Welcome to the CMC Strategy Forum We are pleased to welcome you to the CMC Strategy Forum. The purpose of the CMC Strategy Forum is to provide a venue for biotechnology/biological product discussion. The meetings focus on relevant CMC issues throughout the lifecycle of a product and thereby foster collaborative technical and regulatory interactions. The Forum strives to share information with the regulatory agencies to assist them in merging good scientific and regulatory practices. Outcomes of the Forum meetings are published in an appropriate peer-reviewed journal. Each meeting will focus on a CMC related issue such as product characterization, comparability, specifications, etc. The format of each meeting will consist of case studies and presentations by Industry and/or FDA experts to introduce the topic and the key issues of concern. Breakout sessions will then be conducted to allow for additional discussion on the technical and regulatory details of the topics. It is envisioned that the final outcome of the workshop discussions will be the development of a document to be submitted to the appropriate Regulatory Agency designees for their consideration in developing and/or clarifying good regulatory practice guidelines for biotechnology derived products. The success of the CMC Strategy Forum will depend on your active participation in discussing and raising issues pertaining to development of biologics. We encourage you to participate wholeheartedly in the workshops that have been designed to stimulate exchange of ideas and information. We would like to thank the speakers who are giving generously of their time and resources, and to you, for your attendance. We acknowledge the generosity of our program partners: AbbVie, Inc., Amgen Inc., Arlenda, Inc., Biogen, Genentech, a Member of the Roche Group, Gilead Sciences, Janssen Pharmaceutical R&D, LLC, MedImmune, A member of the AstraZeneca Group, Merck & Co., Inc., Novo Nordisk A/S, Pfizer, Inc. and Tunnell Consulting, Inc. We are grateful for the expert management from CASSS and the audio-visual expertise of Michael Johnstone from MJ Audio-Visual Productions. Their experience and guidance in the preparation of this Forum has been invaluable.

ACKNOWLEDGEMENTS

CMC STRATEGY FORUM NORTH AMERICA PROGRAM COMMITTEE Siddharth Advant, Kemwell Biopharma Yves Aubin, Health Canada John Bishop, CBER, FDA Barry Cherney, Amgen Inc. JR Dobbins, Eli Lilly and Company Julia Edwards, Biogen Sarah Kennett, CDER, FDA Joseph Kutza, MedImmune, A member of the AstraZeneca Group Kimberly May, Merck & Co., Inc. Anthony Mire-Sluis, Amgen Inc. Stefanie Pluschkell, Pfizer, Inc. Nadine Ritter, Global Biotech Experts, LLC Reb Russell, Bristol-Myers Squibb Company Dieter Schmalzing, Genentech, a Member of the Roche Group Timothy Schofield, MedImmune, A member of the AstraZeneca Group Zahra Shahrokh, STC Biologics and ZDev Consulting Jeffrey Staecker, BioPhia Consulting, Inc. Andrew Weiskopf, Biogen CMC STRATEGY FORUM GLOBAL STEERING COMMITTEE Siddharth Advant, Kemwell Biopharma, USA John Dougherty, Eli Lilly and Company, USA Steven Kozlowski, CDER, FDA, USA Junichi Koga, Daiichi Sankyo Co., Ltd., Japan Rohin Mhatre, Biogen, USA Anthony Mire-Sluis, Amgen Inc., USA Marcelo Moreira, ANVISA - Brasilian National Health Surveillance Agency, Brasil Wassim Nashabeh, F. Hoffmann-La Roche Ltd., Switzerland (Chair) Ilona Reischl, AGES - Austrian Agency for Health & Food Safety, Austria Anthony Ridgway, Health Canada, Canada Nadine Ritter, Global Biotech Experts, LLC, USA Daisaku Sato, PMDA – Pharmaceutical and Medical Devices Agency, Japan Mark Schenerman, MedImmune, A member of the AstraZeneca Group, USA Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland Karin Sewerin, BioTech Development AB, Sweden

The Organizing Committee gratefully acknowledges the pharmaceutical and biotechnology industry for their generous support

of the CMC Strategy Forum series:

SUSTAINING DIAMOND PROGRAM PARTNER Genentech, a Member of the Roche Group

SUSTAINING PLATINUM PROGRAM PARTNERS AbbVie, Inc.

Biogen MedImmune, A member of the AstraZeneca Group

SUSTAINING SILVER PROGRAM PARTNER Pfizer, Inc.

PROGRAM PARTNERS Amgen Inc.

Gilead Sciences Janssen Pharmaceutical R & D, LLC

Merck & Co., Inc. Novo Nordisk A/S

EXHIBITOR PARTNERS Arlenda, Inc.

