CPP4 Disintegration Specification Limit

CPP18 (CMA) Disintegrant Particle Size distribution Limits

DP Physical Characteristics

= f (CPP5 CPP6)

CPP5 = f (CPP7) CPP6 = f (CPP23)

CPP7 = f (CPP13 CPP14 CPP19)

CPP6 (CMA) API Particle Size Distribution Limits

CPP23 API Crystallization Solvent Proportions

CPP5 DP Dissolution Specification Criteria

CPP7 IPC Drug Product Particle Size Distribution

CPP13 Lubricant Quantity

CPP14 Tablet Compression Force

CPP19 Blend Time

Patient Compliance-Taste

= f (CPP10) CPP10= f (CPP20)

CPP10 Flavor/Sweetener Quantity

CPP20 (CMA) Flavor/Sweetener Specification Criteria

Identity Confirmation = f (CPP8) CPP8 API ID Specification Criteria, cGMP

Potency

Content Uniformity

= f (CPP9)

CPP = f (CPP9 12 CPP CPP )15 16

CPP9 DP Stratified Sampling Criteria

CPP12 Blend Time

CPP15 Agitator Speed

CPP16 Component Feed Rate

API Assay = f (CPP21)CPP21= f (CPP22) CPP22 API Mother Liquor Impurity Levels IPC

CPP21 (CMA) API Specification Limits




There are a number of red CPPs, critical process parameters, and a number of green process parameters. After a risk-assessment you distinguish which process parameters are important and wich process parameters are not necessarily as important or relevant.

If you do that and you link them to the CQAs the way I have here – so I have cut out a lot of steps in the risk-assessment process – you end up with something like this (see second box on p. 13), which basically says that your control strategy is defined by the linkages that you have established between the critical quality attributes of the product and your critical process parameters or critical material attributes. It includes the CMA’s here – they are equally relevant.

You can tabulate this. So I did. I made it up based on a lot of experience with a lot of folks. I basically said your QTPP attributes are purity, quality, identity, and potency. You have CQAs associated with that, and you have relationships. And those relationships link those drug product quality attributes to your process parameters.

Again, this is all stuff we have been doing for the last 12-15 years, more or less with the advent of quality by design. We used to do some of this before quality by design, but we did it retrospectively when we had a problem – not necessarily up-front in cases. So now we are doing it prospectively because there is a relevance to it and it is a help to us, especially when we want to make post-approval changes. Now we have much better process and product understanding to go into the post-approval change focus.

The PhRMA Proposal and Key Messages

So based on that, I came up with a few key messages that I just want to leave with you. I am going to go through each one in a little detail.

This is a proposal that I am providing to the FDA. PhRMA is in the last few days of reviewing it and making sure it makes sense, so that we can get it to FDA to review. I think it aligns a little bit with what Daniel was saying….

So industry and FDA agree that conveying quality-by-design approaches in regulatory applications can be improved. There is no question about that.

I think the pilot had 11 or 12 products that went through it for quality-by-design – Pfizer and Wyeth had four of those. We felt it was a success in the sense that we learned a lot about what we could do better. It was a failure in the sense that we really didn’t get what we expected at the end of the day.

We put in a lot of work, time, and effort, and developed a lot of great information, but the post-approval world wasn’t what we thought it was. It was pretty much the same as always. So this is one of the reasons post-approval change and life-cycle management associated with quality-by-design is so important to the innovator, not just to the generics industry.

The FDA wants industry to improve the confidence in quality. I am trying to express a way of doing that by focusing on the control strategy. And industry wants FDA to adopt more risk-based approaches in the way they review our submissions. I think we have some ideas on how to help FDA do that, and also have FDA help us understand some of their use of the terms.

One of them is we need to make sure we integrate the inspection with the regulatory review for this to work – [to say] ‘this is inspectable and this is review stuff.’ In order for this to work appropriately, we have to make sure the two are integrated so that the confidence is there.

If a reviewer understands that company X has a really good change management and knowledge management system through the life-cycle, and has provided the requisite control strategy to make them confident that the product is well controlled, there is going to be a lot more probability they are going to approve that product and be comfortable with it, and also, carrying that through the life-cycle, much more comfortable with a [more flexible] post-approval change approach.

Effectively conveying enhanced process understanding and product knowledge has been a challenge for us and we




need to absolutely recognize that. We have had a lot of discussions in the last years to try to address that. I don’t think we have succeeded entirely, but I think we are lot closer than we have ever been.

We actually are in a perfect position right now. This is a personal position. I am not representing PhRMA or even Pfizer. I am not worried at all about trying to look at the generics and the innovator products together when we look at this, because the same rules apply. You have to provide a robust control strategy, and if you do, you are going to be fine, and if you don’t you are going to have to put more controls in place and you are going to have to justify them.

Responding to FDA and Industry Concerns

I think there is some real opportunity here and I am an advocate for moving this forward. FDA’s concerns are still valid to date, because we haven’t gotten there.

● One of them is lack of transparency in risk assessments.

This is a tough one. For those of you who do risk-assessments, I don’t know if you have ever looked at the amount of paper or amount of data that is involved, but literally thousands and thousands of pages are involved, even for a small molecule. And for a biologic, forget it. We are talking about 20,000-30,000 pages of information on risk-assessments. The real question is how do you distill that into confidence that you have done your risk-assessments appropriately?

● Prior knowledge:

What is it? Pfizer and a lot of companies do roller compaction all the time. We can probably do roller compaction in our sleep. That is prior knowledge for us. But if we don’t explain it and people don’t understand that we understand it, then there is a disconnect. We have to be able to figure out how to target that information – condensing that into a distilled way that makes it really valuable for regulators to understand without having to submit it all, because I don’t think they want to wade through all that. It is really kind of a critical moment to move this forward.

● There is an absence of a coherent and complete description of the product control strategy.

We have a hard time figuring out where to put the control strategy….. I have heard that we should put it in the regional section of the CTD. I have heard we should put it in P5.4. I have heard we should put it in P2. I have heard we should put it in S2.6. The control strategies are regulatory commitments. They are already there. Just define them and I think we will be okay.

● Understanding the life-cycle and change management:

Again, if we integrate the inspection with the review a little better through quality metrics, you will understand whether a company really has a handle on change management.

Industry concerns are:

● There has been a lot of inconsistency in the few years, particularly with quality-by-design in terms of theregulatory assessments on our products.

We can cite chapter and verse on the differences and inconsistencies. That is not important. The importance is why or what have we failed as an industry to do to convey the message, and what has the regulatory environment done to make some regulators [not accept it], and I think we have to come to terms on what that means.

● Lack of integration between inspections and assessments, and

● Absence of incentives:

As I mentioned, if we have a few more incentives rather than punitive actions to what we do, I think we are going to be in a much better place. One way to do that is through some kind of post-approval change management plan. That is what PhRMA has kind of recommended going back. It was a concept that many companies proposed




during the pilot, and it kind of went away. But I think we ought to resurrect it because it brings a lot of value….

Improve the quality of the applications to effectively convey a comprehensive control strategy and everyone would benefit from and use that, I think. I have a bit of a proposal to share, and I will share more detail on it.

The structure of module 3 is not amenable. Right now, the structure of Module 3 is very difficult to navigate if you want to convey a control strategy easily….

So the proposal is to use the module 2 QOS as the basis for conveying that very effectively. It doesn’t mean we won’t put things in module 3. We have an obligation and a commitment to put everything that we normally would in module 3. We just want to summarize it in way in module 2 that is easy to find.

Proposed Content of a Comprehensive QOS

So this is my coup de grace for the afternoon. The comprehensive QOS would contain five elements in the pharma world:

●The first is the TPP and description of the TPP. There is guidance from FDA on what the TPP contains.

● A subset of that is what the Quality TPP is. It describes our quality attributes and our control limits. If youlook across the top, I have linked where the elements of the CTD would reside or be linked to as well as the question-based-review questions [see box below]. So I went through the question-based reviews and saw that that belongs here. This is where we are answering those questions.

Proposed Content of a Comprehensive Quality Overall Summary

# CQOS SECTION DESCRIPTION OF CONTENTS LINK TO CTD MODULE 3.2

LINK TO QBR (Q#)

S P A/R DS DP

1. TPP Description of ProductAttributes

2. QTPP Description of Quality Attributes & Control Limits S.1 P.2.2

3. Summary of Comprehensive Control Strategy

• Regulatory Commitments• Reference to PQS Change Management

S.2.1S.2.2S.2.3S.2.4

P.3.1P.3.2P.3.3P.3.4

A.2 3, 4,5, 6,7, 8,9, 10,

1, 5, 8,17, 18,22, 23,24, 25,

S.4.1 P.4.1 11,16, 28, 29,S.4.2 P.4.2 17,19, 30, 33,S.6 P.5.1 21, 24 35, 36,S.7.2 P.5.2 37, 38

P.7P.8.2

4. PharmaceuticalDevelopment

• Justification for Control Strategy• Summary of Product Design & Development History• Summary of RiskAssessment Approach & Results• Summary of Results from Experiments

S.2.5S.2.6 S.3 S.4.3S.4.4

P.1P.2 P.3.5P.4.3P.4.4

A.1A.3

1, 2,7, 12,13,14,15,16,17,18,

2, 3, 4,6, 7, 9,10, 11,12, 13,14, 15,

• Summary Justification for Product & Process Design S.4.5 P.4.5 20,22, 16, 19,

• Summary Justification forAnalytics S.5 P.4.6 23 20, 21,

• Summary of BatchAnalyses S.7.1S.7.3

P.5.3P.5.4

26, 27,30, 31,

P.5.5 32, 34,P.5.6 36, 37P.6P.8.1P.8.3

5. Post-ApprovalChange Management Plan

Description of Regulatory Obligations forPost- Approval Changes

R 16


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● Element three is a summary of the comprehensive control strategy. It is a listing of all the regulatorycommitments. If you need to know what those are I can tell you: The process descriptions for both the API and the drug product. They are the specifications for all the materials. They are any commitments for protocols that are put into the submission. And those would constitute the control strategy, because together they would demonstrate that you would have a robust control for your filing. And all those sections that I have linked up in S, P, and A, would be what we would link to this quality overall summary. And the questions from the question-based-review are in the columns on the right.

● You can’t just provide regulatory commitments. You have to provide substantiation. You have to provide data…in the submission. Our proposal for the QOS is to summarize the data, summarize the justification, summarize the risk-assessments, and provide the substantiation for the control strategy and how it all fits together. And again, the references are made to the various CTD module elements as well as to the QbR questions.

● Then finally, some post-approval change management – something that would define or describe in a broad-sense or even in a not so broad sense what change management might look like. We have a lot of examples that have been provided to FDA during the QbD pilot that we are going to resurrect and see if they have any relevance.

For small molecules, many of them are associated with things like scale and site change. Because one of the things that we typically do pretty much immediately after the filing, depending on the volume of the product and how it is doing, is to make those kinds of changes. So those are relatively direct and simple to make.

For biologics, it may be chromatography changes, changes in some of the filters, because we do a lot of that for throughput and flow. We may need to increase scale of lyophilization. But it could be more generic than that. If you have a good robust control strategy, and you can measure this in terms of CpK, you may be able to justify more than this with a very generic type of post-approval change management system….

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Guides on FDA’s Generic Drug Review Process Continue Apace in July; EU Pilot Pursues Generic Drug Review Streamlining InternationallyThe efforts by the Office of Generic Drugs (OGD) to clarify and streamline the Abbreviated New Drug Application (ANDA) process and facilitate the implementation of the Generic Drug User Fee Act (GDUFA) continued apace in mid-July with the release of draft guidances on post-approval supplements and easily correctable deficiencies. Comments on the drafts are due by mid-September.

Also released in July were: ● revised bioequivalence recommendations for specific ANDA products ● an update on proposed changes to OGD’s question-based review (QbR) application approach, and ● clarification of the user fee policy regarding waivers and fee reductions.

The OGD July releases follow on the heels of a draft guidance on the content and format of ANDAs released in June (see IPQ “Monthly Update” June 2014, p. 11-13). In May, OGD put out a Q&A that is intended to clarify the June 2013 ANDA stability guidance (ibid.).

Guidances Explain GDUFA Impact

FDA’s July draft guidance on post-approval supplements (PASs) for ANDAs explains how GDUFA impacts the PAS process with regard to the agency’s performance metric goals and how PAS submissions and amendments will be handled to help the agency meet the goals.

The draft describes specifically how the GDUFA performance metric goals apply to a PAS: ● subject to the refuse-to-receive (RTR) standards ● that does or does not require an inspection, and ● amendment. Also included in the appendix of the 17-page draft is a flow chart detailing the GDUFA supplement review process, annotated to show how filing amendments to supplements lengthens the review timeline.

Guidance for post-approval changes for drug products has been a recent focus both in the US and Europe as efforts continue to bring the CMC review paradigm into closer alignment with the continuous improvement orientation on the GMP/quality systems side.

In March, FDA and EMA issued final guidances intended to help industry better understand and manage the regulatory expectations for post-approval CMC changes (see IPQ “Monthly Update” June 2014, pp. 11-13).

