PRELIMINARY PROGRAM

WCBP 2016

20th Symposium on the Interface of Regulatory and Analytical Sciences for

Biotechnology Health Products

Symposium Co-Chairs: Michael Kennedy, CBER

Juhong Liu, CDER Brian K. Nunnally, Biogen

The Mayflower Hotel Washington, DC

January 26-28, 2016

Table of Contents

The Organizing Committee gratefully acknowledges the Symposium Program Partners for their generous support of WCBP 2016

Sustaining Diamond Program Partner

F. Hoffmann-La Roche, Ltd.

Sustaining Platinum Program Partner

AbbVie, Inc.

MedImmune, a member of the AstraZeneca Group

Sustaining Silver Program Partner

Pfizer, Inc.

Gold Program Partners

Bill & Melinda Gates Foundation Celgene Corporation

Silver Program Partners

BioMarin Pharmaceutical, Inc.

Bristol-Myers Squibb Company Catalent Pharma Solutions

Eli Lilly and Company ProteinSimple

SCIEX Waters Corporation

Bronze Program Partners

Bruker Daltonics, Inc.

Genzyme Corporation, a Sanofi Company

Friend of CASSS Program Partners

Bayer Healthcare, LLC

Janssen Pharmaceutical, Research & Development, LLC

Exhibitor Partners

AAPS ABC Laboratories, Inc. Agilent Technologies Avid Bioservices, Inc. Bio-Rad Laboratories, Inc. BioReliance Corporation Bruker Daltronics, Inc. Caprion Catalent Pharma Solutions Covance, Inc. Eurofins Lancaster Labs Hunter Lab Genedata

Genovis AB KBI Biopharma Inc. Nano Imaging Services New England Biolabs, Inc PPD Protein Metrics, Inc. ProteinSimple ProZyme, Inc. SCIEX SGS Life Science Services Thermo Fisher Scientific Waters Corporation Wyatt Technology Corporation

Media Partners

The Scientific Organizing Committee gratefully acknowledges the following media for their promotional consideration of WCBP 2016

American Laboratory American Pharmaceutical Review

Bio Process International BioProcessing Journal Bio Tech International

Genetic Engineering and Biotechnology News IPQ Publications

LCGC North America Pharmaceutical Outsourcing

RSC Advances The Analytical Scientist

The Medicine Maker The Pathologist

SeparationsNOW.com Technology Networks Limited

Acknowledgements Symposium Co-Chairs Workshop Committee Co-Chairs Michael Kennedy, CBER, FDA Anissa Cheung, OVRR, FDA Juhong Liu, FDA Michele Dougherty, CDER, FDA Brian K. Nunnally, Biogen Joe Kutza, MedImmune, a member of the AstraZeneca Group Shawn Novick, Seattle Genetics, Inc. Steering Committee John Dougherty, Eli Lilly and Company Christopher Joneckis, CBER, FDA Kathy Francissen, Genentech, a Member of the Edwin Moore, University of Illinois Roche Group Ilona Reischl, BASG/AGES John Frenz, Alnylam Pharmaceuticals, Inc. Marjorie Shapiro, CDER, FDA Robert Sitrin, PATH Emeritus Members of the Steering Committee Robert Cunico, Pacific Bio Labs William Hancock, The Barnett Institute, Northeastern University Michael Kunitani, Marin Analytical Consulting Thomas Layloff, Supply Chain Management System WCBP 2016 Program Committee Sid Advant, Kemwell Biopharma Vince Anicetti, Coherus Biosciences Mehrshid Alai-Safar, Baxter Healthcare Corporation Kris Antonsen, BioMarin Pharmaceutical, Inc. Laura Bass, Bristol-Myers Squibb Cheryl Blasie, Bristol-Myers Squibb Marcus Blȕmel, Novartis Pharma AG Andrew Chang, Novo Nordisk, Inc. Xiao-Ping Dai, Celgene Corporation Bharat Dixit, Genocea Biosciences, Inc. John (JR) Dobbins, Eli Lilly and Company Roman Drews, LFB-USA Julia Edwards, Biogen Idec William Egan, GlaxoSmithKline Elizabeth Fowler, CMC Consulting Services Michelle Frazier, AbbVie, Inc. Rajesh K. Gupta, Biologics Quality & Regulatory Consultants, LLC Reed Harris, Genentech, a Member of the Roche Group John Hennessey, NovaDigm Therapeutics, Inc. Ping Hu, Janssen Pharmaceutical R & D, Inc.

David Lee, AbbVie, Inc. Karen Lee, Sanofi Global Biotherapeutics Kathy Lee, Eli Lilly and Company William Matousek, Regeneron Pharmaceuticals, Inc. Jamie Moore, Genentech, a Member of the Roche Group Shawn Novick, Seattle Genetics, Inc. Joann M. Parker, Pfizer, Inc. Stefanie Pluschkell, Pfizer, Inc. Lesley Redfern, Abbvie Inc. Roberto Rodriguez, Bristol-Myers Squibb Mark Schenerman, MedImmune, a member of the AstraZeneca Group Sally Seaver, Seaver Associates, LLC Emily Shacter, Think FDA Zahra Shahrokh, STC Biologics, Inc. Joseph Siemiatkoski, Criterion Biotech Consultants Brian Silvey, Baxalta, Inc. Dan Some, Wyatt Technology Corporation Arne Staby, Novo Nordisk A/S Lisa Stephenson, MedImmune, a member of the AstraZeneca Group

Stephen Hadley, Bill & Melinda Gates Foundation Chi-Ting Huang, Bioanalytix, Inc. Peter Johnson, 3M Drug Delivery Systems Maura Kibbey, United States Pharmacopeial Convention (USP) Carol Krantz, ProNAi Therapeutics, Inc. Bob Kuhn, Amgen Inc.

Annie Sturgess, Bristol-Myers Squibb Garry Takle, Merck, Sharp and Dohme Michael Washabaugh, MedImmune, a member of the AstraZeneca Group Ziping Wei, Novavax, Inc. Yuan Xu, Merck Research Labs Heidi Zhang, Genentech, a Member of the Roche Group

WCBP 2016 Scientific Program Summary

TUESDAY, JANUARY 26, 2016 07:00 – 17:00 Registration in the Senate Room 07:00 – 08:00 Continental Breakfast in the East/State Rooms 08:00 – 08:15 CASSS Welcome and Introductory Comments 08:15 – 08:35 5th Annual William S. Hancock Award Announcement in the Grand

Ballroom Sponsored by CASSS and Presented by

08:35 – 08:45 WCBP Welcome and Introductory Comments Brian K. Nunnally, Biogen 08:45 – 09:00 Tribute to Past Chairs of WCBP 09:00 – 09:45 Keynote Speaker – Gerd Binnig, Definiens AG 09:50 – 10:50

Opening Regulatory Panel with the FDA Panel Discussion in the Grand Ballroom

Session Chair: Brian K. Nunnally, Biogen Moderator: Stefanie Pluschkell, Pfizer, Inc.

Panel Members: Ashley Boam, Acting Director, CDER/OPQ/OPPQ, FDA, USA David Deloski, CDER, FDA USA Christopher Joneckis, Associate Director, CBER,, FDA, USA Steven Kozlowski, Director, CDER, FDA, USA

10:50 – 11:15 AM Break – Visit the Exhibits in the East/State Rooms and the Posters in

the Promenade Room

TUESDAY, JANUARY 27 continued

One Global Specification Plenary Session in the Grand Ballroom

Session Chairs: Neha Frantz, Biogen and Annie Sturgess, Bristol-Myers Scribb

11:15 – 11:40 Barry Cherney, Amgen Inc., Washington, DC USA 11:40 – 12:05 Diane Wilkinson, Biogen, Berkshire, United Kingdom 12:05 – 12:30 Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency

(PMDA), Japan 12:30 – 12:45 Panel Discussion - Questions and Answers

12:45 – 14:15 Lunch Break - Participants on their own 13:00 – 14:00 Technical Seminars Sponsored by Waters Corporation Chinese Room NOTE: Lunch is provided for first 100 attendees Sponsored by ProZyme, Inc District Room NOTE: Lunch is provided for first 100 attendees Sponsored by Catalent Pharma Services Palm Court Room NOTE: Lunch is provided for first 100 attendees Pay Now or Pay Later: Diverse Process Development Pathways that Ultimately Support Commercialization

Plenary Session in the Grand Ballroom Session Chairs: Xiao-Ping Dai, Celgene and Jamie Moore, Genentech, a Member of the