Tunnell Consulting, Inc.

The Scientific Organizing Committee gratefully acknowledges the following media for their promotional consideration of the CMC

Strategy Forum series:

LEADING MEDIA PARTNERS

BioProcess International International Pharmaceutical Quality

MEDIA PARTNERS

The Analytical Scientist BioProcessing Journal BioTech International

Genetic Engineering & Biotechnology News The Medicine Maker

The Pathologist separationsNOW.com Technology Networks

Forum Abstract The Evolution of the Biopharmaceutical Control Strategy through Continued Process Verification FORUM CO-CHAIRS: JR Dobbins, Eli Lilly and Company Stefanie Pluschkell, Pfizer, Inc. Timothy Schofield, MedImmune, A member of the AstraZeneca Group SCIENTIFIC ORGANIZING COMMITTEE:

Jörg Gampfer, Baxalta Philip Krause, CBER, FDA Anthony Lubiniecki, Janssen Pharmaceutical R&D, LLC Anthony Mire-Sluis, Amgen Inc. Shawn Novick, Seattle Genetics, Inc. Julia O’Neill, Tunnell Consulting, Inc. Patrick Swann, Biogen Joel Welch, CDER, FDA

As defined in ICH Q10, a control strategy is “…a planned set of controls, derived from current product and process understanding, that assures process performance and product quality. Every biopharmaceutical manufacturing process has an associated control strategy. FDA’s 2011 Guidance for Process Validation describes process validation activities in three stages. A primary goal of stage 1 is to establish a strategy for process control, to assure the commercial process consistently produces acceptable quality products. Biopharmaceutical development culminates in the commercial control strategy, a comprehensive package including analytical and process controls and procedures. Stage 2 process performance qualification is needed to establish scientific evidence that the process is reproducible and will consistently deliver quality products. Stage 3 of validation, Continued Process Verification (CPV), provides an opportunity to improve control through the lifecycle of the product. The 2011 Guidance clearly outlines the expectation for manufacturers to understand, detect, and control variation beyond development, throughout commercial manufacturing. This goal of CPV is a natural extension of Control Strategy development begun in Stage 1. The Process Validation guidance also emphasizes the need to understand and anticipate future sources of variation. Specifically, after, “… establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.” Thus, a long-term perspective beginning from Stage 1 and following through to Stage 3 can be advantageous. This is consistent with guidance in ICH Q10 on knowledge management: “Knowledge should be managed from development through the commercial life of the product up to and including product discontinuation.”

The outcome of stage 3 activities should be to provide continual assurance that the process remains in a state of control. In addition, there may be possibilities to loop back and improve the overall control strategy.

“Good process design and development should anticipate significant sources of variability and establish appropriate detection, control, and/or mitigation strategies, as well as appropriate alert and action limits. However, a process is likely to encounter sources of variation that were not previously detected or to which the process was not previously exposed.”

Because the lifecycle validation approach demands a continuous improvement cycle for Control Strategy, manufacturers in the whole range from early biotech start-up to legacy biopharmaceutical manufacturing will find meaningful points for discussion in this workshop. Smaller companies can gain competitive advantage by learning how to avoid issues with later CPV; legacy manufacturers can learn from modern QbD approaches to product development. This workshop will focus on issues that arise for biopharmaceuticals during control strategy development and Continued Process Verification, with special focus on the interface between the control strategy and CPV. Topics will include the following:

• Identifying and controlling short-term versus long-term variability; • Business and quality systems needed to support CPV; • Effective control strategies resulting from “enhanced development” including CPV implications • Regulatory filings: what gets submitted as part of the BLA/MAA vs. what remain on site for

inspection; • Application of CPV to legacy products; • CPV for products approved under accelerated time frame (e.g. breakthrough therapies)

CMC Strategy Forum Program Summary The Evolution of the Biopharmaceutical Control Strategy through Continued Process Verification

Monday, July 20, 2015

07:30 – 17:30 Registration in the Washingtonian Ballroom Foyer 07:30 – 08:30 Continental Breakfast in the Washingtonian Ballroom Foyer 08:30 – 08:45 CASSS Welcome and Introductory Comments in Salons D - G Nadine Ritter, Global Biotech Experts, LLC

CMC Strategy Forum Welcome and Introductory Comments in Salons D - G Julia O’Neill, Tunnell Consulting, Inc. Patrick Swann, Biogen

Regulatory and Strategic Considerations In Salons D - G

Session Chairs: Patrick Swann, Biogen and Joel Welch, CDER, FDA 08:45 – 09:15 Biotech Homonyms: Control (the verb, not the noun), Strategy (the plan, not

the document) and Validation (the state, not the event) Emanuela Lacana, CDER, FDA, Silver Spring, MD USA 09:15 – 09:45 Principal Approach to CPV and Integration with Quality Systems &