In both cases, the final FDA and EMA versions were impacted by a plethora of comments that came in on the drafts – reflective of the level of industry concern with the global filing burdens when making CMC changes. [Editor’s

Note: An in-depth review of the problems that global manufacturers face in making post-approval changes and the current industry/regulator dialogue around what can be done to address them is provided in IPQ’s February 2014 Monthly Update.]

The 28-page FDA draft guidance on ANDA “amendments and easily correctable deficiencies” under GDUFA, released at the same time as the PAS guidance, once finalized, will replace the 2001 guidance on “major, minor, and telephone amendments to ANDAs” – put in place prior to GDUFA.

The guidance describes the “tier” system for the different types of amendments and how they may affect the application’s original review dates. It also explains FDA’s performance metric goals based on the amendment tiers as well as the process for submitting amendments and the agency’s classification process.

Three appendices provide examples of major and minor amendments and easily correctable deficiencies. A fourth appendix includes a flow chart detailing the process the agency uses to evaluate solicited, unsolicited, and administrative amendments and the different timing goals associated with each.

A solicited amendment is one made in response to a complete response (CR) letter from FDA, whereas an unsolicited amendment is one the applicant chooses to make. An administrative amendment is one that is routine in nature and does not require a scientific review.

QbR Questions Revised

FDA’s Office of Generic Drugs has been working on revising the list of CMC questions it is asking DMF holders and ANDA sponsors to answer under its question-based-review (QbR) approach to enhance quality-by-design in the development, submission and review process.

The effort takes on added significance as the QbR approach is being considered for use in innovator applications as well as for generics (see IPQ “Monthly Update” June 2013, pp. 21-35).

The membership of the QbR working group, originally drawn only from OGD, now includes Office of New Drug Quality Assessment (ONDQA) staff as well. The team has made refinements to the questions to make sure that they would be applicable beyond generic drugs.




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

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

Jerry

Line






At the GPhA/FDA CMC Workshop in mid-2013, OGD Reviewer Jennifer Maquire discussed the changes OGD was considering, explaining the motivation for the rewordings and additions and what it is looking for in the company responses to them (ibid.).

In July, 2014, OGD released a current draft of the updated QbR questions for comment, which incorporates a few additional changes beyond those discussed by Maquire a year earlier.

Added in the new proposal are questions on: ● in-line production monitoring ● rationale for dosage form selection for 505b(1) drugs ● characteristics of reference products for 505b(2) and 505j drugs ● excipient/excipient compatibility ● micro evaluations, and ● previous FDA inspections (seebox below).

Comments Requested on Fee Waiver and BE Drafts

FDA draft guidances on user fee waivers/reductions and on bioequivalence (BE) are out for comment until August 15 and September 22, respectively.

The fee waiver guidance describes the types of waivers and reductions permitted under the user fee provisions of the FD&C Act, including fee exemptions for orphan drugs, and the procedures for submitting the requests.

The revised bioequivalence recommendations for specific ANDA products in July flow from the agency’s 2010 bioequivalence guidance. 421 new recommendations were added in July 2014, and 15 revisions were updated in early August.

FDA also posted information on 2015 user fee rates in the Federal Register on August 1. Of note are the higher fees required from non-US companies, reflecting the additional cost overseas inspections incur.

Pharmaceutical manufacturing facilities located outside of the US will now be required to pay more in annual facility fees for certain applications and supplements – 12% more for finished dosage form manufacturers, and 15% more for active pharmaceutical ingredient (API) manufacturers. If a plant site contains both finished dosage and API production, it will be required to pay both fees.

New and Revised QbR Questions

The following is the list of the QbR questions that were added/revised in the July, 2014 version. The new text is bolded.

Drug Substance:

● If applicable, what on-line/at-line/in-line monitoring technologies are proposed for routine commercialproduction that allows for real-time process monitoring and control? Provide a summary of how each technology was developed.

Drug Product:

● For 505b(1) applications, what is the rationale for selecting the proposed dosage form for the drug product?For 505b(2) and 505(j) applications, what are the characteristics of the listed reference listed drug product? What is the Quality Target Product Profile (QTPP) of the finished product based on the proposed indication and patient population? How is the QTPP justified?

● What evidence supports excipient drug substance compatibility and if applicable, excipient-excipientcompatibility?

● When applicable, what microbiological attributes were evaluated on the finished product?

DS and DP:

● Who manufactures the drug substance/drug product? List each participant and facility involved in the manufacturing/testing activities and clearly state their function. List the date of the last FDA inspection of each facility involved and the result of the inspection. Has the manufacturer addressed all concerns raised at the FDA inspection?


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EU Pilot on Generics Applications Advancing

As FDA moves forward with its efforts to use GDUFA fees to create a more transparent and streamlined generic drug approval process in the U.S., the European Union (EU) is making strides to accelerate the assessment of generic drug applications in non-US countries as part of the International Generic Drug Regulators Pilot (IGDRP). The pilot was announced in July.

The EU is leading the international pilot project, which is modeled after its decentralized procedure. The pilot allows European regulators, upon request from generic drug firms, to share assessment reports in real time with collaborating regulatory agencies outside the EU.

By offering to share its assessment reports, the EU aims to reinforce collaboration and information-sharing between regulatory authorities around the world. The goal is to accelerate and improve scientific assessment processes and enable coordinated reviews between participating agencies.

The first phase of the pilot project will involve the EU, Australia, Canada, Chinese Taipei and Switzerland.

Other members of the IGDRP that may decide to take part in the pilot program at a later stage include Brazil, China, Japan, Korea, Mexico, New Zealand, Russia, Singapore and South Africa. The European Directorate for the Quality of Medicines & Healthcare (EDQM) and the World Health Organization (WHO) participate as observers.

DOWNLOADS FROM THE STORY:

• Post-approval supplements draft guidance• Amendments and easily correctable deficiencies draft

guidance• QbR July �01� revised questions• Draft revised bioequivalence guidelines• Draft guidance for waivers and fee reductions• �01� GDUFA user fee rates

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.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM401139.pdf

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm

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Amgen “Analytics of the Future” Initiative Develops MS-based “Multi-Attribute Methodology” to Streamline Biotech Development and QC Testing

INTERNATIONAL

Amgen is among the major biotech companies working hard on empowering, while at the same time streamlining, their analytical toolbox at the development and quality control testing levels as the next frontier of quality by design.

How to realize “the promise of analytics of the future” using what Amgen is calling “multi-attribute methodology” (MAM) was the theme of a presentation by the biotech company’s Contract and Product Quality VP, Anthony Mire-Sluis, during a session focused on QbD implementation challenges at CASSS’ CMC Strategy Forum Europe held in Sorrento, Italy in May 2014. Prior to joining Amgen in 2004, Mire-Sluis played a key role in biotech CMC policy setting at FDA.

At the session, he revealed: ● the purpose and rationale of Amgen’s MAM program ● how the vision was pursued using mass spectrometry (MS) methodology ● examples of its power in assessing product quality attributes, and ● the regulatory implications in moving to its use in specification-setting and routine QC testing.

The presentation shed light on the issues that come to the fore as the rapidly advancing analytical technology pushes up against existing biotech regulatory policies and on the adjustments that need to be made to accommodate these advancements. As such, it speaks to the intent of the CASSS CMC strategy forums as a vehicle to bring industry and agency experts together to explore biotech developments and the regulatory concerns they engender.

Also presenting at the session were Sweden Medical Products Agency (MPA) biotech product assessor Mats Welin, who offered “a regulator’s view” on “how to assure quality and consistency in an evolving QbD scenario,” and MedImmune UK’s Derek Murphy, who addressed the impact of QbD on QA and the Qualified Person (QP).

A significant discussion period followed the presentations that focused heavily on Amgen’s single multi-attribute method approach and the regulatory issues it raises.

One Method, More Power

The rationale behind the development program, Mire-Sluis explained, was “to have a single method with the power

to be able to be literally the cornerstone for our process development and our product characterization.”

Given the limitations in the current array of general methods in assessing product attributes, Amgen targeted a single method that could measure directly, for example, oxidized, deamidated, and glycosylated protein forms. The company also wanted a method that could be used on line – providing the ability to monitor what is happening to the product as it is being produced.

The overall goal of Amgen’s “analytics of the future program,” Mire-Sluis explained, is to “really move through QbD to more modern methodologies – trying to get rid of gels and other methods that aren’t particularly useful,” and replace them with methodology “where you are actually measuring the attributes that you think are important.” QbD efforts are focusing on criticality of attribute assessments and need to be supported by a method that can “actually pick up those particular attributes, rather than ones that are more generalistic.”

Highlighting the gaps in the ability of the standard approaches to assess various quality attributes, Mire-Sluis explained that the MS methodology Amgen has developed “not only does it all in one go, but actually covers a whole host of attributes that you can’t actually routinely detect” using them.

During process development, he stressed, “to be able to get that information in real time with that amount of power is

Rationale for a Multi-Attribute Method

● Cornerstone analytical method for development of pro-cesses and analytics that embrace QbD principles

● Direct monitoring of biologically relevant product qualityattributes (PQA’s) rather than indirect monitoring by con-ventional methods (CEX) thereby ensuring safety and effi-cacy

● More complete analysis of the product quality profileduring and after processing compared to current method-ologies

● Reduces the number of assays used for process devel-opment, product disposition and in-process control sup-porting the Analytics of the Future initiative and reducing cost


WWW.IPQPUBS.COM AUGUST/SEPTEMBER 2014 ��


very valuable for understanding your process, which is, as you know, a big part of quality by design – true process understanding and building a robust process.”

Along with more complete analysis of the product quality profile and critical quality attributes (CQAs) during and after processing, the multi-attribute method allows for reducing the number of assays used for process development, product disposition, and in-process control.

The Amgen expert went on to explain the challenges his firm has been addressing in: ● gaining the “extensive knowledge” needed of the method’s capability in view of its high sensitivity ● validating it ● correlating the MAM with current release methods, and ● incorporating it into regulatory filings.

At the Regulatory Interface

Amgen’s initial regulatory strategy is to file the MAM as a characterization method – using it alongside rather than inside regulatory specification setting.

For less sophisticated regulators, Mire-Sluis commented, it is challenging enough to “explain the normal methods that we use. So we are going to start off with having it as a characterization method to get everybody feeling more comfortable with it. Then probably by the time it gets to licensure, we would replace the old methods with this single method moving forward.”

Amgen does believe that it has put in place the fundamentals to move to the single multi-attribute method for specification use.

The automated MS quantification technology is “very flexible” and usable in a QC environment, Mire-Sluis stressed. “It is amazing the amount of information you can get out of this machine that you can use for process

development, for characterizing your product, as well as using it for lot release and stability.”

The MAM does more targeted assessment of CQAs, allows for better product control for patients, and reduces the cost of quality. Another benefit is its universality, the Amgen official pointed out.

“So once jurisdictions around the world get used to this type of methodology, import testing becomes much easier when you are working with regulatory authorities that like to retest your material during development. It is a single method, rather than transferring eight or nine methods around the world to multiple jurisdictions and paying for it and sending it to everybody. Once these regulatory authorities have these mass-specs, it should be easier to transfer tests around the world.”

MAM Meshes with Understanding Clinical Import

During the discussion period that followed in the session, Mire-Sluis commented on how the MAM interfaces with the focus Amgen has had on understanding the clinical import of variations in the test results given the increasing sensitivity the methodology offers.

As Amgen has been doing with the traditional methods, the read outs are assessed in view of Amgen’s learnings about what happens to the product in the patient based on serum analysis (see IPQ Jan./Feb. 2013, pp. 50-62).

When you take product molecules back out of patient serum to see what is actually happening in vivo, he said, “you find that lots of things you have been worried about, you don’t need to be worried about. I gave this example before: We were very worried about deamidation until we took it back out of the patient and found that, within half an hour, 100% of the molecules were already deamidated. So who actually cares about controlling it to 0.1% or 0.5% or whatever it was in the example?”

The MS technology can be applied in doing the antibody analysis on patients to expand this realm of understanding.

The finding, for instance that “deamidation is spread all over the place,” means that “we are not really worried or focused on one particular area.” While the criticality of variations such as “an oxidation here, a deamidation there” may not be predictable, “at least it gives us the ability to have those discussions. Maybe we will learn something. Maybe we will finally see what immunogenicity is really about. Maybe we can learn something about the function and structure of molecules that we have never seen before.”

Advantages of the MAM Mire-Sluis cited the following advantages of the MAM

over conventional analytical methods. The MAM uses Thermo Fisher’s “Orbitrap” mass spectrometer.

● Orbitrap mass spec: High resolution scans,fast scan speed, small footprint

● Technology allows for “plug and play” pep-tide map analysis.

● Simple to use and more robust due todesign and minimal features (1 button tuning, calibration)

● Automated software is used to generate a comprehensive attri-bute target list and automated quantification.

● Alignment of method and instrumentation for process develop-ment, PAT control and product disposition.

http://www.ipqpubs.com/issues/ipq-monthly-update-jan-feb-2013/


AUGUST/SEPTEMBER 2014 �� ......... ....