Roche Group 14:15 – 14:40 Laurie Graham, CDER, FDA, Silver Spring, MD USA 14:40 – 15:05 Trent Munro, Amgen, Inc., Thousand Oaks, CA USA

TUESDAY, JANUARY 27 continued

15:05 – 15:30 John Joly, Genentech, a Member of the Roche Group, South San

Francisco, CA USA 15:30 – 15:45 Panel Discussion - Questions and Answers

15:45 – 16:00 Transition Time and PM break for Roundtable Session 16:00 – 16:45 Roundtable Session:

Select Your Table Topic in One of Four Rooms Chinese Room District Room Exhibitor Hall (East/State Rooms) Palm Court Room

Please refer to table topics listing in the back of this program book. Table seats are on a First Come, First Serve Basis

16:45 – 17:00 Transition Time 17:00 – 18:15 Workshop Session 1 Regulatory and Compendial - Combination Products Rakhi Dalal, CDER, FDA, Donna French, Genentech, a Member of the Roche Group, Steve Hertz, CDER, FDA, Ed Patton, CBER, FDA, Michael Soberg Christensen, Novo Nordisk AG, John Weiner, OCP, FDA Pay Now or Pay Later: Prioritizing CMC Development Activities in Early Development Christopher Downey, CDER, FDA, Catherine Eakin, Seattle Genetics, Inc., Michelle Frazier, AbbVie, Inc., Sara Gagneten, CBER, FDA Regulators’ Perspectives on Trends in the Regulation of Biopharmaceutical Products in Europe and Asia Co-chairs:Anthony Ridgway, Health Canada, Kathy Francissen, Genentech, a Member of the Roche Group – Presentations By: Peter Richardson, European Medicines Agency (EMA), United Kingdom, Daisaku Sato, Pharmaceuticals and Medical Deveices Agency (PMDA), Japan, and Anis Talib, Malaysian Health Authority Emerging Trends for Higher Order Structure Characterization in Biopharmaceutical Development Natalya Ananyeva, CBER, FDA, Anders Dybdal Nielsen, Novo Nordisk, Frances Namuswe, CDER, FDA, William Weiss, Eli Lilly and Company  

18:15 – 19:15 Poster Session I in the Cabinet Room 19:15 – 19:30 Transportation will be provided at 19:15

19:30 – 22:30 Welcome Reception at the National Archives Museum

WEDNESDAY, JANUARY 27, 2016 07:00 – 17:00 Registration in the Senate Room 07:00 – 08:40 Continental Breakfast in the East/State Rooms 08:30 – 08:40 Announcements by Brian K. Nunnally, Biogen

Implications of Product-Specific Monographs for Biotherapeutic Products Parallel Session in the Grand Ballroom

Session Chairs: John Dougherty, Eli Lilly and Company and Tina Morris, USP 08:40 – 09:05

Emmanuelle Charton, EDQM, Council of Europe, Strasbourg, France 09:05 – 09:30 Anthony Mire-Sluis, Amgen, Inc., Thousand Oaks, CA USA 09:30 – 09:55 Xiaoyu Chen, Pfizer, Inc. 09:55 – 10:10 Panel Discussion - Questions and Answers

Analytical Control Strategy of Vaccine Products Parallel Session in the District Ballroom

Session Chairs: Arifa Khan, CBER, FDA and Ziping Wei, Novavax 08:40 – 09:05 Jennifer L. Dashnau, Merck & Co, Inc., West Point, PA USA

09:05 – 09:30 Freyja Williams, CBER, FDA, Silver Spring, MD USA 09:30 – 09:55 Definition of Analytical Control Strategy for Robust Vaccine

Development Christina Campa, GlaxoSmithKline Vaccines, Siena, Italy

09:55 – 10:10 Panel Discussion - Questions and Answers 10:10 – 11:00 AM Break - Visit the Exhibits in the East/State Rooms and the Posters in

the Cabinet Room, or attend one of the Technical Seminars

10:20 – 10:50 Technical Seminars

Sponsored by Thermo Scientific Chinese Room

Sponsored by Wyatt Technology Corporation Palm Court Room

11:00 – 12:15 Workshop Session 2 Product Quality Attributes, Risk Assessment and Control Strategies Amin Khan, GlaxoSmithKline, Robin Levis, CBER, FDA, Pat McGeehan, MedImmune, A member of the AstraZeneca Group, Leslie Rivera-Rosado, CDER, FDA, Joseph Siemiatkoski, Criterion Biotech Consultants How to Succeed with Breakthrough Kimberly May, Merck and Company, Mikhail Ovanesov, CBER, FDA, Emily Shacter, Think FDA, Joanna Zhou, CDER, FDA Global Regulators Focus Americas Gerald DiDonato, Bristol-Myers Squibb, Thomas Schreitmueller, F. Hoffmann-La Roche, Ltd. Analytical Control Strategy for Vaccine Products Steven Rubin, CBER, FDA, Garry Tackle, Merck, Sharp and Dohme, Michael Washabaugh, MedImmune, A member of the AstraZeneca Group, Freyja Williams, CBER, FDA

12:15 – 14:00 Lunch Break – Participants on their own

12:45 – 13:45 Technical Seminars Sponsored by Agilent Technologies Chinese Room NOTE: Lunch is provided for first 100 attendees Sponsored by Bruker Daltonics, Inc. District Room NOTE: Lunch is provided for first 100 attendees Sponsored by SCIEX Palm Court Room NOTE: Lunch is provided for first 100 attendees

Facing the Challenges of Drug Product and Device Development & Manufacturing

Plenary Session in the Grand Ballroom Session Chairs: Shan Jiang, Seattle Genetics and Margaret Speed Ricci, Amgen Inc. 

14:00 – 14:25 Anthony Mire-Sluis, Amgen Inc., Thousand Oaks, CA USA

14:25 – 14:50 Donna French, Genentech, a Member of the Roche Group, South San

Francisco, CA USA 14:50 – 15:15 Patricia Hughes, CDER, FDA, Silver Spring, MD USA 15:15 – 15:30 Panel Discussion - Questions and Answers 15:30 – 15:45 PM Break and Transition Time 15:45 – 16:30 Round Table Session II: Select Your Table Topic in One of Three

Rooms

Chinese Room District Room Exhibitor Hall (East/State Room) Palm Court Room

Please refer to table topics listing in the back of this program book. Table seats are on a First Come, First Serve Basis

16:30 – 16:45 Transition Time 16:45 – 17:45 Poster Session II in the Cabinet Room

17:45 – 19:15 Exhibit Reception in the East/State Rooms

THURSDAY, JANUARY 28, 2016

07:00 – 17:00 Registration in the Senate Room 07:00 – 08:45 Continental Breakfast in the East/State Rooms 08:30 – 08:45 Announcements by Brian K. Nunnally, Biogen

Biosimilars Parallel Session in the Grand Ballroom

Session Chairs: Martin Schiestl, Sandoz and Marjorie Shapiro, CDER FDA 08:45 – 09:10 Thomas Stangler, Sandoz GmbH, Kundl, Austria 09:10 – 09:35 Maria-Teresa Gutierrez-Lugo, CDER, FDA, Silver Spring, MD USA 09:35 – 10:00 James Anderson, Momenta Pharmaceuticals, Inc. Cambridge, MA USA 10:00 – 10:15 Panel Discussion - Questions and Answers

Comparability for Blood Products – How Did We Get Here and Where Are We Going? Parallel Session in the District Ballroom

Session Chairs: Andrew Chang, Novo Nordisk and Timothy Lee, CBER, FDA 08:45 – 09:10 Nancy Kirschbaum, CBER, FDA, Silver Spring, MD USA 09:10 – 09:35 Stephen Raso, Biogen, Cambridge, MA USA 09:35 – 10:00 Peter Turecek, Baxter Innovations GmbH, Vienna, Austria USA 10:00 – 10:15 Panel Discussion - Questions and Answers 10:15 – 11:15 AM Break – Visit the Exhibits in the East/State Rooms and Posters in the Cabinet Room

10:30 – 11:00 Technical Seminars Sponsored by Eurofins Lancaster Laboratories Chinese Room