Operating Mechanisms Jörg Gampfer, Baxalta, Vienna, Austria 09:45 – 10:15 Pharmaceutical Product Life Cycle Management: Maintain the Validated

State for Commercial Manufacturing Processes Andrew Chang, Novo Nordisk A/S, Washington, DC USA 10:15 – 10:45 AM Break in the Washingtonian Ballroom Foyer 10:45 – 11:15 Line of Sight to Continued Process Verification

Timothy Schofield, MedImmune, A member of the AstraZeneca Group, Gaithersburg, MD USA

11:15 – 12:30 PANEL DISCUSSION – Questions and Answers Andrew Chang, Novo Nordisk A/S, USA Laura Durno, Health Canada, Canada

Jörg Gampfer, Baxalta, Austria Emanuela Lacana, CDER, FDA, USA

Timothy Schofield, MedImmune, A member of the AstraZeneca Group, USA

Monday, July 20 continued… 12:30 – 13:45 Hosted Lunch Break in the Washingtonian Ballroom Foyer

Pre-approval Work in Support of Post-approval Validation Activities In Salons D - G

Session Chairs: JR Dobbins, Eli Lilly and Company and Shawn Novick, Seattle Genetics, Inc. 13:45 – 14:15 Design of a Process Qualification and Continued Process Verification

Program within an Enhanced Development Framework Ciaran Brady, Eli Lilly SA, Kinsale, Ireland

14:15 – 14:45 Late Stage Control Strategies in the Development of Vaccines and

Biotherapeutics to Deliver Successful Commercial Products Aparna Deora, Pfizer, Inc., Chesterfield, MO USA 14:45 – 15:15 Process Validation for Biologics Manufacturing with Process Analytical

Technology and Real-time Release Testing Eliana Clark, Biogen, Cambridge, MA USA 15:15 – 15:45 PM Break in the Washingtonian Ballroom Foyer 15:45 – 17:00 PANEL DISCUSSION – Questions and Answers

Ciaran Brady, Eli Lilly SA, Ireland Eliana Clark, Biogen, USA Aparna Deora, Pfizer, Inc., USA Laura Durno, Health Canada, Canada

Ellen Huang, CBER, FDA, USA Emanuela Lacana, CDER, FDA, USA Hoang Phan, Genentech, a Member of the Roche Group, USA

17:00 – 17:15 Break

Exhibitor Partner Scientific Showcase in Salons D - G Session Chairs: Julia O’Neill, Tunnell Consulting, Inc. and Timothy Schofield, A member of the

AstraZeneca Group 17:15 – 17:30 Introduction 17:30 – 17:45 Realizing the Value of Continued Process Verification

Julia O’Neill, Tunnell Consulting, Inc., King of Prussia, PA USA 17:45 – 18:00 The “Maze of Statistics” in Lifecycle Process Validation Tara Scherder, Arlenda, Inc., Flemington, NJ USA 18:00 – 19:30 Exhibitor and Networking Reception in the Washingtonian Ballroom Foyer 19:30 Adjourn Day One

Tuesday, July 21, 2015

08:00 – 17:00 Registration in the Washingtonian Ballroom Foyer 07:30 – 08:45 Continental Breakfast in the Washingtonian Ballroom Foyer

Practical and Statistical Considerations In Salons D - G

Session Chairs: Jörg Gampfer, Baxalta and Philip Krause, CBER, FDA 08:45 – 09:15 The Practical Difference Between Cpk and Ppk Mark DiMartino, Amgen Inc., Thousand Oaks, CA USA 09:15 – 09:45 Process Monitoring Applying QbD Principles in a Biopharmaceutical

Environment Michael Kraus, Baxalta, Vienna, Austria

09:45 – 10:15 Continued Process Verification: Practical Automated Control Charting

Tools for Quality Control and Manufacturing Brian K. Nunnally, Biogen, Research Triangle Park, NC USA

10:15 – 10:45 AM Break in the Washingtonian Ballroom Foyer 10:45 – 11:15 Novel Data Analysis Methods for Continued Process Verification Using

Change-point Analysis Bernhard Pasenow-Grun, GlaxoSmithKline, Marburg, Germany 11:15 – 12:30 PANEL DISCUSSION – Questions and Answers Mark DiMartino, Amgen Inc., USA

Michael Kraus, Baxalta, Austria Brian K. Nunnally, Biogen, USA Julia O’Neill, Tunnell Consulting, Inc., USA Bernhard Pasenow-Grun, GlaxoSmithKline, Germany Martha Rogers, AbbVie, Inc., USA

Meiyu Shen, CDER, FDA, USA 12:30 – 13:45 Hosted Lunch in the Washingtonian Ballroom Foyer

Application to Legacy Products In Salons D - G

Session Chairs: Anthony Lubiniecki, Janssen Pharmaceutical R&D, LLC and Julia O’Neill, Tunnell Consulting, Inc.