Amgen, he added, truly believes, for example, “that if we can do comparisons during development, side-by-side with CEX [cation exchange chromatography], you wouldn’t have to run CEX anymore.” If you know you are controlling the attributes that matter and can correlate the methods, he said, “I can see that those old methods will eventually go.” Like the process of replacing gels over the years with more sophisticated methods, “I just see this as a natural progression. But we have to prove to the agency that truly we are picking up what the old methods used to.”

Pairing species that we know we can isolate from orthogonal methods and comparing them to what we are finding in this MS method is “going to be a learning curve,” Mire-Sluis commented when asked for further input on this comparison process.

As with any mass analysis, the significance of the various sequences that are found need to be understood in a holistic manner. However, Mire-Sluis affirmed, “it is amazing what mass-spec can do. I have seen mass-specs now that could replace size exclusions or could do aggregates. This is one of those fields where you just watch the technology that is out there. I can’t predict whether this is going to be the only test we ever use, but you know what, science is an amazing thing. In ten years times, we may find a single assay that does the whole lot.”

Another issue that was raised during the discussion was Amgen’s reliance on sourcing from a single MS and software provider.

Mire-Sluis acknowledged the danger in a single source supplier disappearing. However, the awareness of this type of MS technology and supporting software is expanding, and similarly to the progression in CE, over the next few years there will be other players “getting onto the same bandwagon,” he affirmed.

While more sophisticated than the gel technology, as regulators get acclimated, “hopefully more vendors will start looking at this stuff, and we will get more software people involved.”

How Should MAM be Sold to Regulators?

Biogen Idec Biopharmaceutical Development VP Rohin Mhatre suggested that it would be to the advantage of the regulatory community for Amgen to position the MAM program as an extension of, rather than a radical shift in, the analytical arena to get more ready buy-in from regulators.

“It is harnessing the power of mass-spec” in the decades-old pursuit of peptide mapping, and is a “very reasonable approach” that “shouldn’t be a big hurdle” if sold in that light, Mhatre maintained.

Lilly Regulatory Advisor John Dougherty, the session moderator, asked Mire-Sluis to comment further on use of the methodology in the PAT context – “the whole feedback loop of the equation.” He cited Mire-Sluis’ example of monitoring a cell culture and finding that oxidation was occurring more rapidly than normal. “Would you understand what levers to pull in the actual bioreactor to kind of slow that down then?”

The Amgen official explained that “that is a very interesting discussion that we have been having in the company. We call it product attribute control.” There are people in development, he noted, that feel that as long as the product is what it is supposed to be, “what you do with the process doesn’t really matter.” He added that the separation-free mass-spec methodology has the ability to characterize the process going on in the bioreactor.

Referencing Mhatre’s comment, he stressed that the new part of Amgen’s effort is “trying to create a method that can actually be run routinely in the [QC] lab. The software wasn’t previously available.”

A question was raised on relating the deamidation, amino acid and glycation findings from the standard peptide mapping with the total overall variance.

“That is where all the work comes in” that he discussed in his presentation, Mire-Sluis responded. “It is all about proving your orthogonal methods are showing you stuff the new method is showing.”

Noting the power of the Amgen MS methodology in understanding the molecule, he queried whether instead of “adding it up” to find that your product is 10% deaminated, one instead says “’I don’t care about the deamidation that is in the FC portion as it has no FC function….’ Those are interesting discussions that we are going to have to think about once we move this forward. Do you even take a site of oxidation or deamidation as the thing you want to have on the spec?”

Upfront Work Speeds Up Process Later

Another participant noted that he was “really impressed” by the Amgen methodology as “bringing a lot of new things” to the table.

He pointed out that during development, the process entails “a fair amount of adapting into a certain molecule, programming to a new peptide, and setting new parameters etc. So I assume that you have a significant investment at one point in your development – which is probably at a later point when you are quite confident that this will play out” and be useful for control, manufacturing, and changes.




Mire-Sluis responded that there are definite advantages to doing this type of analysis upfront. Another option is to wait until you know the product works and then “run like crazy” at that point.

While speed to first-in-human studies is important, if a company has not done a good portion of the product and process characterization, the time from first in humans to marketing application can stretch from five to seven years “because you have to catch up.”

Companies are going to have to make the decision whether to spend less up front, or do more. And if the product “dies, it dies, but if it works we can get it to patients much quicker.” At Amgen, the argument is being made to upper management to buy in on the up-front investment strategy.

Early Discussions with Regulators Recommended

Sweden’s Welin commented that how the specifications would be set in the MAM context would need “some discussion.”

In general, he said, the regulator would need to be convinced that a new approach is equal or better, and it is up to the sponsor to do that. The challenge for both the assessors and the inspectors is how to learn more about these methods, he maintained.

FDA center for drug biotech reviewer Sarah Kennett, who presented FDA’s perspective on recent regulatory trends for biopharmaceuticals in the opening session of the CMC strategy forum, suggested that these discussions could be fostered by sponsors coming in for a Type C meeting

before submitting a marketing application or post-approval supplement.

“I think it is going to take a lot of thought for the agencies to get their heads wrapped around this,” she said, suggesting that it would help to have information and discussions up front.

Roche’s Kowid Ho, who joined the company in late 2013 after serving as a key CMC policy official for the French agency AFFSAPS and on EMA’s Biologics Working Party (BWP), commented that getting the new methodology registered would “not be so difficult” over time.

“There will certainly be some period where the industry may actually have to test the more traditional and new methods until the agencies get sufficiently satisfied with the methods before we drop the more traditional ones,” as has been done “for many other new techniques.” Such an approach, Ho said, “is not new.”

Welin pointed out that the issues involved draw in the larger relationship between the CMC and GMP components of the regulatory equation.

Under discussion in Europe, he pointed out, is how the quality system may be used to help assessors become more comfortable in bringing the new technologies on board and setting wider specifications rather than narrowing them based on process capabilities.

The challenge is working with inspectors “to do this in a proper way, using…not only what is in the file, but also what is in the GMP for us to be reassured that these things are under control and there for release.”

AMGEN’S TONY MIRE-SLUIS ON HIS FIRM’S MS-BASED MULTI-ATTRIBUTE METHODOLOGY PROGRAM

In a session focused on QbD advancement at the CASSS Europe CMC Strategy Forum in May 2014, Amgen’s Tony Mire-Sluis discussed how to realize “the promise of analytics of the future” using what Amgen is call-ing “multi-attribute methodology.” In the presentation, he covered: ● the purpose and rationale of Amgen’s MAM program ● how the vision was pursued using MS-based methodology ● examples of its power in as-sessing product quality attributes, and ● the regulatory implications in moving to its use in specification-setting and routine QC testing.

So in this session…we are going to be talking about QbD and some of the potential challenges of implementing it in what I call the real world.

One of the things I wanted to talk about was around the analytics portion of QbD and how in Amgen we are trying to advance our analytics – some of the work we have been doing, but also the potential challenges as we move forward with this once we start implementing it in our filings.

So what I am going to be talking about is the multi-attribute method [MAM] that we have been creating at Amgen:




● What its purpose is and what we believe is the rationale behind it.

● How we actually developed it, because I can assure you it wasn’t easy. It is a mass spec method. Massspectrometry is something that as we wanted to move from the more process development side into the QC labs is not easy to do, because it is complex technology.

● Some examples of what this method can actually do for us from a measuring of product attribute perspective.

● And then some of the risks working with an MAM method, working with regulators and putting this into filings,as well as, as I said, making it a routine part of what we do in the QC world.

The Purpose/Rationale

So what was our rationale? Well, we wanted to have a single method with the power to be able to be literally the cornerstone for our process development and our product characterization.

At the moment, most of you are probably aware that most of the methods we use for lot release [are] general methods from an attribute perspective. For instance, CEX gives you acidic peaks, basic peaks, and this thing in the middle. But there are many attributes within those peaks, and it doesn’t tell you what they are. It just says you have a certain amount of basic, a certain amount of acidic, and something in the middle.

What we wanted to do was find out if there is a method out there that could actually measure directly oxidized forms of the protein, deamidated forms of your protein, different glycoforms – that sort of thing. And this is where we were moving to with these types of methods.

We also wanted a method that you could actually use online. So you could monitor what is actually happening to your product as it is being produced, following through the cell culture from day one, to day five, to day ten. Then looking during purification to see what is actually happening to your product quality attributes, rather than do as we do now and take those peak profiles of things like CEX, take those individual peaks, and push them through another round of analysis to identify what is within them. That is very time consuming and really isn’t something that we could adopt routinely, whereas this [MAM] method hopefully will be something that you can do during development.

Of course, we have at Amgen something that is called the ‘analytics of the future’ program. [The goal] is to really move through QbD to more modern methodologies – trying to get rid of gels and other methods that aren’t particularly useful, to ones where you are actually measuring the attributes that you think are important. A lot of us in QbD are doing criticality of attribute assessments. Well don’t you want to have a method that could actually pick up those particular attributes, rather than ones that are more generalistic?

So that was the purpose of us looking for the sort of method that we can use to essentially achieve that type of ideal. As I mentioned, currently the sort of CEX separation you have are the various peaks, and within peak one you are going to have a certain number of attributes, within post peaks you are going to have another attribute, and there is something going on in the main peak.

Well, what you can do, which is what we have been doing in the past, is taking those peaks and essentially measuring, for instance, the potency of them – Is it important? Is it not important? What is the portion of biological activity? – but also what actually are all these attributes?

We want to move away from that. Rather than saying, ‘I have got 50 % basic peaks’ – you could, in theory, within that 50 % have huge variations in levels of oxidation, of deamidation, or whatever – actually going to a multi-attribute based method that says, ‘I have this amount of attribute one, this amount of attribute three, this amount of attribute five.’ You can link those to the potency estimates and say which one is important, which one is not important, which is critical or less critical.

I think it is really moving us forward to measuring things that are actually important for safety and efficacy and for the




patients, rather than relying on these types of things, which, to be honest, are a bit more bland. You don’t exactly know what is going on beneath those peaks – [what] caused a peak to go up. You don’t know until you split it up and do a whole lot of other tests.

The Development

So what have we developed? We have worked with the manufacturers of a mass-spectrometry machine – you will see here we have an Orbitrap mass spectrometer – as well as a developing the software. This is very important. There was a great collaboration between us, industry, and the vendors of this equipment without which we could never have gotten this achieved.

It is very high resolution, has a fast scan speed, and a small footprint. You don’t want a mass-spec that fits into the size of a rugby field to get that into the QC lab – or actually where we want to put it is on the floor in the manufacturing plant. Our new plant in Singapore, which is built around manufacturing using future concepts, is actually going to have a lot of testing on the floor directly attached to the manufacturing process.

It allows for plug and play peptide map analysis. It is very simple to use…. Mass-spec used to be in the world of the technical experts. They were the only people who knew how to use it. We needed to create something that could be done in a QC lab or on the manufacturing floor. So it is done in a way that you literally push a button and it auto-calibrates and will tell you whether it is okay to put the sample in. And an analyst, be it somebody who is on the floor or someone in QC, just puts the sample in. It has automated software that is used to tell you what attribute you should be looking for.

MAM Replaces Non-Attribute Specific Assays

Amgen’s MAM will replace non-attribute specific assays with a method capable of specifically detecting and measuring critical attribute.

CEX separa�on

70% PotencyA�ribute 1A�ribute 2A�ribute 3A�ribute 4

CurrentRelease Method

150% PotencyA�ribute 5

100% PotencyMain peak

Product Understanding

FutureRelease Method

Sub-frac�on Potency Assessment

CEX separa�on

MAM MS Based method

A1

A3A5

A1, A22 x A3

A3, A4

A5

A�ribute Potency

Main peak 100%

A1 50%

A2 110%

A3 95%

A4 102%

A5 150%

Replacing CEX monitoring of pre-peaks with more specificmethod monitoring relevanta�ributes:• A1 (efficacy)• A3 (safety)• A5 (safety and efficacy)




Obviously, our process development people who are analytical experts are the ones who will set up that program. But once it is ready, the answers that come out the other end are, ‘you have 10% of oxidized material, you have 15% of deamidated – something that is really easy for the QC analyst or someone working on the floor to be able to push that data into your laboratory information system and come out with specs or whatever you want to use it for in the future.

What we want to do is make sure that the method and instrumentation is useful across process development, PAT. You want to use this to make decisions on the floor at the time of manufacturing – looking at the cell culture process, looking at howpurification is going, as well as eventually product disposition. So you really need to have the ability to cope with all those different scenarios.

Most of you are probably aware how you do peptide map analysis. Essentially, you take your proteins, you denature them, you reduce them, alkylate them in digestion, and then it goes into the machine. So pretty simple, really. Well it sounds simple. Saying that, you have got to make sure that those steps are well controlled enough so that you don’t get artifacts through arbitrary trypsin digestion or over-digestion or under-digestion.