Sponsored by SGS Life Science Service Palm Court Room

11:00 – 11:15 Transition Time 11:15 – 12:30 Workshop Session 3 Stability: Strategy and Expectations for Biotech/Biological Products Bazarragchaa Damdinsuren, CDER, FDA, Annick Gervais, UCB, Philip Krause, CBER, FDA, Patsy Lewis, Seattle Genetics, Donnie Pullman, Biogen Steps Towards Developing a CASSS Global Health Initiative Workshop presented through a collaboration between MIT/CBI and CASSS John Frenz, Alnylam Pharmaceuticals, J. Christopher Love, Massachusetts Institute of Technology, William Hancock, The Barnett Institute, Northeastern University Advanced Process Control Opportunities for Biologics Jay Higgins, Amgen, Inc., Richard Ledwidge, CDER, FDA, Hailun Ma, CBER, FDA, Arne Staby, Novo Nordisk Facing the Challenge of Drug Product Manufacturing, Validation, and Comparability Strategies Hung-Wei Chih, Genentech, a Member of the Roche Group, Emily Dubis, Biogen, Chikako Torigoe, CDER, FDA, Nicole Trudel, CBER, FDA

12:30 – 13:45 Hosted Lunch Break in the East/State Rooms

THURSDAY, JANUARY 28 continued

13:45 – 15:00 Workshop Session 4 Endotoxin Testing: Not Always as Easy as it Seems Michael DeFelippis, Eli Lilly and Company, Patricia Hughes, CDER, FDA, Jenny Kenney, CBER, FDA, Maura Kibbey, USP, Edwin Moore, University of Illinois “Hot Topic” Workshop Kathy Lee, Eli Lilly and Company, Nadine Ritter, Global Biotech Experts New and Emerging Analytical Technologies that have been driven by the Characterization of Biosimilars Chi-Ting Huang, Bioanalytix, Inc., Peter Johnson, 3M Drug Delivery, Eva Marszal, CBER, FDA, Rachel Novak, CDER, FDA Comparability Studies in Blood derived Products and Their Recombinant Analogs Mahmood Farshid, OBRR/CBER, FDA, Reed Harris, Genentech, A Member of the Roche Group, Alexey Khrenov, OBRR/CBER, FDA, Bryan Silvey, Baxalta

15:00 – 15:30 PM Break in the Promenade Foyer

15:30 – 15:55 Achieving Product Attribute Control by Implementation of

Predefined Product Quality Targets and Process Analytical Technologies

Rohini Deshpande, Amgen, Inc.,

15:55 – 16:20 Innovative Facility Designs for a Diverse Pipeline Future Parrish Galliher, Xcellerex Inc. GE Healthcare Life Sciences,

Marlborough, MA USA 16:20 – 16:45 Oxygen Uptake as a Virtual Cell Culture Probe Steven Rose, MedImmune, A member of the AstraZeneca Group,

Gaithersburg, MD USA 16:45 – 17:00 Panel Discussion - Questions and Answers 17:00 – 17:15 Closing Comments and Invitation to WCBP 2017

Joseph Kutza, MedImmune, A member of the AstraZeneca Group,

Next Big Thing in Biologics Processing and Controls Plenary Session in the Grand Ballroom

Session Chairs: Richard Rogers, JUST Biotherapeutics, and Richard Scott Rosenthal, MedImmune, A member of the AstraZeneca Group

Keynote Speaker

Gerd Binnig, Definiens AG, München, Germany

Plenary Session Abstracts 2016 WCBP Opening Regulatory Panel with FDA Session Chair: Brian K. Nunnally, Biogen, Research Triangle Park, NC Moderator: Stephanie Pluschkell, Pfizer, Inc., Groton, CT Panel Members: Ashley Boam OPQ/OPPQ, FDA, USA David Deloski, CDER, FDA USA Christopher Joneckis, CBER, FDA, USA Steven Kozlowski, CDER, FDA, USA This year’s opening regulatory panelists represent leading members of FDA who have been invited to have an open conversation at WCBP 2016 to discuss key developments and focus areas for the FDA that can have substantial impact on the regulatory development pathways of biologics from the very early stages of clinical evaluation through license application and market entry. Topics will include (1) the reorganization that has established the Office of Pharmaceutical Quality (OPQ) and its go-forward imperatives; (2) recent experiences and new perspectives on the acceleration of patient access to highly innovative breakthrough biotherapeutic medicines and vaccines, and any potential hurdles in this effort; and (3) insights and key learnings from the progression of the biosimilar development pathway in the US to date. Regarding the first theme, the Office of Pharmaceutical Quality (OPQ) was officially launched in January 2015, after having first been announced by longtime Center for Drug Evaluation and Research (CDER) director Janet Woodcock in September 2012. "Quality is the underpinning of everything we do, and it is imperative that we have a drug quality program as robust as those programs we presently have for drug efficacy and drug safety," said Woodcock in a 2012 memo to FDA staff. The conversation with the panelists will include details on the organizational changes and how they have impacted or are intended to impact both pre- and post-approval quality oversight, the speed of reviews and decision making, and the industry’s implementation of innovative, superior manufacturing technologies along the entire lifecycle of a product. In addition, the ability of the new OPQ to manage the reality of increasingly complex global supply chains for the manufacture of medicines and vaccines and the sourcing of raw materials will also be discussed. On the topic of accelerated development pathways, the dialogue will include an update on FDA’s recent experience with its programs that are intended to expedite patients’ access to critical medicines, including therapies designated as “breakthrough”. The focus will center on the challenges of expedited clinical development on the sponsors’ CMC organizations and any recommendations that FDA can make on how to prioritize and streamline the elements of regulatory CMC requirements either before or after market entry (may also include specifics for combination products, devices). Furthermore, a discussion of a variety of issues that can hinder innovation and speed of development will also take place, including any obstacles to science- and risk-driven decisions on manufacturing process and quality testing strategies (e.g. the role of product-specific monographs for biotherapeutics).

For the discussion on biosimilars, we look forward to FDA’s insights into their growing experience interacting with sponsors of biosimilar development programs, pre-approval expectations to demonstrate biosimilarity, and the evolution of FDA’s biosimilar guidelines. The FDA’s perspective on their requirements for biosimilar market entry relative to other geographical regions such as the EU or Canada, biosimilar naming (e.g. relative to WHO proposals) and product labeling will also be covered. NOTES:

Chasing the Holy Grail: A Global Approach to Specifications: Session Chairs: Neha Frantz, Biogen and Annie Sturgess, Bristol-Myers Squibb Specifications ranges for biotherapeutics have traditionally been defended based on process capability and statistical analysis of manufacturing experience. As the industry implements the principles of quality by design (QbD) both in bioprocess and assay development as well as and “fit-for-purpose” control strategies, we find ourselves at odds between increased product and process understanding and antiquated arguments for defending the tests and acceptance criteria that define the specifications that support commercial registration and life-cycle management of products globally. Building on the WCBP themes since 2013 with the mindset of global regulatory convergence, and driven by the increasing complexity of the biotherapeutics commercialized world-wide, this plenary session will explore through case studies the industry’s desire to move to a scientifically-sound, patient-centered and risk-based approach to developing and defending specifications, with the goal of ensuring and maintaining the integrity of global supply.

NOTES:

Barry Cherney, Amgen Inc., Washington, DC USA NOTES:

Diane Wilkinson, Biogen, Berkshire, United Kingdom NOTES:

Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan NOTES:

Pay Now or Pay Later: Diverse Process Development Pathways that Ultimately Support Commercialization

Session Chairs: Jamie Moore, Genentech, a Member of the Roche Group, and Xiao-Ping Dai, Celgene This plenary session will highlight two distinct aspects of CMC development: CMC activities completed proactively in early development that can expedite late stage development; accelerated early phase CMC development to support fast to FIH and proof of concept. It will consist of case studies examining successful technical development approaches such as implementation of molecular/developability assessment, developing comprehensive host cell protein (HCP) assays, sequence variant analysis, establishing clonality; as well as strategies to speed development and delivery for FIH. NOTES:

Laurie Graham, CDER, FDA, Silver Spring, MD USA NOTES:

Trent Munro, Amgen, Inc., Thousand Oaks, CA USA NOTES:

John Joly, Genentech, a Member of the Roche Group, South San Francisco, CA USA NOTES:

Implications of Product-Specific Monographs for Biotherapeutic Products Session Chairs: John Dougherty, Eli Lilly and Company and Tina Morris, USP Product-specific monographs for biologics have been used in the major pharmacopoeias of the world since the early 20th century. As biologics manufacturing, development and quality control have changed over time, especially with the introduction of recombinant biotherapeutics into the market, development challenges and expectations for compendial standards have also evolved. Most recently, the global discussion about quality expectations for biosimilars has added another dimension in considering the role of product-specific compendial standards. This session will bring together different viewpoints on the value, role, and challenges in the development, applicability and use of compendial monographs for modern biotherapeutic medicines. In addition, the session will endeavor to establish a conceptual framework for productive dialogue around the use of standards in enabling access to quality biotherapeutic medicines for patients worldwide.