13:45 – 14:15 Use of Bayes Statistics and Cross-product Performance Variance Data to

Further Inform Product-specific Process Control Limits Thomas Mistretta, Amgen Inc., Cambridge, MA USA

14:15 – 14:45 Using Legacy Product Data to Inform and Improve Control

Heather Eurenius, Merck & Co., Inc., West Point, PA USA

Tuesday, July 21 continued… 14:45 – 15:15 A Case Study of Continued Process Verification and Life Cycle Approach for

a Well Characterized Insulin Analog Warren MacKellar, Eli Lilly and Company, Indianapolis, IN USA

15:15 – 15:45 PM Break in the Washingtonian Ballroom Foyer 15:45 – 17:00 PANEL DISCUSSION – Questions and Answers

Marcus Boyer, Bristol-Myers Squibb Company, USA Heather Eurenius, Merck & Co., Inc., USA Steven Fong, CDER, FDA, USA Warren MacKellar, Eli Lilly and Company, USA Ingrid Markovic, CBER, FDA, USA Thomas Mistretta, Amgen Inc., USA

17:00 – 17:30 Recap of Program Summary Slide Presentation Nadine Ritter, Global Biotech Experts, LLC Invitation to the CMC Strategy Forum January 25, 2016 The Mayflower Hotel, Washington, DC USA 17:30 Adjournment

Regulatory and Strategic Considerations

Session Chairs: Patrick Swann, Biogen and Joel Welch, CDER, FDA Both FDA and EMA have provided process validation guidance which has emphasized the importance of a lifecycle approach when maintaining a state of control for commercial production.

FDA: The lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production. EMA: Process validation incorporates a lifecycle approach linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production.

NOTES:

Presenter’s Abstracts and Presentations

Biotech Homonyms: Control (the verb, not the noun), Strategy (the plan, not the document) and Validation (the state, not the event) Emanuela Lacana CDER, FDA, Silver Spring, MD USA Abstract was not available at the time of printing. Slides were not available at the time of printing. NOTES:

NOTES:

Principal Approach to CPV and Integration with Quality Systems & Operating Mechanisms Jörg Gampfer Baxalta, Vienna, Austria Content:

• Product and Process Development in the Light of Current Guidance • Quality by Design - A Life-cycle Approach to Process Validation • The evolution of Control Strategies During the Process Life-cycle • Opportunities for Efficient Continuous Improvement Programs

It is in the interest of patients, regulators and pharmaceutical companies to develop consistent manufacturing processes that are delivering product with high quality and yield. Current guidelines are proposing a lifecycle approach starting in product development and lasting until its discontinuation. A clear description of product attributes and in depth understanding of influencing process factors is required to implement efficient control strategies. Process knowledge obtained during routine manufacturing should be used to identify the need for modification of these control mechanisms. The concept of “Continued Process Verification” (CPV) should be the driver for constant evaluation of process control. Signals from CPV should trigger actions leading to efficient continuous improvement. It is important to come to agreement among pharmaceutical industry and regulators on the operating mechanisms of CPV or systems that that are leveraging from it. A generally accepted roadmap can increase speed of implementation into company structures, and help to increase focus of work effort on continuous improvement of critical aspects that are directly linked to product quality and process consistency. NOTES:

Pharmaceutical Product Lifecycle Management: Maintain the Validated State for Commercial Manufacturing Processes Andrew Chang Novo Nordisk A/S, Washington, DC USA Maintain the validate state for commercial manufacturing processes is a regulatory requirement. FDA Process Validation Guidance issued in 2011 emphasized that continued process verification (CPV) is an integral part of the process validation lifecycle. CPV provides the manufacturer with assurance that a validated process remains in a validated state for commercial manufacturing processes. In Novo Nordisk, the overall verification concerning the maintenance of the validated state is executed at least yearly according to the very well defined instructions. In this presentation I will share with you Novo Nordisk’s approach to maintain the validated state of product, process and system/equipment and the process to enable continued improvements. NOTES:

Line of Sight to Continued Process Verification Timothy Schofield MedImmune, A member of the AstraZeneca Group, Gaithersburg, MD USA FDA Guidance for Industry, Process Validation: General Principles and Processes states for Continued Process Verification (CPV) that “Good process design and development should anticipate significant sources of variability and establish appropriate detection, control, and/or mitigation strategies, as well as appropriate alert and action limits.” It states further that “Data gathered during this stage might suggest ways to improve and/or optimize the process by altering some aspect of the process or product, such as the operating conditions (ranges and set-points), process controls, component, or in-process material characteristics.” Thus, the CPV strategy is informed through knowledge obtained during development, and is adaptive to the broader opportunities experienced during commercial manufacture. Line of sight to the biopharmaceutical control strategy, and CPV specifically, should begin when process studies and manufacturing experience yield meaningful insights into the appropriate control of the process and the product. As a component of the control strategy, CPV works in concert with specifications and change control to ensure commercial product quality and supply. The approaches used for CPV should be both sensitive to unexpected process deviations, and specific to parameters and attributes which are attuned to “process health.” CPV can likewise be used to build on process knowledge and evolve as new information becomes available. This talk will frame CPV in the context of the commercial control strategy, and provide insights into opportunities during clinical and commercial manufacturing that allow for the creation and maintenance of an agile and responsive quality system. NOTES:

Regulatory and Strategic Considerations

Workshop Session Panel Discussion – Questions and Answers Andrew Chang, Novo Nordisk A/S, USA Laura Durno, Health Canada, Canada Jörg Gampfer, Baxalta, Austria Emanuela Lacana, CDER, FDA, USA Timothy Schofield, MedImmune, A member of the AstraZeneca Group, USA The following questions will guide the panel discussion:

1. In the U.S., how does Continued Process Verification (CPV) differ from the annual product review expected per 21 CFR 211.180?

2. Is a formal CPV approach needed to document a state of control? 3. Is a formal CPV approach an additional regulatory requirement? 4. If not a requirement, is there a regulatory opportunity?

a. Can an agreed-upon CPV plan facilitate post-approval regulatory change management? b. Could there be a role for CPV to facilitate approval of breakthrough therapies in the US

or as a component of an Adaptive Pathway in the EU? 5. Requirement or opportunity, what gets submitted as part of the BLA/MAA vs. what remains on

site for inspection? 6. What is the relationship between CPV and Continuous Process Verification (an alternative

approach based on PAT and as defined in ICH Q8 and EMA guidelines)? 7. Can analytical methods used within a CPV program be “qualified” (i.e. documented as accurate

and reliable) but not formally validated (i.e. as found in 3.2.S.4.3 or 3.2.P.5.3)? 8. What are “best practices” for developing and incorporating knowledge management into CPV

programs? 9. What should be considered when establishing a CPV program within the context of contract

manufacturing? 10. Is the potential regulatory value of a CPV program diminished if recognition is limited to ICH

regions? NOTES:

NOTES:

Pre-approval Work in Support of Post-approval Validation Activities

Session Chairs: JR Dobbins, Eli Lilly and Company and Shawn Novick, Seattle Genetics, Inc. The development of an effective control strategy is fundamental to ensuring that a process is reproducible and delivers a quality product throughout the lifecycle of a biotherapuetic. This session will provide insight into how development of the commercial control strategy links to the initial process performance qualification (PPQ) exercise and ultimately sets the foundation for the continued process verification (CPV) throughout the commercial lifecycle of the product. Perspectives from both industry and regulatory will be shared during this session. NOTES:

Presenter’s Abstracts and Presentations

Design of a Process Qualification and Continued Process Verification Program within an Enhanced Development Framework Ciaran Brady Eli Lilly SA, Kinsale, Ireland Having a well understood and robust process control strategy is foundational in order to effectively validate a commercial manufacturing process and maintain a well-controlled and capable process over the product lifecycle. This presentation will provide an outline of Lilly’s approach to development of a platform process for production of monoclonal antibody drug substance, and how the development of a holistic control strategy sets the basis for process validation. The approach to PPQ based on this enhanced development approach will also be described, as well as an overview of the subsequent design of a continued process verification program based on the principals of ICH Q8-Q11. The presentation will also highlight learnings and challenges encountered during regulatory reviews of initial dossiers utilizing this platform development and validation approach. NOTES:

Late Stage Control Strategies in the Development of Vaccines and Biotherapeutics to Deliver Successful Commercial Products. Aparna Deora Pfizer, Inc., Chesterfield, MO USA Development of successful commercial products hinges on building an effective control strategy throughout product development. This presentation will present an approach of building the control strategy throughout development based on increasing product and process understanding across multiple biological modalities. Case studies from a vaccine, antibody-drug conjugate (ADC), and a monoclonal antibody (mAb), all looking at progressing with speed and efficiency, will be presented to highlight that while each program has unique challenges, the fundamental approach and strategy across these diverse modalities is aligned. NOTES: Slides were not available at the time of printing.