To be honest, that is probably where most of the work actually occurred – trying to make sure that we had very robust handling processes – because that is the piece that the people in the QC labs are going to have to be doing on a routine basis. The machinery itself, ironically, once we had been working with the vendors, was kind of the easy piece to sort out.

What the MAM Can Do

We ended up with a process that seems to work reasonably well. The advantage of this – if you look down the product quality attributes you can have for a monoclonal down the side, and there is a whole ton of them – is that this single method can give you information about essentially 95% of all the attributes you want to look at for a monoclonal antibody…. Whereas for the conventional release method, you always need one or the other to tell you what is going on. In fact, you need the whole load of them to cover the whole aspect.

And, in fact, if you look there are whole gaps even in the current methodology that we have around various quality attributes. So this method not only does it all in one go, but it actually covers a whole host of attributes that you can’t actually routinely detect on our routine specifications that we currently have in place. So this is a very useful and hopefully more valuable way of looking at products moving forward.”

What you would normally get out of CEX [is] a number that has a certain percent acidic, a percent main, and a percent basic. Well, what we can now get is all these different attributes, and more of them, coming out of that single assay. It will tell you what is in this peak, what is in the main peak, what is in the basic peaks, the oxidation types, and where they are. It is not just how much oxidation you have, but where it is in your protein that the actual oxidation occurs. So you can imagine, this is a ton of really useful information.

Not just for specifications, and we will get into that later, because honestly do you really need all this information to release a lot? But you can imagine during process development – developing your fermentation conditions and all that stuff – to be able to get that information in real time with that amount of power is very valuable for understanding your

MAM Peptide Map Sample Preparation

● Denature the sample● Reduce and alkylate● Desalt● Digest with trypsin● Inject the digest● Analysis

DenatureProteins




MAM and Conventional Release Methods ComparedMul�-A�ribute Method Conven�onal Release Methods

ANTIBODY PQA Pep Map-MS SEC CEX rCE-SDS nrCE-SDS HILIC ID ELISA HCP ELISAAggregate AssessmentDeamidation (Isomerization) AssessmentDisulfide Isoform AssessmentGlycation AssessmentHigh Mannose AssessmentMethionine Oxidation AssessmentSignal Peptide AssessmentUnusual Glycosylation Assessment CDR Tryptophan Degradation AssessmentNon-consensus Glycosylation AssessmentN-terminal pyroGlutamate AssessmentC-terminal Lysine AssessmentGalactosylation AssessmentDimer AssessmentFragmentation (peptide bond) AssessmentDisulfide Reduction (DS Fragmentation) AssessmentHost Cell Protein AssessmentMutations/Misincorporations AssessmentHydroxylysine AssessmentThioether AssessmentTrisulfide AssessmentNon-glycosylated Heavy ChainDNA AssessmentCysteine Adducts AssessmentC-terminal Amidation AssessmentCDR Conformers (HIC Isoform) AssessmentO-linked glycans AssessmentFucosylation AssessmentResidual Protein AIdentity

MAM Serving as ID AssayAmgen’s MAM will replace non-attribute specific assays with a method capable of specifically detecting and measuring critical attributes.

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NL : 1 .47E 8TIC F : F TM S + c E S I F ull m s [300 .00 -2000 .00 ] M S HC 20130708_A M G224_TS 1_D S I_T1

NL: 1 .40E 8TIC F : F TM S + c E S I F ull m s [300 .00 -2000 .00 ] M S HC 20130708_A M G224_TS 2_D S I_T1

Parameters

System Suitability

ΔRT of reference peaks

Total peak area of reference peaks from RS runs%RRA (ratio of relative peak area) of reference peaksMass accuracy < 5 ppm

S/N for reference peptide ≥ value (TBD)The levels of PQAs (2-3) monitored from product specific reference standard within historical range

Sample Acceptance Criteria

Total peak area of reference peaks from sample runs

Sample Pass/Fail Criteria

ΔRT of sample reference peaks

%RRA of sample reference peaks

Mass accuracy < 5 ppm

No new peak above IL limit




process, which is, as you know, a big part of quality-by-design – true process understanding and building a robust process. This is really helpful for that.

It could also serve as an ID assay. You could imagine the readouts of this machinery are very complex. It truly tells you whether it is the monoclonal that you want. Obviously, there are similarities between monoclonals. That has always caused a bit of annoyance on how you do an ID test. Is it a combination of the potency assay or mass spec or whatever else.

Here you get a one-stop shop, because it is so sensitive. You can truly tell the ID fingerprint. However, you still have to be careful, because there is variability from run to run and variability from lot to lot.

It took us a while to make sure that we got the system suitability right – how much noise can you have in the system to allow you to truly ID the product? Because you can imagine a slight variability in some of these small peaks, and the machine kicks out [that] it is not the same. How similar does it have to be? We did a reasonable chunk of work to make sure that our acceptance criteria are going to be appropriate so that we truly were looking at identification.

We, as you do, when you are creating a new method, compare it to pre-existing methods. Here we have comparing the glycan map with a method a lot of people use, the HILIC method, and we get really nice agreement across the board

Comparison of HILIC Glycan Map and MAM

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with all the different glycoforms that we were looking at.

So you can imagine whenever you are going to file something new with the agency, you always have to compare to existing orthogonal methods to show that what you are really picking up is actually what people are used to seeing. That is part of the development that we do, and will be included in the packages that we provide to an agency.

Assessing Product Quality Attributes

Where does it really start helping? Well, tomorrow, we are going to be talking about all different sorts of control strategies, and that is really where this really starts helping.

Most people do an assessment to look for the criticality of the product quality attributes. Well what actually are your product quality attributes? You can see that with this method. You first of all can detect with a single method a whole ton of your product quality attributes all in one go.

So when you are trying to do those experiments – to say, ‘okay, here is my list of quality attributes. What sort of severity do they have?’ – you kind of do them off line, and then go, ‘how does my process influence those quality attributes?’ You can actually do that all in one go with this method, rather than every single time going, ‘okay, oxidation – I now have to take out that basic peak and find out what the level of oxidized material is in there.’ You can do this all in one go as you are doing your process characterization.

So you know that when you do these risk assessments it is always: ● the severity of the potential of your critical quality attribute ● the process capability of either controlling that attribute or causing it to go up or down, and lastly ● the detection. And that is really where this multi-attribute method helps.

Because if you look at the standard way that you would look at methionine oxidation, just as an example, on our calculations, because you can’t directly detect oxidation through current specification testing, it becomes red. Because you can’t say, ‘oh, I know the levels of oxidation at lot release.’ You don’t. You just have a basic peak, in which could be deamidation, oxidation, or god knows what else. You don’t actually have the level of oxidation.

But if you can monitor it over time, and you can actually see the levels of oxidation, that gives you an understanding of how you are controlling it during your process. Even better, if you put it on the specification, you know exactly what the patient is getting from an oxidation perspective. We don’t have that with traditional specification lot release. You get an idea of general level based within those peaks that you have, but you don’t have an actual number.

Here you can actually say, ‘I have been giving, during clinical studies, patients 3-5 % of oxidized methionine on the particular methionine site during clinical studies.’ It gives you a much better control, so you end up having a low overall risk if you manage to monitor that during clinical studies and process development. So it is actually very valuable for decreasing the risk of particular attributes, depending on which ones you select, for giving it to patients.

Now saying that, it was wasn’t easy. It looks all great because of the results that we got, but this was not an easy journey, and we are still not there yet because we are just about to file it with the agency.

Advancing Highly Sensitive Analytical Technology

When you are start using these highly sensitive methods, you have really got to make sure you understand the robustness of your method. You have got to understand how reproducible it is. Simply because you can detect a thousand species doesn’t mean you can detect it day after day, lot after lot, run after run. How rugged is it? Will you get the same answer if you run it on a Tuesday compared to when you run it on a Thursday?

Depending on what you have done to the machine itself you can get different results. What actually affects the results? What can affect the sensitivity of your method? Very importantly, what interferes?

We were running this method, and then all of a sudden, halfway through development, we kept getting this unusual




profile that we couldn’t understand that we kept getting out of nowhere. Would you believe it was somebody in the labs who just swapped from a clear Epindorf tube to using ones that were colored? They were blue or pink or whatever because they were trying to sort out their samples. They said, well it is easy, I am going to put my oxidized samples in the red ones, and this in the blue ones and whatever. Well, in the few minutes the material was sitting in those Epindorfs, you managed to leach out a very small amount of color, some sort of dye thing, that impacted this method.

We spent around a month chasing around what the heck these extra peaks were. Because it doesn’t say in your SOP, ‘use Epindorf color number whatever.’ A simple change like that can have an impact. We went even further to actually specify the manufacturer of the Epindorf tube we used, because we went across three different manufacturers and found you can get completely different profiles just from the plastic they use. These methods are that sensitive.

So you have got to be careful, because if you do this incorrectly and you are starting to use these methods for process characterization and lot release, you could be in a world of hurt if you don’t understand what is going on. These are very sensitive methods.

You do want to identify what the species are. The machine can tell you, we think it is oxidation or deamidation depending on the algorithm, but you want to try and actually create those actual attributes and put them in there by purifying them out just to confirm what you are doing. We will get into data interpretation, and, of course, as I say that link to other methods. You really do need to correlate what you are seeing with existing methods that everybody understands.

So we do have criteria for evaluating a peptide or an attribute in the method, and I am not going to go through this. This is very specific for those of you who are mass-spec experts. But we have had to decide what the criteria are for the actual peptides that we are going to be able to analyze versus ones we don’t and what the variability is for the ones that we believe are below the level of sensitivity or below the level of reproducibility. We came out with these sorts of specific attributes for the peptides themselves.

Now as you can imagine you can’t do this with manual interpretation. It is just impossible with the kinds of chromatograms or whatever you want to call them that come out of this machine. It would contain almost, you know, five hundred different peaks that someone would have to be staring at to try and work out what is going on. So we had to rely on the vendor of the analysis program to help us with this.

So then you start getting in to the Part 11 business of making sure that everything is okay from a GMP perspective – that the algorithms they are using aren’t hiding peaks or creating peaks that aren’t there. That took us, I think, about two years to work with the vendor of this software to make sure that it was Part 11 compliant and validatable per the GMPs.

So the advantage is that we get a ton of data of out this equipment. But the disadvantage is that we now have to make sure that we can convince regulators and our inspectors that the algorithm itself isn’t doing something untoward. You know it is easy when you are looking at a gel to hand that to a regulator and they can see the bands on the gel and go, ‘oh yeah, I can see that there is stuff going on.’

Here, we are just going to hand you a table that says, here is the amount of oxidation and here is the amount of deamidation. You are going to have to take it on faith that the software that we have is actually giving reasonable answers. Obviously, there will be packages you can stare at, validation packages, but it is not as easy as it would be for something that you can just visualize. That is the world that we are all going to have to get used to as we move to these sorts of technologies.

And, of course, the other issue is that we are going to get tons more data than we have ever seen before out of this method. What do you do with that? You compare it to mass-spec NMR analysis. How much of this data are you actually going to use? I believe that if we pick the relevant quality attributes, those are the bits that we are going to be looking at.

But as we have heard, regulators are somewhat conservative, and they are going to go, ‘well are you looking at




any of these other peaks that are floating around, and how are you going to control anything that goes up or down?’

When you have got 500 of them, are we going to have to work with 500 different peaks and work out how they wobble up and down from lot to lot and from day to day and all that stuff? We are never going to be able to achieve that with these sorts of methods. So to a certain extent we are going to have to stick to the parts of the readout that these complex methods give that are relative to the quality attributes we are looking for.

Now hopefully we will be able to set some sort of threshold to say that if some peak trebles in size then all of a sudden the system will ping us. That actually took a long time to work with the vendors of the analysis material to get that. Rest assured, we cannot possibly provide control over every single peak that comes out of this analysis.

That is also something with the increasing technology and QbD understanding that we are going to have to get used to as an industry and regulators as we move forward.

So the qualification is underway. You saw that we have already defined some useful system suitability criteria. We have looked at the specificity of the method to understand how it is actually working and how relevant it is from day to day. You have got precision…looking specifically at those attributes you want to look at. The accuracy: obviously we have done work to compare to theoretical mass, so when it tells us this is a deamidation of position x, it truly is a deamidation of position x.

We looked at linearity. That is always a useful check to make sure that as you dilute material that the machinery comes up with the relevant appropriate levels of the material. The LOD/LOQ, et cetera.

Robustness was a tough one because you are relying on people doing sample analysis. One day it would be lovely to be able to literally take a sample straight off the floor and put it into the machine. We are not there yet, but I am sure the technology will get there. We do have to do some sample prep. You have to make sure the chromatography conditions if you are using them are going to be appropriate, and especially the mass-spec conditions as you are using them.

The Regulatory Interface

So the path forward is, we are currently completing our correlation with existing methods [for] the products we want to apply this to and file it with. You do have to compare with the CEX, the size exclusion, and all the other methods you are going to be using – all the glycolization analysis, the traditional ones.