NOTES:

Emmanuelle Charton, EDQM, Council of Europe, Strasbourg, France NOTES:

Anthony Mire-Sluis, Amgen, Inc., Thousand Oaks, CA USA NOTES:

Xiaoyu Chen, Pfizer, Inc. NOTES:

Analytical Control Strategy of Vaccine Products Session Chairs: Arifa Khan, CBER, FDA and Ziping Wei, Novavax This plenary session will discuss how the analytical control strategy evolves over the course of vaccine product development. Stage-appropriate and risk-based analytical control strategy needs to be developed to meet the product development needs. At the early stages of vaccine product development, analytical control strategy is based on limited product understanding and process knowledge. As the product moves to late stage development, product understanding and process knowledge accumulate and it is expected that an enhanced analytical control strategy is established to ensure product quality. As an example, product development for a Phase 1 clinical program, where the major concern is patient safety and less product knowledge is gained, would likely have a very different analytical control strategy in comparison to one being performed for a Phase 3 pivotal study, where safety and efficacy are relevant factors and more product knowledge has been accumulated. The wide range of vaccine products (which include recombinant proteins, live-attenuated viruses, inactivated viruses, polysaccharides, and polysaccharide-protein conjugates) present unique aspects and challenges for establishing analytical control strategy. Depending on the complexity of vaccine type, it may be challenging to characterize or measure quality attribute changes, and define complexity of process and product attributes. This plenary session will give examples for how to set control strategy when there is limited product and process knowledge and how it evolves as vaccine products move to late stage development. NOTES:

Jennifer L. Dashnau, Merck & Co, Inc., West Point, PA USA NOTES:

Freyja Williams, CBER, FDA, Silver Spring, MD USA NOTES:

Definition of Analytical Control Strategy for Robust Vaccine Development

Christina Campa, GlaxoSmithKline Vaccines, Siena, Italy

The establishment of a strong Analytical Control Strategy is instrumental to achieve consistent manufacturing of safe and efficacious products. For this reason, it is critical to build analytical knowledge since early development, leading to a systematic increase of product and process understanding during life cycle. This presentation will focus on some key elements allowing the realization of such challenging objective:

Definition of requirements of analytical methods (Analytical Target Profile, ATP), applicable to lot release/ stability testing, characterization/ comparability testing and process monitoring

Systematic reliability evaluation of methods for the scope, including considerations on reference standard use and suitability

Continued refinement of analytical approaches for ATP fulfillment during product life cycle, ensuring application of up-to-date analytical technologies

Implementation of Quality by Design in method development (e.g., identification & ranges of critical variables impacting analytical result), with assessment of implications on method qualification/ validation, as applicable.

Case study examples will be provided on vaccine development, demonstrating how the implementation of the above- mentioned concepts can be successfully achieved in this field.

NOTES:

Facing the Challenges of Drug Product and Device Development & Manufacturing Session Chairs: Margaret Speed Ricci, Amgen Inc. and Shan Jiang, Seattle Genetics This plenary session will cover the perspectives of both regulators and industry on challenges in drug product and device development and manufacturing for therapeutic biologics. The criticality of integrated drug product design considerations across formulation, drug product process, container, and device will be discussed. Learnings from the development and commercialization of adaptive manufacturing systems and new container and device technologies will be reviewed. Establishing comprehensive control strategy and drug product comparability for aseptic manufacturing of biologic products will be demonstrated with industry examples. Case studies will be shared that illustrate technical considerations in container closure integrity, extractables and leachables testing, process validation as well as new regulatory expectations for manufacturing of parenteral products. NOTES:

Anthony Mire-Sluis, Amgen Inc., Thousand Oaks, CA USA NOTES:

Donna French, Genentech, a Member of the Roche Group, South San Francisco, CA USA NOTES:

Patricia Hughes, CDER, FDA, Silver Spring, MD USA NOTES:

Evolving Biosimilar Regulatory Science – Case Studies Session Chairs: Martin Schiestl, Sandoz, and Marjorie Shapiro, CDER, FDA The regulation of biosimilars is founded on the scientific principles of comparability, which were established - with the publications of the FDA Guidance “Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products” in April 1996, followed by the ICH Q5E concept paper established in 2002 and the final adoption of ICH Q5EComparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process in 2004/2005. Prior to this, a biological product was often defined by its manufacturing process. Without the acceptance of the concept of “comparability”, along with advances in analytical methods, there would be no biosimilars today. The comparability concept has also been used for the approval of follow-on-versions of biological products regulated in the US for historic reasons as drugs using the 505(b)(2) pathway. One example is a Somatropin approved by FDA in 2006 based on comparative quality, non-clinical and clinical data. In the same year the same product was also approved as the first biosimilar product in the EU using basically the same data package. In the EU, EMA issued the first biosimilar guideline already in 2004 and the first products were approved in the following years. In the US, the legal basis was created by the Biologics Price Competition and Innovation act in 2009. Since then, the regulatory science evolved quickly and continues to move forward, for example, new concepts with regard to quality evaluation taking into account the clinical relevance of quality attributes, tailored confirmatory clinical studies, and the scientific requirements for extrapolation have been developed allowing the science-based and efficient development of safe and effective biosimilars. The revised and newly established biosimilar guidances in US and EU reflect the current state-of-the-art in regulatory science, while remaining open for further innovation in the field. This is important for the next step in the evolution: the move from biosimilars to interchangeable biologics. This session will illustrate this evolution in regulatory science with case studies of approved biosimilar products or those currently in development. Speakers from FDA and Sponsors developing biosimilar products will share their experience and provide an outlook to the future. NOTES:

Thomas Stangler, Sandoz GmbH, Tirol, Austria NOTES:

Maria-Teresa Gutierrez-Lugo, CDER, FDA, Silver Spring, MD USA

NOTES:

James Anderson, Momenta Pharmaceuticals, Inc., Cambridge, MA USA

NOTES:

Comparability for Blood Products – How Did We Get Here and Where Are We Going? Plenary Co-chairs: Andrew Chang, Novo Nordisk, Inc. and Timothy Lee, CBER, FDA

This plenary session will address comparability issues related to plasma-derived and recombinant blood coagulation factor products. Our speakers will describe how the comparability approach has been applied, evolved and leveraged, against a historical backdrop of advancements of recombinant technology in product manufacture, improvements in analytical capability and changes in regulatory policies. We will set the stage by reviewing the comparability paradigm as it is applied throughout the past 20 years since its inception. We will then look at case studies illustrating some of the challenges related to specific classes of coagulation factor products, some of which are unique to coagulation factors, and others which are relevant to biological products in general. In the examples, we hope to cover the following topics:

• How differences in quality attributes in pre- and post-change materials were reconciled either during product development or post-approval

• How interactions between the manufacturer and regulator helped resolve comparability-related issues

• What are the considerations in the selection of analytical methods for the comparability exercise? Are new analytical methods always considered?

• What are the characteristics that the manufacturer considers to be unique to blood products, and those that are shared amongst other biopharmaceuticals, and how that affected the design of the comparability exercises? For example, impurities in plasma-derived products could have their own biological activities that can either be beneficial or deleterious.

Nancy Kirschbaum, CBER, FDA, Silver Spring, MD USA

NOTES:

Stephen Raso, Biogen, Cambridge, MA USA

NOTES:

Peter Turecek, Baxter Innovations GmbH, Vienna, Austria

NOTES:

Back to the Future: The Next Big Thing in Biologics Processing and Controls Plenary Co-chairs: Richard Rogers, JUST Biotherapeutics, and Richard Scott Rosenthal, MedImmune, A member of the AstraZeneca Group The tools, technologies and hardware that enabled the establishment of the biotechnology industry continue to evolve and change, and as a result the current state of the industry looks very different than it did in its infancy. Much of this evolution occurs as a result of incremental improvements, which over time results in greater efficiency, capacity, robustness, utility, etc. Fundamental paradigm shifts occur far less frequently, but can result in true step changes in terms of how the industry operates. This session seeks to highlight disruptive technologies and processing trends with the potential to bring about transformative change to the current state of the industry with respect to bioprocessing and product attribute controls.