NOTES:

Process Validation for Biologics Manufacturing with Process Analytical Technology and Real-time Release Testing Eliana Clark Biogen, Cambridge, MA USA The current state of biological process platforms and process understanding has enabled us to develop robust processes that yield consistent product quality. Investment in process technology has resulted in high output processes with a good understanding of levers that control product quality. Our next-generation drug substance manufacturing processes utilize process analytical technology and real time release testing with automated and adaptive controls that will enable us to predict and assure product quality. This presentation will provide an overview of our next generation manufacturing processes based on advanced process control (APC), some of the APC enabling technologies being implemented, and the approach that we are taking to validate the APC process. NOTES:

Pre-approval Work in Support of Post-approval Validation Activities

Workshop Session Panel Discussion – Questions and Answers Ciaran Brady, Eli Lilly SA, Ireland Eliana Clark, Biogen, USA Aparna Deora, Pfizer, Inc., USA Laura Durno, Health Canada, Canada Ellen Huang, CBER, FDA, USA Emanuela Lacana, CDER, FDA, USA Hoang Phan, Genentech, a Member of the Roche Group, USA The following questions will guide the panel discussion:

1) What are the key elements to conducting a successful PPQ exercise? 2) What are the challenges? What has worked well? 3) How does the PPQ link to the CPV through the lifecyle? 4) How does early work in process design support PPQ and CPV? 5) How can a Sponsor use process design elements and commitments to CPV to support a limited

PPQ? 6) How does early work in process design support PPQ and CPV? 7) How can a Sponsor use process design elements and commitments to CPV to support a limited

PPQ? NOTES:

NOTES:

Exhibitor Partner Scientific Showcase

Session Chairs: Julia O’Neill, Tunnell Consulting, Inc. and Timothy Schofield, MedImmune, A member of the AstraZeneca Group The January 2011 FDA Guidance on Process Validation states “We recommend that the manufacturer use quantitative, statistical methods whenever appropriate and feasible.” Implementation of Continued Process Verification (CPV) requires selection of appropriate statistical software and the skills to adapt the software to regulatory requirements and business needs. This session will feature brief presentations from software and consulting companies that are engaged with industry in implementation of CPV. Strategy Forum participants will be encouraged to interact with our exhibitor partners both during the Scientific Showcase and at their stations between sessions. NOTES:

Realizing the Value of Continued Process Verification Julia O’Neill Tunnell Consulting, Inc., King of Prussia, PA USA The 2011 FDA Guidance on Process Validation provides additional motivation for manufacturers to monitor process performance and make continual improvements. The business and regulatory incentives for monitoring are clear, but for biological processes, implementation may be challenging. Key strategies for maximizing the value of CPV will be highlighted, including:

• Selection of most powerful statistical models appropriate to biological manufacturing. • Knowledge-based approaches for focusing effort on areas of highest variation and risk. • Opportunities to standardize and streamline data gathering and management.

NOTES:

NOTES:

The “Maze of Statistics” in Lifecycle Process Validation Tara Scherder Arlenda, Inc., Flemington, NJ USA The questions you must answer in each stage of the lifecycle process are best answered (for both patient and business) with optimal use of statistics. But the incorporation of statistics in Lifecycle Process Validation should not feel like an endless maze. Truly, if you design and execute a holistic strategy, combining development, measurement and manufacturing knowledge with statistics, it is a competitive advantage. In this talk, we will provide an end-to-end example of leveraging statistics with process knowledge across the validation lifecycle to accelerate development, reduce risk, and increase efficiency. Business and regulatory expectations will be incorporated. Specifically, in this example, we present statistical solutions to the following questions within the three stages: Design: What is the design space of my product? How do I minimize experimentation? How does this work inform PPQ, and eventually CPV? PPQ: How does the choice of statistical method influence the number of samples? How can I assess process capability? How do I transition to CPV? CPV: What are the key elements of the “who, what, when and how” that influence the efficiency and effectiveness of a CPV program? What statistical considerations really matter? NOTES:

NOTES:

Practical and Statistical Considerations

Session Chairs: Jörg Gampfer, Baxalta and Philip Krause, CBER, FDA The concept of “Continued Process Verification” has been described within the FDA process validation guideline issued in 2011. Other guidelines and GMP /Annex 15 outline the same general principles. Continued process verification can ensure and improve the efficiency of established and effective control strategies. It facilitates the sponsor’s communication with regulatory bodies and warrants a supply with product of consistent quality to patients. But what does the practical application of this concept in a routine manufacturing environment look like? What operational mechanisms are needed and how can large amounts of data be processed to get relevant and valuable information quickly? Advances in information technologies and automation techniques are a driver to reduce operational efforts for continued process verification activities, and to increase benefit by pushing evaluation, signaling and reporting of results close to the actual events. It is also important to agree upon general terminologies and the use of appropriate statistical tools to be able to get the right signals from the process, react accordingly and communicate in a consistent manner. The objective of this session is to share experiences and to discuss practical and statistical aspects required for successful implementation and execution of control strategies and their verification by continued evaluation of process data. NOTES:

Presenter’s Abstracts and Presentations

The Practical Difference Between CpK and Ppk Mark DiMartino Amgen Inc., Thousand Oaks, CA USA An important aspect of developing a risk based monitoring strategy for a continued process verification program is an assessment of the ability of a process to meet the requirements defined in the product control strategy. Process capability indices are tools that provide simple and standardized assessments of this ability. One question firms often face when evaluating process capability is which of the multitude of measures available should be used. The most common indices are process capability adjusted for shift (Cpk) and process performance adjusted for shift (Ppk). The intent of this talk is to discuss the practical and mathematical differences between these indices, and provide some examples of where the choice of one measure over the other may impact validity of the measure. NOTES:

Process Monitoring Applying QbD Principles in a Biopharmaceutical Environment Michael Kraus Baxalta, Vienna, Austria Statistical process control charting is used throughout the industry. However, as for any statistical model, these control charts may only provide relevant information, if the underlying mathematical model is adequately reflecting the real process behavior. The author will describe the specific challenges, violation of control chart assumptions and potential solutions in the biopharmaceutical environment. Considering these specifics makes control charting a very powerful tool for gaining deeper process knowledge and better control of manufacturing processes. This is only partially a matter of mathematics, but substantially involves process understanding and application of formalized risk management approaches. In combination, it is the sound basis for effective life cycle management of product quality and process consistency. NOTES:

Continued Process Verification: Practical Automated Control Charting Tools for Quality Control and Manufacturing Brian K. Nunnally, Kayla Woodlief, Andrew Lenz Biogen, Research Triangle Park, NC USA With the publishing of the Health Canada and FDA guidances on Process Validation, a three stage approach to validation was moved into the mainstream. Considering validation to be a continuum rather than a discrete event is a superior methodology. Implementation of the first two stages is easy since these stages were already in place. The implementation of Continuous Process Verification (Stage 3) can be more complex. This talk will describe the implementation of Continuous Process Verification and approaches to automated statistical process control in a Quality Control setting. NOTES:

Novel Data Analysis Methods for Continued Process Verification Using Change-point Analysis Bernhard Pasenow-Grun GlaxoSmithKline, Marburg, Germany The pharmaceutical industry has been encouraged to implement the concept of “Continued Process Verification” and the requirement to institute analysis of process stability and capability. Most guidance documents recommend the use of appropriate process behavior charts such as I-MR control charts. However these tools have some significant drawbacks and often result in false alarms. A novel integrated approach, combining change-point analysis, process capability analysis and a simple Shewhart chart is presented. A highly automated tool for data management, analysis and reporting is presented. NOTES:

Practical and Statistical Considerations

Workshop Session Panel Discussion – Questions and Answers Mark DiMartino, Amgen Inc., USA Michael Kraus, Baxalta, Austria Brian K. Nunnally, Biogen, USA Julia O’Neill, Tunnell Consulting, Inc., USA Bernhard Pasenow-Grun, GlaxoSmithKline, Germany Martha Rogers, AbbVie, Inc., USA Meiyu Shen, CDER, FDA, USA The following questions will guide the panel discussion:

1. How should signals from CPV interface with your deviation systems? 2. What do you do in the early stages of commercial production just after PPQ? Should your

response to signals depend on how much experience you have? 3. How do you capture experience from long-term process performance and integrate this not only

into limits for process control but also specifications? 4. What is a reasonable expectation for Ppk/Cpk in biopharma? 5. Corresponding to the choice between Ppk and Cpk, do you set control chart limits using short-

term sigma or long-term sigma? 6. How do you address concerns with data normality and sample size? 7. How is the monitoring system integrated in a holistic QbD approach and how is it integrated into

the validation program? 8. How do you balance sensitivity (few statistical tests/signals) with bright shiny objects (more

statistical tests/signals)? 9. The system requires quite a sophisticated combination of process and statistical knowledge. How

do you help internal and external auditors to understand that? 10. How can CPV be integrated into the regulatory reporting structure? Could monitoring be used to

downgrade submissions? 11. How do you set limits for CQAs and intermediate attributes without having any experience (or

signals from pre-clinics) for clinical risk? 12. If large amount of data is monitored, can automation help to evaluate and send only relevant

signals to appropriate personnel? NOTES:

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Application to Legacy Products

Session Chairs: Anthony Lubiniecki, Janssen Pharmaceutical R&D, LLC and Julia O’Neill, Tunnell Consulting, Inc. The challenge for legacy products is that PPQ is typically a historical memory, and there’s no chance, unless doing process or site changes, to use PPQ as an opportunity to understand the sources of variation. Instead, the information must be acquired in other ways. CPV can provide an opportunity to examine or re-examine sources of variability, quantify their impact on product quality CQAs, distinguish variation from different sources, and predict the level of expected variation. Historical process data can be used to evaluate and understand process and analytical variability, and to estimate between- and within-batch variation. For legacy products, regulatory complexity, lack of process design space understanding, and lack of efficient quality and data systems often need to be overcome to achieve the benefits that are promised by CPV programs. Legacy product manufacturers also must wrestle with whether or not to apply extended sampling paradigms to legacy products. Some may choose to mine QC data; others may do additional work. There are pros and cons to both approaches. Industry is grappling with how to implement and report CPV, and at the same time wondering what inspectors will look for. We will discuss the current experience of companies in inspections and how the represented companies are presenting their CPV programs to agencies. NOTES:

Presenter’s Abstracts and Presentations

Use of Bayes Statistics and Cross-product Performance Variance Data to Further Inform Product-specific Process Control Limits Thomas Mistretta Amgen Inc., Cambridge, MA USA Establishment of appropriate performance parameter control limits at the earliest point of validation is inherently challenged by the limited exposure of the process to real-world sources of variance. Traditional design-of-experiment approaches for process characterization are appropriate means for estimating performance parameter variance effects from operating parameter fluctuations. Unfortunately, unpredictable sources for performance variation are difficult to intentionally characterize owing to their unpredictable nature. Biopharmaceutical firms with extensive experience developing and commercializing products via platform approaches have, however, unintentionally sampled these many sources of variance in the course of ordinary operations. This talk concerns the application of a Bayes statistical approach, in combination with high-reliability product data-sets, to estimate the contribution of real-world sources of variance to further inform limit specifications. Further extensions of the methodology to compound process performance variance knowledge during continued process verification at part of life cycle management will also be discussed. NOTES:

Using Legacy Product Data to Inform and Improve Control Heather Eurenius Merck & Co., Inc., West Point, PA USA Legacy products were often developed long before Quality by Design approaches were routine, and thus the inherent process variation may not be fully accounted for in the process design. Identifiable and controllable sources of variation must be addressed in order to mitigate the impact of additional unidentified sources. Continued Process Verification provides a mechanism for driving investment in process understanding and control. A case study of process measurement system variability is presented. NOTES: Slides were not available at the time of printing.

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A Case Study of Continued Process Verification and Life Cycle Approach for a Well Characterized Insulin Analog Warren MacKellar Eli Lilly and Company, Indianapolis, IN USA Abstract was not available at the time of printing. Slides were not available at the time of printing. NOTES:

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Application to Legacy Products

Workshop Session Panel Discussion – Questions and Answers Marcus Boyer, Bristol-Myers Squibb Company, USA Heather Eurenius, Merck & Co., Inc., USA Steven Fong, CDER, FDA, USA Warren MacKellar, Eli Lilly and Company, USA Ingrid Markovic, CBER, FDA, USA Thomas Mistretta, Amgen Inc., USA The following questions will guide the panel discussion:

1. Are manufacturers or inspectors seeing that increased effort into CPV process understanding is providing value in terms of improved process understanding and control, reduced rework or discards, reduced deviations, improved reliability, etc.?

2. Does CPV provide a benefit to manufacturers approaching regulatory hurdles for legacy products? For instance, has process understanding gained through CPV been a sufficient basis for reducing testing on a licensed product?

3. What are inspector expectations for CPV for legacy products? 4. Should extended sampling paradigms be applied to legacy products? 5. The March of Science unearths some amazing things. How are both manufacturers and

inspectors dealing with newly discovered preexisting variation? 6. Data for legacy products often comes from older process designs and analytical methods, and

may have higher inherent variability than newer products. Does this create limitations on interpretation of CPV monitoring? What approaches have been effective for data with high inherent variability?

7. How are manufacturers experiencing the cost/benefit equation for CPV? How much extra work is this? What resources are required?

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