It is going to be a reasonable package that is going to be going into the agency. What we hope is that eventually as you all get used to it over the next two to three years, we wouldn’t keep on having to do that. The fact is, if you show for five

products, or five monoclonals, that every time we do it, it correlates well with the traditional methods, hopefully we can say goodbye to the traditional methods. Like with anything, it is going to take a while. It is a progressive movement.

Specification strategy: We are working on that now. It is not that easy, because of course we have never looked at these individual attributes before. It is almost gaining knowledge, particularly if you want to use legacy products from time zero, because you have to go back and get all that data again. But hopefully it shouldn’t be so bad for new products as we move forward.

MAM Qualification● System suitability: Based on reference peak area, RT andS/N

● Specificity: Based on Mass accuracy, isotopic distribution,retention time

● Precision: Based on area % of peptide measured by MS ex-tracted ion chromatogram. Includes repeatability and intermedi-ate precision

● Accuracy: Based on comparison to theoretical mass

● Linearity: Based on area of peptide measured by MS ex-tracted ion chromatogram

● LOD/LOQ: Based on quality of spectral data (TBD)

● Integrity limit: Still defining threshold peak detection param-eters




The validation strategy, as I said, wasn’t easy. The validation of these methods, especially for something like mass-spec, is not easy, which is why it hasn’t moved as rapidly into the QC world as we may have liked over the last few years. And of course, making sure that is ticks all the GMP Part 11 buckets.

What we are going to do is start applying these now in our regulatory filings. Our initial strategy is to file it as a characterization method, so that the agencies get used to seeing it side-by-side with our specifications. We decided it was too scary to have both run side by side in our specs. It causes complications if you are a global company like Amgen is.

You can imagine there are some forward-thinking agencies like the FDA and Europe or whatever. But you can imagine that sending a multi-attribute method to some of the regions that we may end up is going to just blow their minds. They are now having trouble enough with the normal methods that we use, let alone sending this. So we are going to start

off with having it is a characterization method to get everybody feeling more comfortable with it. Then probably by the time it gets to licensure, we would replace the old methods with this single method moving forward.

Conclusion

So in conclusion, we believe we have the fundamentals to move to the single multi-attribute method on our specs. We have the automated quantification combining this Orbitrap technology and the dedicated software that allows us to do it in a QC environment. It is very flexible. It is amazing the amount of information you can get out of this machine that you can use for process development, for characterizing your product, as well as using it for lot release and stability.

We believe that it is science-based, because we are going to hopefully be able to move to basically presenting you critical quality attributes and actual measurements, rather than saying that they are buried within a peak. I do believe that you can see from the methods that scientifically it is superior to existing methods. It gives you much more information, much more quantitative information that I think is better for all of us and better for patients to control our products moving forward.

And at the end of the day, which our upper management love, it does reduce the cost of quality. Because you can replace probably six, seven, or eight methods with this one. And the reagents aren’t particularly expensive, whereas they are for some of the methods we are replacing.

It is a universal method. So once jurisdictions around the world get used to this type of methodology, import testing becomes much easier when you are working with regulatory authorities that like to retest your material during development. It is a single method. It takes us a lot of time to transfer eight or nine methods around the world to multiple jurisdictions. We will probably end up paying for it and sending it to everybody, but once regulatory authorities have these mass-specs, it should be easier to transfer tests around the world.

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Future USP Global Education and Training Courses, Meetings, Workshops and More!

Global Education and Training Courses

Featured Classroom Courses

§ Brazil: Excipient Performance; Developing and Validating Dissolution Methods

§ China: Essentials of Compendial Microbiology Testing; Analysis of Elemental

Impurities; Pharmaceutical Waters; Dissolution: Theory and Best Practices

§ Europe: In-Vivo In-Vitro Correlation (IVIVC); HPTLC for Identification

of Articles of Botanical Origin

§ India: Pharmaceutical Stability; Effectively Using USP–NF; Practical

Applications of Chapter <467> Residual Solvents

§ United States: Effectively Using FCC; Good Manufacturing Practices;

Analysis of Elemental Impurities; Dissolution: Theory and Best Practices

Webinars Increase your knowledge of compendial activities!

The USP Global Education and Training Department has launched a series of webinars to increase distance learning opportunities for the pharmaceutical industry. These sessions are conducted by USP Scientific Liaisons or Expert Committee Members who are directly involved in the standards-setting process.

For Classroom Course Information and Schedules Contact [email protected], or visit www.usp.org/meetings-courses/courses and click on the appropriate language if other than English. All Europe offerings are available in English. For India offerings, contact George Mathew at [email protected].

FOR MORE MEETING AND WORKSHOP INFORMATIONVisit www.usp.org/meetings, contact [email protected] or call +1-301-816-8130.

NOTE: Events held at USP Headquarters, Rockville, MD (U.S.) unless otherwise indicated. Courses, symposia, workshops and dates subject to change.

USP Workshop Series

March 24–25, 2014

§ Dissolution Testing of Capsules

June 2–3, 2014§§ 6th Bioassay Workshop

August 2014 (Date–TBA) § DNA Barcoding of Botanical Articles

September 8–9, 2014 § Alternative Microbiological Methods

October 1, 2014 § Synthetic Therapeutic Peptide—Regulations,

Standards and Quality

November 5–6, 2014 § Contaminants in Foods–Compendial

Approaches to Protect Public Health




Transparent Discussions, Long-term Relationships and Global Event Monitor-ing Mark Amgen’s Supply Oversight Program

Detailed, transparent technical discussions with suppliers, long-term supplier relationships, and a wide-ranging event monitoring system are three prongs in Amgen’s intensive effort to avoid supply disruptions and improve quality assurance.

The three prongs of Amgen’s carefully thought-out, systematic supplier program were highlighted by Amgen Quality Senior VP Martin VanTrieste at the IPEC ExcipientFest conference in late April in Raleigh, North Carolina. VanTrieste played a pivotal role in the development of Rx-360, and his work with the supply chain-focused association has enriched his and Amgen’s understanding of the issues and how to address them.

He explained how the Amgen program: ● incorporates the learnings from other industries, including the benefit of global event monitoring ● is supported by a cross-organizational structure ● focuses on total cost of ownership rather than cost per unit, and ● uses in-house and supplier-derived monitoring data and multivariate analysis to control variation that could impact critical quality attributes.

Focusing on the first prong of the program – the supplier technical discussions – VanTrieste described them as “intense,” with transparent two-way information sharing a key component. In some of the discussions, suppliers have advised the Amgen that the use of their material is not appropriate, or that a different product would be better.

“We cannot be afraid of sharing information,” he stressed. “I am not going to make raw materials. And I do not think you are going to make advanced biotech products if you are a glass supplier or a rubber producer. We have to get past this thing of ‘I can’t tell you anything.’”

VanTrieste commented that the “paranoia and suspicion” that has characterized such discussions in the past are “probably not called for.” He cited an example of a large rubber manufacturer that makes closures for Amgen that has had several “key” employees leave to go to a competitor. “Why are they worried about me when their own employees are taking the technical information and going and doing the rounds?” he asked.

Relationship-Building, Event Monitoring Bears Fruit

The second two prongs in Amgen’s supply management program – building and nurturing long-term strategic

relationships with suppliers, and robust monitoring of events that have the potential to disrupt supplies – have yielded positive results.

Relationship building with suppliers takes place at senior levels, VanTrieste explained. As part of his responsibility for one of the suppliers, the Amgen VP meets personally with the firm’s CEO and COO “on a routine basis – in person, face-to-face – just to emphasize the importance of our relationship.”

Building that trusting relationship, he said, is key. “We firmly believe that if you know who I am, and you consider me more than just a business associate – maybe a colleague, maybe a friend – it is less likely that you will do something bad to me, either intentionally or by accident,” VanTrieste emphasized. “That is our strategy. We have really created some win-win situations with our suppliers.”

The third prong in Amgen’s program involves analyzing data from a global event monitoring system aimed at mitigating or preventing supply disruptions, mirrored on Boeing’s approach.

The real-time inputs into the system include events as diverse as natural disasters, political unrest, and labor strikes, which are analyzed to produce predictions of the probability of their impacting the supply chain.

Amgen has been able to leverage the data from this system to prevent or mitigate supply chain disruptions and avoid a crisis management approach.

In the past, VanTrieste explained, a disruptive event would be followed by a spike of resource allocation to respond to the event and the payment of premium prices for other sources of raw materials. This would result in an increase in fixed costs and factory downtime, and lost revenue. The “almost instantaneous” event notification process now in place lessens these negative consequences. [Editor’s Note: VanTrieste’s full remarks at the ExcipientFest conference on Amgen’s supply chain program are included below.]

Heightened Focus on Mission-Critical Materials

In the Q&A after VanTrieste’s presentation, conference participants requested clarification on: ● the scope of Amgen’s program ● the impact of using single-sourced raw materials ● how excipients are viewed in the process, and ● how many disruptive events to date have resulted fromunforeseen factors.




One participant asked what Amgen considers raw materials in the context of its supply chain program – for example, whether they include the starting materials used to make drug substance, the components of the syringes and the rubber stoppers, or excipients.

“All of them,” VanTrieste replied. “We try to treat all of them as a raw material that could affect the quality and the reliability of our products, and then ask which are critical to our mission. And that is where we are focusing our hardest and deepest efforts on – the things we think are most critical.”

On the other hand, he pointed out, even non-critical items such as packaging cartons can impact product availability. If the cartons become unavailable, product can no longer be shipped.

Asked about using single-sourced raw materials, VanTrieste commented that “if it is a critical raw material, it should never be single-sourced.”

The only raw materials that Amgen uses from single sources, he said, are those used in its legacy products. For other products, the strategy employed is one of redundant sourcing, where suppliers of proprietary materials, or those that Amgen feels work particularly well in its process, are requested to make the material in two facilities to reduce the possibility of a supply disruption when one facility has problems.

Regarding using multiple suppliers, Amgen believes “that competition is a good thing. Competition drives people to improve. So we have no problem getting a critical raw material from multiple suppliers to get better quality, better supply, faster delivery, and lower cost – all the good things.”

What About Black Swans?

VanTrieste maintained that “black swan events,” including volcano eruptions, tsunamis, and nuclear plant meltdowns do happen, and that drug firms “need to be able to recover” from them.

The “black swan” term is a reference to Nassim Taleb’s 2007 book, “The Black Swan,” that takes a look at events that seem unpredictable and yet have wide-spread ramifications.

Black swan events, according to Taleb, are also characterized by certain psychological limitations and biases that prevent people from foreseeing the events, while also thinking that the events should have been easily predictable after they occur.

“If I had talked about this five years ago, you guys would have said, ‘you are crazy,” VanTrieste pointed out. “No nuclear power plant is going to melt down and affect the pharmaceutical supply chain.’”

A participant asked how many of the supply disruption issues Amgen has seen to date resulted from information or product characteristics that were unknown or unpredictable at the time they occurred.

“Most of what we have seen so far – and we are only a year and a half or two years into the multivariate statistical process control – I would say the vast majority, 75% plus, are from these unknowns,” VanTrieste commented.

Included were product quality parameters that were not characterized and that neither the supplier nor Amgen tested or monitored for. He noted that Amgen is using what it has learned to build a database to help better understand where to look for unknowns.

Conventional Wisdom on Excipients Explored

Another questioner at the IPEC conference session asked whether there is “anything in particular for excipients that we should be thinking about as excipient manufacturers that you consider in the supply chain?”

In his response, VanTrieste addressed the conventional wisdom that pharma manufacturers have little leverage over excipient manufacturers – which he characterized as “not always true.” Healso provided his firm’s expectations regarding excipient quality.

Using sodium chloride as an example, he pointed out that when purchasing the salt, Amgen pays “about five times more per kilo than if I go to the grocery store and buy it for my table at home.” The result, he maintained, is that while the pharma industry is only 1% of the salt manufacturer’s business, it is responsible for 20% of the profit.

“I always challenge that argument when someone says, ‘oh you are only 1% of my business,’” he stressed. “I ask, ‘how much am I of your profit? Because I know I am not getting the same price as the guy who buys metric tons.”

Regarding his perspective on excipient quality, the Amgen VP outlined a set of questions he asks excipient manufacturers: “Do you meet my requirements – the requirements that I put on the product? What is your quality history? What is your quality culture? Are you robust and reliable? When I ask you for information, do you provide it to me? That is kind of what I am looking for.”




From Blind Compliance to Supply Chain OpEx

VanTrieste contrasted the proactive efforts that are needed in an effective supply chain management program with the “blind compliance” approach the industry has tended toward over the past few decades.

The compliance focus industry has been taking since the 1990s “is not something that the FDA by themselves caused,” he stressed.

The trend has been to read 483s and warning letters and react to them without having the appropriate context. The problem is that “when you say ‘I am going to fix something’ and you don’t have the context, you are probably fixing the wrong thing.”

With so much focus on compliance, VanTrieste stressed, fewer resources are available to work on continuous improvement and product quality.

“I have had this conversation with Dr. Woodcock, and she, in general, kind of agrees with that,” he said. “She has heard this message from a couple of heads of quality.”