NOTES:

Achieving Product Attribute Control by Implementation of Predefined Product Quality Targets and Process Analytical Technologies

Rohini Deshpande

Amgen Inc., Thousand Oaks, CA USA

Quality by Design (QbD) is a systematic approach to development of pharmaceuticals that begins with pre-defined objectives, and emphasizes product and process understanding and attribute control, based on scientific understanding and quality risk management. This requires an understanding of how product, materials, methods, and process variables influence final product quality. An integrated product development paradigm starts with a well-defined TPP and QTPP to implement attribute control strategies that allow for better real time control of process and product. Such an approach, if successfully implemented will permit testing on the manufacturing floor while at the same time move the testing paradigm of biologics towards RTRT. In this presentation, we will share our progress in application of a QTPP and process analytical technologies for achieving attribute control and designing quality into the product. NOTES:

Innovative Facility Designs for a Diverse Pipeline Future Parrish Galliher, Xcellerex Inc. Marlborough, MA USA

The last 20 years has witnessed increased diversity in medical treatment modalities, drug pipelines, expression systems and manufacturing technologies. In parallel, biomanufacturers have employed many innovations to improve cost, speed and flexibility, including single use technology, higher titer and continuous processes in some cases. These trends have increased demands on manufacturing facility design, operations, and agility. The presentation will provide examples of various classes of facility layouts and will compare advantages, disadvantages and regulatory risks of their design and operations.

NOTES:

Oxygen Uptake as a Virtual Cell Culture Probe Steven Rose MedImmune, a member of the AstraZeneca Group, Gaithersburg, MD USA During the scale-up and tech transfer of cell culture processes, we routinely evaluate whether the bioreactors are capable of supporting the required cell culture oxygen demands. We have developed a first principle oxygen transfer model to define how best to run the bioreactor to meet the oxygen demand. The model enables us to successfully specify larger scale bioreactor operating conditions without needing to perform an engineering run. We have found that we can also leverage this engineering model as a virtual probe to monitor and control the cell culture process. We have shown that with a virtual oxygen uptake rate probe, we can manage the carbon dioxide accumulation and predict titer and cell culture growth performance. This provides greater insight into the biology and results in consistent control for enhanced process performance. This presentation will share the model results and its predictive ability across bench, pilot and manufacturing scales. NOTES:

Workshop Descriptions

Workshop Session 1 Tuesday, January 26, 2015

17:00 – 18:15

Regulatory and Compendial - Combination Products Rakhi Dalal, CDER, FDA, Donna French, Genentech, a Member of the Roche Group, Steve Hertz, CDER, FDA, Ed Patton, CBER, FDA, Michael Soberg Christensen, Novo Nordisk AG, John Weiner, OCP, FDA In the Chinese Room In January 2015, the FDA issued draft guidance on CGMP requirements for combination products in support of the regulation (21 CRF Part 4). These regulations are intended to promote the public health by clarifying which CGMP requirements apply when drugs, devices, and biological products are combined to create combination products. Combination products are those that consist of two or more different types of products, such as a drug/device combo like a pre-filled syringe. There many different many different types of combination products and this session can address the application of 21 CFR Part 4 to different type of products. This is a challenge for manufacturers of combination products as industry has to the responsibility to comply with these regulations and enforcement of 21 CRF Part 4 compliance is expected. Clarity of expectations regarding CGMP requirements for combination products are crucial for establishing a robust and compliant quality system and ensuring a consistent implementation of 21 CFR Part 4. This session will address some of the important questions and issues for combination products in relation to quality system, experiences/expectations in relation to inspection of combination products as well as experiences from the review process. The following specific question will be addressed:

a. How to establish an appropriate quality system for manufacturing of combination products?

b. How will the interaction between FDA review and inspection teams change future inspections of combination products?

c. How should design controls and purchasing controls be implemented for various types of combination product technologies (e.g., drugs co-packed with class 1 or class 2 devices)

d. How do companies meet the requirements for marketed products that were not developed under design controls?

NOTES:

Pay Now or Pay Later: Prioritizing CMC Development Activities in Early Development Christopher Downey, CDER, FDA, Catherine Eakin, Seattle Genetics, Michelle Frazier, AbbVie, Inc., Sara Gagneten, CBER, FDA, In the District Room With the advent of programs that can rapidly accelerate the normal product development lifecycle, such as Breakthrough Therapy Designation, Industry is re-thinking product development strategies to achieve shortened timelines. This session will consider the CMC activities that can expedite both early and late stage development. Strategies discussed will include the use of platform processes and methods, frontloading of characterization studies early in development, and new approaches such as the use of pooled clones to enable more rapid entry into first in human studies. The risks and benefits of these strategies will be evaluated in the context of technical challenges and overall impact to development timelines. NOTES:

Regulators’ Perspectives on Trends in the Regulation of Biopharmaceutical Products in Europe and Asia Session Chairs: Kathleen Francissen, Genentech, a Member of the Roche Group and Anthony Ridgeway, Health Canada Regulators: Peter Richardson, European Medical Association (EMA) and Daisaku Sato, PMDA and Anis Talib, Ministry of Health Malaysia (MHM) In the Grand Ballroom In this session, regulators that represent EMA, PMDA, and MHM will present the highest priorities of their agencies and discuss current trends in accelerated development strategies, (such as Adaptive Pathways and Sakigake), biosimilars development, and regulatory convergence and harmonization (particularly the involvement of their agency). Among activities that support regulatory system strengthening, the Asia Pacific Economic Cooperation (APEC) Regulatory Harmonization Steering Committee (RHSC) has a mandate to work towards achieving regulatory convergence by 2020 among the 21 APEC economies. Japan was identified as the new chair of RHSC, and will co-chair RHSC meetings with US FDA. In terms of training and capacity building, APEC Training Centers of Excellence (CoE) for Regulatory Science, which are partnerships of academia, regulators, and industry (at various stages of implementation) identified the following priority work areas: (1) Biotherapeutics; (2) Multi-regional clinical trials (MRCT), including Good Clinical Practices (GCP); (3) Pharmacovigilance; (4) Good review practices (GRP), including good submission practices; and (5) supply chain integrity. The potential opportunities and challenges of achieving regulatory convergence in the APEC region and in other regions will be discussed.

Emerging Trends for Higher Order Structure Characterization in Biopharmaceutical Development

Anders Dybdal Nielsen, Novo Nordisk, Frances Namuswe, CDER, FDA, William Weiss, Eli Lilly and Company

In the Palm Court Room

Higher order structure (HOS) characterization is steadily growing in visibility as there is broader recognition of the critical importance of these tools/technologies in supporting biotherapeutic process and product development. Participants will engage in a lively discussion on emerging trends in this space. Topics for discussion will include:

How will emerging tools/technologies change HOS characterization? How do we bridge between current and emerging technologies? How will regulatory expectations for HOS characterization evolve in response? How can industry, academia, and regulators partner together to ensure that emerging HOS

tools/technologies are being leveraged most effectively?

Wednesday, January 27, 2016 11:00 – 12:15

In the Chinese Room

NOTES:

How to Succeed with Breakthrough Kimberly May, Merck& Co., Inc., Mikhail Ovanesov, CBER, FDA, Emily Shacter, ThinkFDA, d Joanna Zhou, CDER, FDA In the District Room Attainment of 'Breakthrough Therapy' status greatly accelerates clinical product development and increases the chances for earlier product approval. However, it also means that CMC activities required for approval must be accelerated to align with the fast-paced clinical development. This includes all elements of process development, manufacturing scale up, and validation; method development and validation; product characterization and critical quality attribute (CQA) assessment; stability testing and expiration dating; and obtaining sufficient batch data to set reasonable specifications. Some regulatory flexibility is possible, and some non-critical CMC achievements could be deferred to post-approval commitments. Nonetheless, the general expectation from the FDA is that the BLA will meet current GMPs and will contain sufficient CMC information to demonstrate product understanding, achieve consistent drug product quality, and ensure continuous market availability. Communication with the Agency during the course of product development is crucial for designing an appropriate CMC development program for Breakthrough products. In this workshop, we will initiate the discussion on several interesting topics:

1. How are companies who are developing Breakthrough Therapies meeting the accelerated timelines for CMC activities?

2. What innovative approaches are being explored? 3. What kinds of flexibility and additional steps is the Agency exercising in order to expedite

the development and licensure of products indicated for serious or life-threatening medical conditions, for which there is an unmet medical need?