“Somehow,” he emphasized, “we need to re-balance the system. Compliance is absolutely important. But it is no more important than product quality and continuous improvement to make it even better for patients. And somehow we have to re-jigger the system, because there is a lot of blind compliance going on in the industry.”

VanTrieste’s comment at the IPEC session echoed the main theme explored at a PDA/FDA ICH Q10 workshop held in the Fall of 2012 (see IPQ “Monthly Update” October 2012, pp. 16-26).

The workshop brought together senior quality and operations managers and key regulatory compliance officials to: ● take stock on where the pharmaceutical industry is on the quality systems implementation pathway ● examine the role that executive management plays in setting the pace of progress, and ● brainstorm on how to increase that pace moving forward.

Industry’s journey from blind compliance to operational excellence was well-articulated by then NSF-DBA Senior Partner Neil Wilkinson in his opening presentation, which helped frame the workshop discussions. Wilkinson’s comments were informed by his extensive experience in pharma operations and quality management at AstraZeneca, his service as a representative of the European Federation of Pharmaceutical Industries and Associations (EFPIA) on the ICH Q10 Expert Working Group, and the insights he has gained as an industry consultant and trainer. [Editor’s Note: Wilkinson’s presentation at the workshop is provided in full in the IPQ story cited above.]

VanTrieste ended his prepared remarks at the IPEC conference by highlighting the role Rx-360 plays in helping chart the territory beyond “compliance” that needs to be traversed for more robust supply chain control and better assurance of patient access to high quality products.

AMGEN’S VANTRIESTE ON CREATING ROBUST SUPPLY CHAINS

At the IPEC ExcipientFest conference in late-April in Raleigh, North Carolina, Amgen Quality Senior VP Martin VanTrieste gave a keynote presentation on the efforts his firm has put in place to reduce drug shortages and improve quality assurance through the control of raw materials. He reviewed Amgen’s: ● cross-functional supply chain organization ● “supplier relationship excellence” process ● supply chain monitoring technol-ogy, including rapid supply disruption notification, and ● in-house drug shortage prevention efforts.

We need to not just think about what is in the four walls of our organizations, but how that material flows between us. The three things we look at to prevent drug shortages around raw materials – and we use this across the network – are: ● how we are organized ● the processes we use, and ● the technologies that we deploy. What we try to do is generate and learn from best practices of other industries and other companies.

At Amgen, we spent a lot of time benchmarking with Boeing. You ask, ‘how does that work? They make big airplanes and you make molecules. What did you learn?’ We wanted to understand when they went through the 787 Dreamliner situation, having difficulties getting parts for the airplane, how did they fix that so they could move forward? We learned a lot from Boeing. We looked at what Apple does. What does Intel do? We looked at people that we would say are experts in that supply chain slice. We went to Amazon and asked, ‘how do you guys do this, and how can we learn from you?’






Cross-Functional Supply Chain Organization

We created a dedicated organization within Amgen to specifically deal with raw materials (see box below).

It is of a cross functional nature – it has manufacturing representatives on it, quality people, purchasing, and supply chain professionals. And we deployed it in our global network in the company. The reason we did this is because we wanted to speak with one voice to our suppliers. I am not saying we do this perfectly. Some of you are my suppliers and would say, ‘what are you talking about, speaking with one voice? You do not do that.’ We are trying to change. We are trying to speak with one voice.

We want to have business partners. We want to have long-term partnerships with our suppliers. We want to take what Toyota and Deming preached and not worry about the cost per unit. That is always important – the cost per unit – and we will focus on that. But we want to look more at the total cost of ownership.

So how do I tell my supplier exactly what I am doing with their product? How does the supplier share information with me so that we can reduce the total cost of ownership? I want to talk a little bit more about that when we get to technology.

The most important thing about this organization is that we have created and nurture strategic relationships at the highest level of both companies. I am responsible for one of our suppliers. I sit down with the CEO and the chief operating officer of that company on a routine basis – in person, face-to-face – just to emphasize the importance of our relationship.

We firmly believe that if you know who I am, and you consider me more than just a business associate –maybe a colleague, maybe a friend – it is less likely that you will do something bad to me, either intentionally or by accident. That is our strategy. We have really created some win-win situations with our suppliers. I think that some of our suppliers would testify to that.

Cross-Functional Supply Chain Organization

Devices1,2,3 etc

Raw Material Leads

Category 1,2,3 etc

Raw Material Leads

Supplier Relationship Excellence (SRE) Teams

Manufacturing Sites

Supplier Quality Management

Product and Process Development/Technology

Global Strategic Sourcing

Supply Chain (Clinical and Commercial)

Manufacturing of the Future

Global Networks

Ad-hoc—Risk, OSP, Finance, IS, Legal, etc

ED Raw Materials & Device Supply Chain

VP External SupplyEach category has a dedicated owner to:

• Drive strategies linked to business needs

• Provide prioritization

• Unify supplier management and direction

• Integrate approach to risk

• Provide oversight of all suppliers

• Increase knowledge managementcapability/expertise

Each lead has dedicated cross-functional support

[Note: Provided April 29, 2014 as part of an oral presentation and is qualified by such; contains forward-looking statements; actual results may vary materially; Amgen disclaims any duty to update.]




“Supplier Relationship Excellence” Process

The process that we use is an intense process (see box below). It starts with an intense technical engagement with the supplier where we exchange exactly what we are doing with their product, and how we use their product, and why we do it in a certain way. The suppliers tell me how they are making a certain product. By the way, we have had these exchanges, and the supplier will say, ‘you shouldn’t be using that product for that. We have a different one that is more attuned to what you are doing.’ Or, ‘we don’t have a product that will meet that need.’ That is our intense technical exchange.

What we do at the end of that exchange is we really determine what the critical parameters are that help me make quality biotech products. We then identify, track, and control variation – not only within our company, but we do it from supplier. That is what ITCV is. We put in all of the data from the supplier into a statistical process control program using multivariate analysis. And we use all of our data and all of their data and we crank it together to try to predict if we are going to have a failure of a finished product.

Believe it or not, we have been able to make predictions and adjust our process so that we do not have a failure. And we have been able to say, ‘that raw material lot – we are not saying it is bad, we are just saying that it doesn’t fit into the design space that works for us. We are going to pay for it. But we are not going to use it until we have done further investigation.’

It is a very intense technical exchange. We optimize our supply chain. And we demand transparency. We are very transparent with our suppliers, [including] what we do, how we do it, how much we are going to use, what plant we are using it in, and what products we use it in. We also want that transparency from our suppliers. We use a lot of distributers. And we demand that transparency from the distributors.

Supply Chain Monitoring Technology

We want to know all the links in the supply chain and all the different types of materials. We take all that

Amgen’s Supplier Relationship Excellence Program

Complete transparency and synchronization of supply

chain

Outputs • Line of sight• Lot definition• Optimized inventory• Reliable supply• Reduced Waste

Supply ChainOp�miza�on

Mutual technical understanding of key raw

materials, their manufacture, use, and

interactions

Outputs• Raw material and process

characterization• Clear, critical attributes and

specifications• Improved in-process controls• Aligned Quality systems

Intense Technical Engagement

Collaboration with well defined teams and

continued focus at the executive level

Outputs• Joint goals• Regular executive reviews• Clear communication channels• Two way feedback• Sharing of benefits

RobustRela�onships1

Multi-Tier Transparency

ITCV and MVA Supplier Lot Genealogy Total Cost of Ownership

Operational Excellence is pursued in all three elements to create value

2 3




data and put itinto a monitoring piece of software that a company called Resilinc makes. And when there is an earthquake, or a tsunami in Japan, I look at the system, and it will tell me if I have any materials at risk – not only from my suppliers, but from their suppliers. So we go back quite a bit in the supply chain.

We read the reports from the company who monitors this for us. If they read in the newspaper about a labor issue or political problems in a certain part of the world, they put that in the computers as that may affect any part of my supply chain. It allows us to react much faster to the globalization of our supply chain.

I talked about robust relationships that we have with the supplier. Part of the process…is that we look at supplier selection and approval – that is very critical to us, as is material qualification and approval.

In the past, you would go and talk to our R&D guys at Amgen, maybe buy them a pizza, and they would incorporate a raw material into our process. We would then see that it works. We would run our clinical studies. They would get approved. Then we would file it with regulators all around the world. And we could not change it very easily.

So we have gone back to our R&D colleagues and said, ‘don’t do that anymore.’ Supplier selection is critical. We need to look at a supplier cross-functionally: Are they technically capable? Are they financially stable? Do they have the right quality culture? Is the culture of that supplier compatible with Amgen’s culture? And finally, are they willing to enter into this intense technical exchange and relationship building?

For material qualification, [what we do] is pretty similar to what everybody else does. Once we do [supplier selection and material qualification], we have a continuous monitoring system that provides our supplier feedback and us feedback on how that process is working.

So the technology – here are some screenshots of the technology that we use where we have inputs from Amgen, from our supplier, and from every place else in the world (see box below).

Surveillance Technology Inputs and Outputs




I think they go to Google. They have intelligence people in countries that gather information. And it is all put into this computer model and it generates algorithms and tells me when we should be concerned. By the way, we didn’t invent this, this wasn’t our bright idea – this is what Boeing did. They created a war room using these types of analytics to predict when they were going to have supply issues. And when they did, they were able to adjust and correct before the supply issues.

Supply Chain Disruption Notification

Here is a very classical curve where there is a disruption in the supply chain. You have your initial event when you figured out that something happened. Then you have a big spike of resources to respond to that event. Then you pay premium prices for raw materials as you go off and looking for them all over the world. Your fixed costs go up. Down time in your factories goes up. And you lose revenue. It is a very typical crisis management approach response (see box below).

Using this technology to do supply chain surveillance, we have been able to do this to that process such that event notification is almost instantaneous (see box on next page). The computer has options for us to look at and analyze so we do not use a lot of resources doing that. We have very little downtime in our factories.

We are deploying this for all of our raw materials and our suppliers. Some suppliers are extremely supportive of this idea. And some of them actually use this software now in their firms. Other suppliers are resisting being transparent with Amgen, and are telling us this. And like I said, for my legacy products, I am kind of stuck with that supplier. But those suppliers no longer have access to my pipeline and to the future of the company.

I think that is what it takes to play ball in this business – being transparent. Amgen is not going to try to make a raw material. We are not going to try to go around a supplier. But part of that transparency is the trust of the partnership that we are developing.

Crisis Management Supply Chain Disruption

Lack of awareness

• Which suppliers• Which parts• Alternate sites

available• Inventory positions

Competing in the marketplace for:• Inventory• Capacity• Freight lanes

• Running out of materials

• Allocation• Lines down• Reduced efficiency• Customer shipment

delays

The long-term fallout:• Revising business

expectations• Customer

satisfaction hit• Competitive

positioning readjustment

How can this be improved?

Business as usual Discovery Response Downtime Recovery




We talked a little bit about what it was before versus what it is today. What it was before is you found out things in the newspaper, or from Rx-360, or from a friend who works for another company, and it caused a big turmoil. Where we are today is we are a little more efficient and our suppliers are a little more transparent. But where we want to be in the future – and we aren’t there yet – is to get to a very sophisticated model of instant notification. We want to have alternatives already pre-planned and available to us and be able to execute those so that we aren’t disruptive to the supply chain.

In-House Drug Shortage Prevention

It would be unjust for me to try to blame suppliers for every drug shortage in the world. Most supply shortages happen in the four walls of the pharma company. So I just want to talk a little bit about what we do to prevent drug shortages within our own walls.

First of all is prevention. We try to always be compliant with a robust quality system. We try to prevent governments from taking actions against us that could cause disruption to the supply chain. We are a big operational excellence company. We believe in a right-first-time approach. We actively pursue that. We invest in supply chain security and we make sure for the materials transported through the supply chain that we get what we bought. And we have made some business continuity decisions.

Then we invest in technology. Do we have the best technology to make our products? And are we maintaining it so that it is robust and reliable?

We keep a bunch of inventory at all stages, [including] raw materials, drug substance, and drug product – unlabeled and labeled. And we keep it in various places around the world.

The last part of that strategy is diversification of our manufacturing network. We try to have two of our plants always qualified to make our products. And if we can’t get two plants qualified based on capacity or technology, we go to a

Supply Chain Disruption with New Amgen Systems in Place

With this approach, we can minimize impact to patients…

• Discovery stage almost eliminated• Response initiated within hours

D Response Downtime




contract manufacturer and we share our manufacturing with them.

We believe in using these four levers with different products at different times. We pull on different levers and we can prevent drug shortages to the patient and live up to our responsibilities.

Variability. We talked about identifying, tracking and controlling variability. I have always said – I am a Deming/Juran guy – variability is evil. Not understanding the variability of what you are using will not allow you to make high quality product.

An old colleague of mine who is now retired from Pfizer, Jerry Migliacco, used to say that the pharmaceutical industry makes three sigma products, but we release them at six sigma quality. So that means that because of that variability of our processes, our products, our raw materials, everything in the network, we are inspecting and testing in quality. We have high rejects, high scrap rates, high reworks, and we have a lot of investigations for non-conformances.