NOTES:

Global Regulators Focus Americas Session Chairs: Gerald DiDonato, Bristol-Myers Squibb and Thomas Schreitmueller, F. Hoffmann-La Roche, Ltd. Regulators: Adriana Hernández Trejo, COFEPRIS, Fabiola Muñoz Espinoza, Instituto de Salud Pública de Chile, Marcelo Moreira, ANVISA In the Grand Ballroom

In May 2014 for the very first time the 67th World Health Assembly recognized with two resolutions A67 R20 on regulatory systems strengthening and A67 R21 on access to biotherapeutic products including similar biotherapeutic products the importance of biotech products for public health including the need for proper implementation of regulations covering this product class. This was followed by the 16th International Conference of Drug Regulatory Authorities (ICDRA, Rio de Janeiro, Brazil, August 2014) with concrete recommendations. Among many other recommendations WHO member states are asked to:

Ensure regulatory oversight throughout the life cycle of biotherapeutic products, including similar biotherapeutic products, (SBP) to assure quality, efficacy and safety of these products

Improve efficiency of regulatory evaluation of biotherapeutic products, including SBP, in order to improve access to products of assured quality, safety and efficacy

Make efforts on regulatory convergence as a tool to increase global access to biotherapeutic products and SBPs of quality, safety, and efficacy

Implement existing WHO guidelines WHO guidelines on biotherapeutic products and on SBP as well as subsequent updates in full, and monitor levels of implementation over time

Involve all relevant stakeholders (e.g. manufacturers, academia, health care providers, patient associations) during development of national regulatory requirements and create opportunities for regular feedback on regulatory practices

Managing decentralized Good Manufacturing Practice (GMP) systems serving the ultimate goal of creating mutual trust and recognition between inspectorates

Promote innovative approaches to enhancing quicker access of medicinal products, without compromising safety

In our workshop with representatives from X agencies we want to explore how agencies perceive these recommendations, what initiatives they have undertaken towards implementation, what are potential hurdles and how can they overcome and what should be the priorities for the upcoming years.

NOTES:

AnalyticalControlStrategyforVaccineProducts In the Palm Court Room Steven Rubin, CDER, FDA, Garry Tackle, Merck, Michael Washabaugh, MedImmune, a member of the AstraZeneca Group, Freyja Williams, CBER, FDA The impact on global public health realized by the availability of effective vaccines cannot be overstated. Maintaining a reliable supply of vaccines requires well-established and validated production process. But even with well controlled manufacturing processes, producing vaccines that consistently and reliably meet critical quality attributes is a major challenge and requires a well-designed analytical control strategy. The analytical control strategy can be expansive, ranging from qualification of raw material inputs to complex analyses of product intermediates and final filled containers. Regardless of the nature of an analytical control strategy, its main component is testing, often involving development of novel assays specific for the parameter to be measured. Such assays require extensive characterization, validation, and monitoring, and often necessitate development of reference reagents. Key questions to discuss are (1) how much assay characterization is enough (i.e., qualification vs validation); (2) when is re-qualification or re-validation needed; (3) what elements can be incorporated into a vaccine control strategy to limit the amount and frequency of testing; (4) what are the best strategies to establishing product specifications; and (5) what can we learn from analytical control strategy success stories? NOTES:

Workshop Session 3 Thursday, January 28, 2016

11:15 – 12:30

Stability: Strategy and Expectations for Biotech/Biological Products In the Chinese Room Bazarragchaa Damdinsuren, CDER, FDA, Annick Gervais, UCB, Philip Krause, CBER, FDA, Patsy Lewis, Seattle Genetics, Inc., Donnie Pulliam, Biogen Current ICH guidance Q5C, “Stability Testing of Biotechnological/Biological Products”, was published almost 20 years ago. Since then, advances in analytical technologies have opened new insights into modes of degradation and generated new questions from both manufacturers and regulatory authorities, such as the following:

‐ How can forced degradation study design and results be leveraged to assign expiry or to demonstrate comparability within the product development continuum?

‐ What stability study and expiration dating strategies should be used in multi-stage drug substance production?

‐ What bearing does detection of sub-visible and visible particulates during manufacture and product storage have on expiry in light of recently established relevant pharmacopeial guidances, such as USP <790>?

‐ To what extent should the conditions of ICH Q1B photostability studies, originally established for small molecules, be applied in determining expected effect on product quality for large molecules? Are these conditions appropriate for biologics?

‐ What are the current regulatory expectations or best practices for phase-appropriate stability monitoring during drug development in order to justify product usage period during clinical trials? How can accelerated/stressed studies help to justify a shelf life?

Join with colleagues from industry and regulatory agencies to discuss strategic and compliance considerations of questions such as these, collaborating to discuss best practices in this fast-paced and interactive workshop.

NOTES:

Steps Towards Developing a CASSS Global Health Initiative In the District Room John Frenz, Alnylam Pharmaceuticals, William Hancock, The Barnett Institute, Northeastern University The largest unmet needs for global health encompass those diseases in developing countries where access to biotherapeutics is limited in part to constraints imposed by existing technologies and practices, and where new approaches have the potential to meaningfully expand access. This workshop will focus on the landscape of global needs for biotherapeutics, factors limiting our ability to meet these needs, and innovations needed to overcome these limitations. The need for lower cost vaccines for infectious disease is clear, but through this workshop we will also address biotherapeutics for use in treating noncommunicable diseases. For example, globally at least 50% of diabetics, as well as 25% of diabetic children, do not have access to recombinant insulin treatment. Examples of manufacturing systems and technologies with the potential to address these issues will be shared as a way to leverage and engage the expertise and experience of WCBP participants in building creative technical solutions alongside policy efforts toward improving global health. The goal of this workshop is to stimulate discussion on how CASSS and the MIT BioMAN Consortium can contribute to addressing the global unmet need for pharmaceuticals, especially in the area of protein therapeutics. NOTES:

Advanced Process Control Opportunities for Biologics In the Grand Ballroom Jay Higgins, Amgen Inc., Richard Ledwidge, CDER, FDA, Hailun Ma, CBER, FDA, Arne Staby, Novo Nordisk Development and implementation of process analytical technology and real-time release testing requires an approach to product development that emphasizes product and process understanding and process control, based on sound science and quality risk management (i.e. quality by design). Mathematical models can enhance scientific understanding of a process and be utilized for their predictive capability even with highly complex biopharmaceutical products. Topics for discussion in this workshop include the following: 1) What is the appropriate timing of implementation of advanced process control strategies?

2) What are the practical challenges faced by industry when developing and implementing control strategies based on CQA impact assessments, process capability and product stability?

3) How are companies exploring the use of advanced analytical tools (such as PAT enabling devices) and process understanding to implement real-time product quality monitoring and control?

4) When is the best point and time to test a given CQA? i.e. end-product testing, in-process testing or process validation?

NOTES:

Facing the Challenge of Drug Product Manufacturing, Validation, and Comparability Strategies In the Palm Court Room There are many challenges in the world of drug product manufacturing, some expected and others unexpected. In this interactive workshop we will discuss some of the following commonly faced challenges of drug product manufacturing and validation:

Manufacturing: Production issues involving raw materials and components from suppliers, along with processing issues during compounding, mixing, filtration, and lyophilization, as well as quality issues with less robust molecules or processes.

Validation: Determining the process qualification strategy appropriate for your product.

Additional complexities might include differences in scale and batch size, or a product with multiple strengths.

Comparability: How to show comparability when changes are made to the manufacturing

process, or an additional manufacturing facility is added. Through facilitated discussion at this workshop, you are invited to share your knowledge and experience with others from across the industry to compare best practices and helpful information. NOTES:

Workshop Session 4 Thursday, January 28, 2016

13:45 – 15:00

Endotoxin Testing: Not Always as Easy as it Seems In the Chinese Room Michael DeFelippis, Eli Lilly and Company, Patricia Hughes, CDER, FDA James Kenney, CBER, FDA, Maura Kibbey, USP, Edwin Moore, University of Illinois Endotoxin testing for biopharmaceutical products used to be considered a rather straightforward activity. Industry routinely verified the published compendial method, USP <85>, for the product of interest, completed additional confirmatory studies relative to USP <151>, and proceeded with USP <85> for routine testing. However, in 2013, reports started to appear in the public domain describing low recovery when certain product samples were spiked with known amounts of lipopolysaccharide (LPS) used as a standard to perform the USP <85> tests. Since that time the recovery issue has been termed low endotoxin recovery (LER), and any sponsor of a BLA submitted for review will be expected to assess their product with respect to the LER phenomenon. Ensuing research efforts have provided further insight into LER and the potential mechanistic causes. Certain matrix components, such as, chelating buffers and the surfactant polysorbate 80 have been implicated. However, there are reports of LER in matrices containing non-chelating buffers. The lack of standardized testing protocols across industry could be contributing to inconsistencies in reported data. Alternative assays for endotoxin testing as well as the use of naturally occurring endotoxin (NOE) are also being pursued with mixed results due to the lack of consensus on test methodology and recognized standards for comparison and control. Some sample preparation procedures intended to improve recovery have also been proposed, but to date no single approach has emerged as being capable of overcoming all LER effects. Clearly, continued collaboration between industry and regulators is needed to resolve the LER issue and ensure patient safety. This workshop is intended to stimulate discussion on the various issues related to the current and future state of endotoxin testing. NOTES:

Hot Topic Workshop In the District Room Kathy Lee, Eli Lilly and Company, Nadine Ritter, Global Biotech Experts, LLC The next year’s WCBP planning process begins immediately after the past conference ends. With this kind of advanced planning cycle, it is impossible to anticipate every topic which will be important at the time of the conference. With this in mind, the Program Committee has instituted a new workshop where the topic is decided by the participants at the WCBP conference. The “Hot” topic will be determined and announced during the conference, allowing for important and timely discussions to happen in the WCBP workshop format. Participants are encouraged to help in determining the topic and to join the discussion by adding their questions and perspectives during the workshop. The workshop will be designed to facilitate a discussion between key stakeholders and to provide participants with information useful to their organizations. NOTES:

New and Emerging Analytical Technologies that have been Driven by the Characterization of Biosimilars In the Grand Ballroom – Plen-Workshop Chi-Ting Huang, Bioanalytix, Inc., Peter Johnson, 3M Drug Delivery Systems, Ewa Marszal, CBER, FDA, Rachel Novick, CDER, FDA The broader adoption of new analytical technologies is predicated on the demonstration of providing novel information in a robust and reproducible manner to enhance protein characterization and to provide additional assurances of safety and efficacy. The characterization of biosimilars for regulatory approval has provided an additional impetus to explore new technologies and reevaluate less commonly applied characterization techniques to raise the bar for biopharmaceutical analysis. In order to reduce uncertainty in the comparability of a biosimilar to the branded biologic molecule, developers need new and enhanced techniques for providing additional structural and functional characterization information. The techniques discussed in this workshop may enable a new level of chemical and biochemical understanding for biologic drugs. New analytical techniques may provide a deeper understanding of biologic drugs, by answering the questions, “What is the chemical and biochemical variability of a branded biologic drug, compared to the chemical and biochemical variability of a proposed biosimilar?” This Plen-Workshop session will include three speakers who will address three specific new and emerging analytical technologies that can be utilized for the characterization of biosimilars. Professor Dwight Stoll (Gustavus Adolphus College) will review two-dimensional HPLC for biologics, Dr. John Marino (NIST) will review NMR for characterizing higher order structure (HOS) of biotherapeutics, and Dr. Billy Wu (BioAnalytix, Inc.) will review in vivo CQA mapping. A discussion period will follow the introduction of these new and emerging analytical technologies. The discussion will address these analytical technologies, as well as other new and emerging technologies that may be utilized for the characterization of biosimilars. NOTES:

Comparability Studies in Blood derived Products and Their Recombinant Analogs In the Palm Court Room Mahmood Farshid, CBER, FDA, Reed Harris, Genentech, a Member of the Roche Group, Alexey Khrenov, CBER, FDA, Bryan Silvery, Baxalta Throughout the life of a product, manufacturing changes including transfers are inevitable. These changes are introduced for manufacturing process optimization, scale up and/or improved product purity and enhanced safety. The comparability studies are intended to assess the potential impact of the manufacturing changes on product quality and safety. These assessments are performed using analytical methods with pre-defined acceptance criteria that are based on manufacturing experience and knowledge of the product and process. Modern analytical methods and relevant assays have by and large provided a reliable approach to establishing comparability of pre- and post-modification products. This is more so for well-defined biologics such as recombinant biopharmaceuticals, but could be less certain for complex biologics such as human and animal plasma derived products. For complex biologics that are undergoing multiple process changes, sole reliance on analytical methods my not be sufficient to establish comparability and ensure product safety. Multiple changes in manufacturing process could cumulatively result in altered safety profile for the modified product, which may need to be investigated further in clinical studies, consisting of PK and safety studies. Prior to initiation of a comparability study, it is advisable to submit the study protocol to the FDA to ensure its acceptability for establishing product comparability. The workshop is intended to cover key themes from the plenary Comparability Issues in Blood Products session, along with other issues and examples that the participants can share. NOTES:

Technical Seminar Abstracts

Tuesday, January 26, 2016 13:00 – 14:00

In the Chinese Room Sponsored by Waters Corporation

Tuesday, January 26, 2016 13:00 – 14:00

In the District Room Sponsored by ProZyme, Inc

Tuesday, January 26, 2016 13:00 – 14:00

In the Palm CourtRoom Sponsored by Catalent Pharma Services

Wednesday, January 27, 2016 10:20 – 10:50

In the Chinese Room Sponsored by Thermo Scientific

Wednesday, January 27, 2016 10:20 – 10:50

In the Palm Court Room Sponsored by Wyatt Technology Corporation

Wednesday, January 27, 2016 12:45 – 13:45

In the Chinese Room Sponsored by Agilent Technologies

Wednesday, January 27, 2016

12:45 – 13:45

In the District Room Sponsored by Bruker Daltonics, Inc.

Wednesday, January 27, 2016

12:45 – 13:45

In the Palm Court Room Sponsored by SCIEX

Thursday, January 28, 2016

10:30 – 11:00

In the Chinese Room Sponsored by Eurofins Lancaster Laboratories

Thursday, January 28, 2016

10:30 – 11:00

In the Palm Court Room Sponsored by SGS Life Science Service

Poster Abstracts

Poster Session One Tuesday, January 26, 2016

18:15 – 19:15 Cabinet Room

Poster Abstracts

Poster Session Two Wednesday, January 27, 2016

16:45 – 17:45 Cabinet Room

Roundtables

Tuesday, January 26, 2016 16:00 – 16:45

We are excited about the expansion of the roundtable discussions for WCBP this year. The plan is for these to be active discussions, not presentations or lectures. There are 27 roundtable topics with 12 seats to a table. Seating will be on a first come, first serve basis. These roundtables will include a facilitator, whose role is to help assist the discussion and ensure a lively exchange, and a scribe, whose role is to make general, anonymous notes about the discussion so others can have a chance to view the discussion even if they could not participate. The discussion notes will be posted to the CASSS Website within a three week period after WCBP ends for all CASSS members to access. Listed Below is a quick view of the Roundtable Topics and the Designated Meeting Room. Roundtable Definition Scope, Facilitator and Scribe names for each table number are listed behind this sheet. Chinese Room

District Room East/State Room Palm Court Room

TABLE 1

TOPIC: Comparability Issues in Biological Products in Regards to Changes in

Critical Raw Materials, Process and Assay FACILITATOR: Steve Raso, Biogen SCRIBE: Fiona Cornel, Health Canada SCOPE: It is often necessary or highly desirable to make changes in critical raw materials, the manufacturing process or assay methods used in the production and testing of biological drug substances and drug products. Whenever such CMC changes are implemented, a comparability assessment must be performed to demonstrate that the product, pre and post-change, is the same with respect to quality, safety and efficacy. This assessment is prospectively planned and documented in a protocol that describes the process changes that are covered and specifies the testing plan, analytical methods and acceptance criteria used to demonstrate that the specified changes do not adversely affect the product. This table discussion will seek to elucidate the regulatory expectations of comparability assessments, and their respective protocols, with a goal toward an appropriate and uniform approach to such studies. BULLET POINTS FOR DISCUSSION:

1. How to determine the overall comparability plan a. Risk-based approach b. How to define scope of testing plan c. Comparability criteria vs. specifications d. At what stage should regulatory agencies be addressed/notified? Based on

significance of proposed change? 2. How to establish acceptance criteria/ranges

a. Statistical methods? b. What to do when historical data are limited? c. How to handle non-numeric results (e.g. spectroscopic data)?

3. Phase-appropriate comparability assessments a. How to support process changes during clinical trials? b. How to support late-stage/commercial and life cycle management?

NOTES:

TABLE 2 TOPIC: Control and Characterization of Biotherapeutic Glycosylation and Other

PTMs FACILITATOR: Philippe de Vilmorin, Biogen SCRIBE: Reed Harris, Genentech, a Member of the Roche Group SCOPE: Biotherapeutics are heterogeneous by nature, with variance in glycosylation one of the main sources of variation. During this session we’ll discuss strategies for characterizing and controlling PTMs. Characterization topics may include assay selection and timing, and how data is used to drive process development and establishment of a control strategy. Control topics may include choice of expression host, cell line selection, and cell culture/purification processes. BULLET POINTS FOR DISCUSSION:

1. What’s the basis for the target product profile with respect to PTMs? Theoretical biology, empirical biology, comparability, biosimilarity?