The idea is to eliminate all of that. Understand the variability. Build your process to accept an expectable variability, and then control that variability around critical attributes and even start to reduce the variability. I think that is the key. It is the key to having a robust supply chain. If I make it, and know it is going to release in ten days, and I do that every time, my supply chain professionals can plan better. They will be able to react faster to changes in the market place.

A little more on how we identify and control variation: We identify the critical raw materials. We identify critical in-process controls and the attributes around that. We exchange and trend all of this information and we share it with the supplier, if it is a supplier kind of issue. We correlate that to our Amgen process using multivariate statistical control. When we see things that have too much variability, we identify and implement improvements working with our suppliers and our internal manufacturing colleagues to control that variability. And we start the process over again. It is a continuous loop.

So what can we all do together to minimize raw material variability? Clearly we need to understand the sources where impurities can come from. We need to understand the manufacturing processes to make those raw materials. We need to make sure that we have process capabilities that are not three sigma, but are six sigma, or greater. We need to put the appropriate controls in place around the raw materials.

What I say is that I do not test raw materials to a compendial requirement, because I don’t know if the compendial requirements will make a good Amgen product. I need to right-size the testing. I need to understand which parameters are important to me, and then test and monitor those. That could mean that I do more testing than the monograph would require. Or it could be that I do none of the testing in the monograph and I do something really special. Those are things that we need to understand together.

We have to have deep technical engagement. We cannot be afraid of sharing information. I am not going to make raw materials. And I do not think you are going to make advanced biotech products if you are a glass supplier or a rubber producer. We have to get past this thing, ‘I can’t tell you anything.’

We do business with a large rubber manufacturer who makes our closures. And getting this information is tough at times. But I read at least once a month that one of their key employees leaves their company and goes to work for another rubber manufacturer. Why are they worried about me when their own employees are taking the technical information and going and doing the rounds? It is kind of a paranoia and suspicion that is probably not called for.

We do the same thing at Amgen – we worry about things. And our employees go to Genentech all the time and Genentech guys come here. It is a kind of irrational fear I think. And the of course and effective audit program, like what we have heard about today.

So what can we do together? Clearly, we can foolproof the ID process and make it more robust. We could do a better job around auditing and how we do audits that are efficient for the supplier, and not burdensome, but give a confidence to the drug manufacturer. IPEA, EXCiPACT, and RX360 [are auditing resources]. How can we leverage that so we get better audits but it is more efficient for the supplier so they get fewer audits? How do we communicate better? How do we make our systems talk? How does that multivariate analysis statistical process control become




the industry norm?

And by the way, it is the industry norm in other industries. Intel does not buy a new material until they know everything about it, because yields in their chips are so important. So these are things that we can learn from other people. A little plug for Rx-360, because I was introduced as the founder. A lot of people at Rx-360 work hard, and what they are trying to do is share information. Information is power. How can we educate each other? How can we learn from each other’s failures?

How can we look at the aviation industry? When they have a failure, there is a very public investigation, and then we know exactly what we all need to do to prevent that from happening again. How can we get our industry in a place where we can learn from each other’s failures and learn faster than having individual inspectors come knocking at our doors in routine GMP inspections asking us questions we cond’t understand where they are coming from? We are not going to implement a corrective action because we do not know what they are doing? How can we change that system and work together better?

It is a call to action. And a call to action is designed so that we all work in the system collaboratively, transparently, with the patients that we serve in mind and try never to have or cause a drug shortage in any of our companies.

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We the undersigned members of Rx-360 fully support the mission of Rx-360 which is to:

PROTECT PATIENT SAFETY BY SHARING INFORMATION AND

DEVELOPING PROCESSES RELATED TO THE INTEGRITY OF THE

HEALTHCARE SUPPLY CHAIN AND THE QUALITY OF MATERIALS WITHIN THE SUPPLY CHAIN.

ABBVIE • AMGEN • AMPAC FINE CHEMICALS • ASH STEVENS • ASTRAZENECA • AURISCO PHARMACEUTICAL CO. LTD. • AVANTOR • BASF • BAXTER • BAYER • BEND RESEARCH • BIOGEN IDEC • BO

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We support our suppliers and colleagues who share our support of Rx-360 and its critical mission to protect patient safety. And, recognizing the power of leadership by example, we

invite others who share our patient safety goals to join us in this important endeavor.

Wes SchmidtVP, Quality Systems

AbbVie

William ReisVP, Global Strategic Sourcing

Amgen Inc.

Martin VanTriesteSVP QualityAmgen Inc.

Gary A. BakerVP, QARA

Ash Stevens, Inc.

Ashley ReadshawChief Procurement Offi cer

Astrazeneca

Peng ZhienPresidentAurisco

Richard M SiberskiGlobal Director of Quality

Avantor Performance Materials

Jaspreet GillVP, Global Quality & ComplianceBaxter Healthcare Corporation

Dr. Paul Heiden SVP QHSE

Bayer HealthCare

Richard SpoorSVP ProcurementBayer HealthCare

Debra KatterVP, Corporate Quality

Bend Research

Melissa Stoutt SeymourSr. Director, Corporate Quality

Biogen Idec, Inc.

Robert PantanoSVP, Warehouse Operations and

Operational ExcellenceCardinal Health

John NicolsPresident and CEO

Codexis, Inc.

Allen WelsherGlobal Head QA

Daiichi Sankyo Co., Ltd.

Jennifer Finnegan McCafferty

VP External QualityGlaxoSmithKline

Luisa PauloCompliance Director

Hovione

Vincent AntleSr. Director of Technical Operations and Quality

AssuranceLigand Pharmaceuticals, Inc.

Robert NassVP Quality and Regulatory

Management Merck Millipore Merck KGaA

Matt AndersonVP Quality

Merz North America, Inc.

Patricia M. LatzoSVP Global Quality and Strategic

SourcingMylan Inc.

Michael CohenManaging Director

Myoderm

Michael HoffmanVP Global Procurement

Pfi zer Inc.

Heiko HackelVP Global Sourcing

Sartorius

Thomas PaustVP Supply Chain Management

Sartorius

Tom BeilVP, Quality and Regulatory

AffairsSigma-Aldrich

Tom TynerVP Quality & Technical Service

Spectrum Chemicals and Laboratory Products

Steve FeldmanVP Quality & Regulatory Affairs

Temptime Corporation

Angélique KlootwijkDirector Quality Management &

Quality AssuranceVWR International

Pfi zer Inc.

Heiko HackelVP Global SourcingVP Global Sourcing

Robert Pantano

Thomas Paust

Richard M Siberski Melissa Stoutt Seymour

GlaxoSmithKline

Luisa PauloCompliance Director

William Reis

Robert NassRobert NassVP Quality and Regulatory

Management Merck Millipore

Wes Schmidt

Tom BeilDebra Katter

Allen Welsher

Hovione

Vincent Antle

Patricia M. Latzo

Ashley Readshaw

Temptime Corporation

Angélique KlootwijkDirector Quality Management & Director Quality Management &

Michael Cohen

Peng ZhienPresidentAurisco

Martin VanTriesteSVP Quality

Myoderm

John Nicols

Sigma-Aldrich

Tom TynerVP Quality & Technical Service

Spectrum Chemicals and

Gary A. BakerVP, QARA

Ash Stevens, Inc.

Jaspreet Gill

Jennifer Finnegan McCafferty






Updates in Brief

CMC/REVIEW

FDA Biosimilar “Purple Book”

In early September, FDA established the “Purple Book” – a list of licensed biological products and interchangeable biosimilars meant to be the biological equivalent of the pharmaceutical “Orange Book.” The Purple Book lists biological products as well as any biosimilar and interchangeable products licensed by FDA. CDER and CBER regulated products are listed separately.

FDA MAPPs Revised Based on PDUFA V

FDA issued revised MAPPs on review timelines and approval information in mid-August to adjust for changes stemming from PDUFA V. Notably, the MAPPs state that information will now be available online, generally three days after approval. CDER agreed in the reauthorized user fee act to notify applicants of planned review timelines for new NDAs, BLAs, and supplements. If an amendment lengthens the timeline the sponsor will be notified of the change and PDUFA goal date.

FDA “CMC Perspective of the IND” Online Course

CDER’s Small Business Industry and Assistance group has put a training course online, designed to give a basic understanding of the CMC information needed for IND submissions.

USP Official Chapter <787> and <1787> for Particulate Matter

USP issued a new official general chapter <787> in early August on particulate matter for sensitive protein formulations. Chapter <787> includes a testing framework for issues regarding the immunological effects of sub-10µm particles. Informational chapter <1787> accompanies the general chapter to provide guidance on sub-visible particles in the 2 to 100µm range and will become official in May 2015.

FDA ANDA Refuse-to-Receive Guidance Finalized

In mid-September, FDA issued the final version of its “Refuse-to-Receive Standards” guidance and a draft guidance on “Refuse-to-Receive for Lack of Proper Justification of Impurity Limits”. FDA had issued a draft RTR standards guidance in October 2013. Changes made included: ● clarification of the definitions of “major” and “minor” deficiencies ● the remedy process and period for minor deficiencies, and ● the addition of a non-exhaustive list of minor deficiencies. The accompanying new draft guidance explains how to justify impurity limits for an ANDA and when the agency will apply RTR. Comments on the draft will be accepted until November 17. [For more on recent ANDA review developments see pp. 18-20.]

Information Collection for Fast Track Drug Development Program

In May, FDA issued a final version of its industry guidance on “Expedited Programs for Serious Conditions – Drugs and Biologics” (see IPQ “Monthly Update” May 2014 p.27), which reflected comments made on the draft issued in June 2013. FDA is now looking for comments specifically on the fast track designation – one of the four expedited pathways covered in the guidance. The guidance states that when submitting a designation request an applicant is expected to include additional information not specified elsewhere by statute or regulation, such as information needed to show that a product has the potential to address an unmet medical need, by way of clinical data, published reports, summaries of data and reports, and a list of references. The comment period is open until September 30.

UNITED STATES

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm

http://www.ipqpubs.com/wp-content/uploads/2014/10/ReviewMAPP.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/ApprovalMAPP.pdf

http://www.accessdata.fda.gov/cder/cmc/index.htm

http://www.ipqpubs.com/wp-content/uploads/2014/10/RTRStandards.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/RTRImpurity.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/RTRImpurity.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/RTRDraft.pdf

http://www.ipqpubs.com/uncategorized/ipq-monthly-update-may-2014/

https://www.federalregister.gov/articles/2014/08/01/2014-18168/agency-information-collection-activities-proposed-collection-comment-request-guidance-for-industry?utm_campaign=subscription+mailing+list&utm_medium=email&utm_source=federalregister.gov




FDA on Removing Duplicative BLA Requirements

In mid-August, FDA issued a proposed rule on removing §§ 610.11, 610.11a, and 680.3(b) – regulations that require manufacturers of biological products to perform a specified test for general safety of biological products. FDA explained in its Federal Register announcement that these regulations are “duplicative, outmoded, or are otherwise unnecessary” in assuring safety, purity, and potency of licensed biological products. This proposed rule is open for comment until November 20.

GMP/INSPECTION

Comment Requested on Recall Regulations

FDA issued a request for comment on its recall regulations and their estimated reporting burdens in early August. FDA explicitly invites comments on: ● whether proposed collection of information is necessary for the proper performance of the agency’s functions ● the accuracy of FDA’s estimate of the burden of the proposed collection of information ● ways to enhance the quality, utility, and clarity of the information to be collected, and ● ways to minimize the burden of the collection of information. The comment period is open until October 3.

Guidance on Formal Dispute Resolution for CGMPs

In early August, FDA issued a comment request on its “Guidance for Industry on Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical Current Good Manufacturing Practice.” The guidance is intended to provide in-formation to manufacturers of human and veterinary drugs on how to initiate and resolve CGMP disputes (see IPQ “Monthly Update” October 2013 pp. 12-19). The comment period is open until October 10.

Hospira Heparin Recall

A recall by Hospira of heparin in mid-September is the latest in a string of particulate-related recalls of Hospira injectables. Other of the firms products recalled for particulates over the past year include lidocaine, bupivacaine, and propofol.

USP Joins Alliance for Safe Online Pharmacies

USP announced in a mid-August press release that it had joined the Alliance for Safe Online Pharmacies “to combat the threat posed by the illegal online sale of medicines.” The USP release notes that “nearly 97%” of online pharmacies that do not comply with applicable drug laws and standards.

More Warning Letters to Compounders

Two more compounding facilities received warning letters in mid-August for cGMP violations – Florida-based The Compounding Shop and Arizona-based Zions Rx Formulations Services. Five out of six citations in the two letters focus on the same problem areas: ● environmental monitoring ● microbial SOPs ● stability testing ● appropriate personnel clothing, and ● determination of conformance to spec – following the pattern seen in previous letters to compounders. Zions Rx was also cited for failure to have an equipment cleaning system, while The Compounding Shop could not prove the identity and strength of each active ingredient. [For an extended analysis of FDA’s compliance activities in the compounding arena see IPQ “Monthly Update” March/April 2014 pp. 36-39.]

Data Integrity Cited at India’s Marck Biosciences

FDA issued a warning letter in late July that highlighted data integrity issues at Marck Bioscience’s finished pharmaceuticals facility in Kheda, India. The integrity issues center around label control and the preparation of batch production and control records. Employee training and the detection of fungus in parenteral product were among the cGMP issues cited. [For an extended analysis FDA’s finding of data integrity problems at Indian and other foreign facilities see IPQ “Monthly Update” March/April 2014 pp. 19-29.]

https://www.federalregister.gov/articles/2014/08/22/2014-19888/revocation-of-general-safety-test-regulations-that-are-duplicative-of-requirements-in-biological?utm_campaign=subscription+mailing+list&utm_medium=email&utm_source=federalregister.gov

https://www.federalregister.gov/articles/2014/08/04/2014-18322/agency-information-collection-activities-proposed-collection-comment-request-food-and-drug?utm_campaign=subscription+mailing+list&utm_medium=email&utm_source=federalregister.gov

https://www.federalregister.gov/articles/2014/08/11/2014-18943/agency-information-collection-activities-proposed-collection-comment-request-guidance-for-industry?utm_campaign=subscription+mailing+list&utm_medium=email&utm_source=federalregister.gov

http://www.ipqpubs.com/issues/ipq-october-monthly-update-october-2013/

http://www.ipqpubs.com/issues/ipq-october-monthly-update-october-2013/

http://www.fda.gov/Safety/Recalls/ucm414201.htm

http://www.usp.org/news/usp-joins-efforts-halt-illegal-online-drug-sales

http://www.ipqpubs.com/wp-content/uploads/2014/10/2014-_-The-Compounding-Shop-Inc.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/2014-_-The-Compounding-Shop-Inc.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/14ZionsWarningLetter.pdf

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


http://www.ipqpubs.com/wp-content/uploads/2014/10/2014-_-Marck-Biosciences-Ltd.pdf



NSF-DBA, NSF-Pharmalytica and Becker & Associates are changing their names to NSF Health Scienceson January 1, 2014.

NSF Health Sciences [email protected] www.nsf.org

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EUROPE

CMC/REVIEW

EDQM Revises CEP Requirements Guideline

EDQM has revised its “Guideline on requirements for revision/renewal of certificates of suitability to the European Pharmaco-poeia monographs” to include the requirements of the revised EU guideline on “Stability testing for applications for variations to a marketing authorization” and to describe the type of change to be submitted when a Certificate of Suitability (CEP) for a start-ing material is used in an application for another CEP. [For more on recent developments in the CEP submission process see IPQ “Monthly Update” September 2013 pp. 39-42.]

EMA Guideline on NIR

In mid-2014, EMA released an addendum to its “Guideline on the use of near infrared spectroscopy by the pharmaceutical indus-try and the data requirements for new submissions and variations.” The addendum gives examples of the scope of use for NIR procedures, such as release testing, assay and content uniformity, and how changes to this scope would be managed according to the guideline. The final version of the NIR guideline, which outlines the requirements for applications in which NIR is used for qualitative and quantitative analysis or in PAT, was released in January, 2014.

Comments on EMA’s Variations Stability Testing Guideline

In mid-August, EMA released a complete list of the comments it had received, along with an explanation of how they were handled, on its draft “Guideline on stability testing for applications for variations to a marketing authorization” issued in June 2011. The final version was issued in March 2014 (IPQ “Monthly Update” March/April 2014 p. 58). Numerous comments were accepted, many regarding the clarification of terms. Some notable comments that were not accepted include an EFPIA statement that the guideline did not differentiate stable from unstable products well enough, and APIC requesting a glossary of terms.

Ph. Eur. Requests Comments on Inhaled Drug QC Methodologies

The Inhalanda Working Party of the European Pharmacopoeia issued an inquiry in August, seeking comments and/or data on Abbreviated Impactor Measurement (AIM) and Efficient Data Analysis (EDA) methodologies for the quality control of inhaled drugs. The working party is looking for information that shows whether AIM and/or EDA can be effectively used in the quality control of orally inhaled products. Users are asked to send their feedback by November 30, 2014.

EMA Dossier Requirements

In early September, EMA issued an updated “Dossier requirements for Centrally Authorised Products (CAPs)” in order to man-date the use of digital submissions and clarify which submission gateway is applicable for different authorities.

EDQM CEP Form Updates

The application forms for requesting certificates of suitability (CEPs) were updated in late September to reflect recent changes to the EDQM guideline on the requirements for revision/renewal of CEPs to the European Pharmacopeia Monograph, issued in July 2014, as well as invoicing changes. These forms are meant to be used for applications submitted from October 2014 onward.

http://www.ipqpubs.com/wp-content/uploads/2014/10/2014-_-Marck-Biosciences-Ltd.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/guideline_on_requirements_for_revisionrenewal_of_certificates_of_suitability_to_the_european_pharmac1.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/06/EU-2014-PAC-stability-guideline.pdf




https://www.edqm.eu/en/Updated-application-forms-available-for-immediate-use-1585.html?mbID=225

http://www.ipqpubs.com/wp-content/uploads/2014/10/guideline_on_requirements_for_revisionrenewal_of_certificates_of_suitability_to_the_european_pharmac1.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/EMANIRAddendum.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/EMANIRGuideline.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/EMANIRGuideline.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/EMAVariationsStabComments.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/EMAVariationsStabDraft.pdf



http://www.ipqpubs.com/wp-content/uploads/2014/10/enquiry_aim_and_eda_for_the_qc_of_inhaled_drug_products.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/EMADossierReq.pdf




GMP/INSPECTION

EU GMP Chapters 3, 5, 8, Finalized

The EU Commission has published final versions of EU GMP chapters 3, 5, and 8, which will go into effect in March 2015. The drafts of the chapters were issued in early 2013. Chapter 3 on premises and equipment was revised to: ● emphasize the use of quality risk management (QRM) principles for cross-contamination when designing facilities, and ● deciding if there is a need for dedicated equipment and facilities. Chapter 5 on production includes changes on: ● storage of poisons ● using a QRM process to control cross-contamination ● qualification of suppliers ● ID testing of starting materials, and ● the need to notify regulators of supply restrictions. Chapter 8 on complaints, quality defects, and product recalls has revisions on: ● addressing the need for qualified staff in quality management ● linking complaints to adverse event reporting, defect investigation procedures ● using QRM to support investigational decisions, and ● product recalls/risk-reducing actions. [For more on recent EU GMP revisions see IPQ “Monthly Update” March/April 2014 pp. 50-56 and p. 59.]

Cocrystals Reflection Paper Open for Comment

A reflection paper on the use of cocrystals in drug products was opened for comment by EMA at the end of July. The paper clarifies EMA’s position on cocrystals as API’s by giving definitions and discussing the regulatory implications of using them.

http://www.ipqpubs.com/wp-content/uploads/2014/10/EUGMPCH3.pdf




http://www.ipqpubs.com/wp-content/uploads/2014/10/EMACocrystalsReflection.pdf

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INTERNATIONALCMC/REVIEW

PDA Post-Approval Change Harmonization Initiative

In mid-September, PDA announced that it was forming a task force to work on harmonizing global post-approval change pro-tocols for typical manufacturing changes and providing a template for post-approval change management. [For a review of a PhRMA proposal for a new approach to CMC submissions approach that would better accommodate post-approval changes see pp. 3-17.]

Caribbean Countries Consider Creating Generic Drug Registry

In mid-July, the Caribbean Public Health Agency (CARPHA) reported that countries of the Caribbean are discussing the estab-lishment of a unified registration process for generic medicines. This process would improve availability, quality, and access to essential medicines within member countries under a framework of developing and strengthening the sub-regional drug regulatory system, CARPHA maintains.

Biosimilar Infliximab Receives Approval in Japan and Turkey

South Korean based Celltrion, received approval for its biosimilar Infliximab in Japan and Turkey in July. The product was developed in collaboration with Hospira, and has been approved in Europe (2013) as well as in South Korea and Columbia.

Thai FDA to Accept eCTD

In late August, the Thai FDA released draft criteria for the specification and validation of eCTD submissions. The agency is accepting pilot submissions starting in mid-October and plans to accept eCTDs officially by May 2015.

China and Taiwan Mutually Recognize Inspections

Chinese and Taiwanese Health Officials have agreed to cooperate on clinical trial regulation and to mutually recognize drug inspections

Same Level of Safety for Fast versus Slow Approvals in Canada

Research published by the Canadian Health Policy Institute (CHPI) in mid-August finds that while regulatory approvals for new drugs in Europe are faster than in Canada, the rate of discontinuation of new drugs for safety reasons is the same in both juris-dictions. The findings indicate that the added Canadian drug approval delay achieves no extra assurance of safety, but instead induces unnecessary costs on patients by preventing the potential health benefits provided by earlier access to new drugs. The study found that over a 10-year period, 186 new drugs were approved by Health Canada compared with 189 by the European Medicines Agency. The median approval delay for the new drugs approved in Canada was 391 days compared with 338 days for new drugs approved in Europe. However, the rate of discontinuation for safety reasons was 1.6% in both jurisdictions.

http://www.pda.org/footer/press-resources/press-releases/press-release-detail/pda-launches-effort-to-harmonize-global-post-approval-changes-protocols

http://carpha.org/articles/ID/23/Centralized-Generic-Medicines-Registry

http://www.celltrion.com/en/COMPANY/notice_view.asp?idx=451&code=ennews&intNowPage=1&menu_num=&align_year=all

http://www.celltrion.com/en/COMPANY/notice_view.asp?idx=452&code=ennews&intNowPage=1&menu_num=&align_year=all

http://www.ipqpubs.com/wp-content/uploads/2014/10/TH-Module-1-and-Regional-Specification.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/TH-Regional-Specification-and-Validation-Criteria.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/TaiwanChinaDrugDevelopment.pdf

http://www.canadianhealthpolicy.com/research/full-text/do-faster-drug-approvals-increase-safety-risks--evidence-from-canada-and-europe-2003-2012.html

http://ctt.marketwire.com/?release=11G020372-001&id=4550869&type=0&url=http%3a%2f%2fwww.canadianhealthpolicy.com




GMP/INSPECTION

Rx360 Launches Traceability Work Group

Rx360 announced the establishment of a new collaborative work group in early August to “support serialization and track and trace legislation that is evolving globally.” The work group will focus on developing conceptual models for the interoperable exchange of information needed to comply with global regulations, and is seeking participation from anyone with knowledge of: ● global pharma supply chains ● country-specific regulations ● serialization and track & trace technology, and ● related standards. The first meeting of the group was held on August 22.

Brazil Guidance on Track-and-Trace Requirements

Brazil’s regulatory authority ANVISA has published a guidance on the reporting requirements for its medicine track-and-trace system (see IPQ “Monthly Update” January 2014 p. 33), which is due to come online in 2016. It specifies that transactions must be reported to the regulator by uploading XML files to its website detailing events such as packaging, receipt and delivery, production, import, and sale. Records must be retained for one year after product expiration and are expected to be maintained in real-time.

India Changes Date for Barcoding Implementation

India, in early August, extended its deadline for the barcoding of pharmaceutical packaging. The labeling being implemented is meant to aid in the track and trace of drug product in order to better secure the supply chain. The requirements for serialization were changed last month (see IPQ “Monthly Update” July 2014 p. 46) but the date for implementation had remained the same.

India to Launch Nationwide Study on Substandard Drugs

The Central Drugs Standard Control Organization (CDSCO) of India is set to begin a study on what areas of the country have a high concentration of substandard drugs. The study is intended to allow CDSCO to have a more focused investigation of the drug supply chain.

Notice on India’s Regulatory Procedures

Following from a meeting discussing Indian regulatory standards, India’s Central Drugs Standard Control Organization (CDSCO) issued a notice in early August to all of India’s state drug controllers on the standards for conducting GMP inspections. Of note is the need for focus on using a risk-based approach for inspections of product development, quality, stability, process validation, complaints, recalls, OOS handling, change control, and sterilization. [For a review of FDA findings in India see IPQ “Monthly Update” March/April 2014 pp. 19-29.]

http://hosted-p0.vresp.com/427409/d69d0b558b/ARCHIVE

http://portal.anvisa.gov.br/wps/content/anvisa+portal/anvisa/sala+de+imprensa/menu+-+noticias+anos/2014+noticias/anvisa+publica+instrucao+normativa+para+implantacao+da+rastreabilidade

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

http://dgft.gov.in/Exim/2000/PN/PN13/pn6813.htm

http://www.ipqpubs.com/wp-content/uploads/2014/10/IndiaDrugConsulativeReport.pdf

http://www.ipqpubs.com/wp-content/uploads/2014/10/IndiaRegulatoryLetter.pdf



INTERNATIONAL PHARMACEUTICAL QUALITY

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Documents

CMC/REVIEW - International Pharmaceutical Quality...quality attributes and how they are mitigated – with hyperlinks to the detailed information in Module 3. This would provide “a