2. What metrics are used to summarize complex product quality attributes? Has the use of summary attributes masked variation or had other unintended consequences?

a. Site-specific vs. total for oxidation, glycation, etc. b. Glycosylation – Galactosylation, fucosylation, total high mannose, total sialic acid

3. Discuss strategies for controlling PTMs: a. Cell line development – host selection, host engineering, clone selection b. Cell culture process – additives, metabolic control, production step duration c. Downstream process – chromatography, synthetic modification

4. How early during development is information about PTMs obtained? Are there opportunities to inform molecule or clone selection based on this information?

5. How early during the manufacturing process is information about PTMs obtained? Are there opportunities for feed-back or feed-forward process control to minimize variation?

NOTES:

TABLE 3

TABLE 4 TOPIC: Forced Degradation Studies: Best Practices & Strategies FACILITATOR: Charles Morgan, Genentech, a Member of the Roche Group SCRIBE: Karen Lee, Genzyme, A Sanofi Corporation SCOPE: A concept paper on forced degradation of therapeutic proteins was recently issued (Sep 2015) by a working group within the European Biopharmaceutical Enterprises. This roundtable will leverage this concept paper as a starting point for further discussion. Forced degradation studies (FDS) are performed to determine possible product degradation pathways under various physical and chemical stress conditions. Most frequently FDS are designed to achieve the following goals

• Selection of stability indicating analytical methods • Understanding of possible degradation pathways and impact to quality attributes • Selection of drug candidates in research • Formulation and manufacturing process development • Comparability assessments.

BULLET POINTS FOR DISCUSSION:

1. What is the purpose of conducting FDS? Where do they provide the most valuable information?

2. What are the common pitfalls and areas for improvement? a. If a high stress condition is required to induce a measureable change, does this say

anything meaningful about the likely degradation pathway under conditions for production, storage and transportation?

b. If no change is observed, is the molecule stable or is the analytical method insensitive?

c. Is the assessment limited to physical and chemical stress conditions or is there value in studying in vivo degradation routes (e.g. serum and plasma).

3. What are the regulatory perspectives and feedback on FDS? Where in the regulatory dossier is the information typically presented and at what phase of development?

NOTES:

TABLE 5 TOPIC: Potency Assays: Cell Based vs. Non Cell Based Formats FACILITATOR: Sally Seaver, Seaver Associates LLC SCRIBE: Cheryl Blaise, Bristol-Myers Squibb Company SCOPE: A test for “potency” is one of the required, listed tests (21CFR610.10) and which “shall consist of either in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in 600.3(s). 21CFR600.3(s) defines “potency” as “the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.” In other words a potency test shows that the sample/lot/batch is “active”. Originally most potency tests were in vivo (animal based) but as biological/biotech products became “well characterized” in vivo tests were replaced with in vitro (cell based) tests. The later are more accurate, precise, faster and more reliable. Now many groups start with non-cell based assays such as binding to an antigen, receptor or other target molecule, which they find to be even more reliable (faster, more accurate and precise). Many regulators consider the non cell based test not a true test of potency. BULLET POINTS FOR DISCUSSION:

1. Does your company have platform formats for potency tests whether cell and non-cell based? How many formats does your company consider for binding tests? For cell based tests?

2. When do you start work on cell based potency tests? Non-cell based tests. How do you show (or do you show) that the binding test leads to a desired therapeutic action?

3. If you have several cell or non-cell based tests, how do you choose which one(s) a. To qualify toxicology material? b. For early clinical material? c. For pivotal clinical trial material? d. To submit for approved product material?

4. As you transition between cell based and non-cell based formats, what does your company do to show the comparability of the old and new formats?

a. Before tox lots b. Before clinical lots c. Before pivotal clinical lots d. After approval

5. How does the qualification of operators for the specific test formats change? a. Before tox lots b. Before clinical lots

c. Before pivotal clinical lots d. After approval

NOTES:

TABLE 6 TOPIC: The Holy Grail: Global Specifications FACILITATOR: Roberto Rodriguez, Bristol-Myers Squibb Company SCRIBE: Helena Madden, Biogen SCOPE: From its inception, the International Conference for Harmonization (ICH) has provided a more consistent approach to most aspects of pharmaceutical and biopharmaceutical development. The efforts of the committee, among many other achievements, have resulted in significant progress towards a reduction in the variability for Health Authority (HA) requirements from country-to-country and a more homogeneous, risk-based approach to development and manufacturing of medicines across the industry. A key element of the published ICH guidances is the idea that product development should generate the process and product knowledge required to establish the safety and efficacy of a product, and its consistent manufacturing. Both the product and process knowledge play key roles in the generation of commercial specifications at the end of development through the identification of product Critical Quality Attributes (CQAs) and the process parameters that affect them. A robust battery of tests should be in place to monitor the quality and stability of the product with particular emphasis on the CQAs. Appropriate limits justified with data are selected and negotiated with Health Authorities. Too frequently, however, the requirements for specifications introduce discrepancies in the release and storage of product when intended for multiple markets. Even minor differences on specifications can introduce significant complexity to areas such as manufacturing, supply management and regulatory filings. The round table on “The Holy Grail: Global Specifications” will provide a (small) forum to identify and discuss the most common differences on specifications requirements, the resulting challenges, and approaches commonly used to remain complaint in a global market. The questions below are intended to stimulate discussion by the participants. BULLET POINTS FOR DISCUSSION:

1. What are the most common differences in specification limits and justification required for global products during development and at licensure?

2. What are the most common/problematic dissimilarities in tests/methodology required by the different HAs?

a. Are there any (MUST have) tests that apply to some countries/regions and not others?

b. Are there significant differences in justifying removal of tests? c. Are there differences on acceptable methodology (e.g. identity test by peptide

mapping vs. other approaches)? 3. Are there major differences on acceptability of control strategy (when and where in the

process tests are performed)? 4. Are there significant differences on life-cycle management? Is the bar higher in some

countries/regions when specification changes are needed? What common approaches are

used to manage supply when specification changes approval in multiple countries is required?

5. What are the main differences on shelf-life assignment? Are different shelf-life (or use periods) provided when the same stability package is presented to HAs?

NOTES:

TABLE 7

TOPIC: Trends in Regulatory Inspections and Best Practices FACILITATOR: Jessica Snow, Bristol Myers Squibb Company SCRIBE: Ken Miller, MedImmune, a Member of the AstraZeneca group SCOPE: Regulatory inspections of GMP facilities is a routine part of doing business. The global regulatory landscape is evolving, as evidenced in shifting inspectional focus, joint inspections and revised guidelines. This discussion will provide an opportunity to evaluate current trends and focus topics from recent GMP inspections as well as to consider best practices for managing the inspection process (from preparation through response). The following questions are intended start and guide the discussion by the participants, with a goal of shared understanding of key learnings. BULLET POINTS FOR DISCUSSION:

1. Trends and emerging inspectional themes from HAs a. Different approaches and area of focus depending on the HA? b. Is there greater collaboration between HAs? c. Different focus depending on product and type of inspection?

2. Changes to HA requirements and guidelines (e.g. EMA) and impact on inspectional focus a. Have these revisions emerged as key topics during inspections? b. What are strategies for demonstrating data integrity? c. How are companies demonstrating their assessments of regulations and guidelines? d. Any challenges with compliance to revisions (e.g. EMA GMP guidelines)?

3. Inspection best practices (prior to and during inspections) a. What are effective logistics processes? Do these vary based on the HA? b. Pros and cons of real-time corrections during inspections c. What approaches have been successful in ensuring site readiness? d. What inspection support / prep is provided to contract labs and TPMs utilized?

4. Inspection knowledge management to ensure continuous learning a. How do we improve readiness? b. Best practices for learning from near misses? c. How is right first time achieved during the observation response process? d. How is inspection experience shared within the company, across industry, and from

our raw material suppliers, contract labs, TPMs? e. Appropriate metrics to measure inspectional success? What’s the benchmark?

NOTES:

TABLE 8

TOPIC: Accelerated Development (Global Considerations) FACILITATOR: Catherine Anderson, Biogen SCRIBE: Lesley Redfern, AbbVie, Inc. SCOPE: Global regulatory convergence towards reduced development and approval time for potentially life-changing therapies is intended to enable earlier patient access. However, these reduced timelines also drive an urgent need to streamline pharmaceutical development and will require increased flexibility from both manufacturers and regulators. This Table will discuss the impact of global accelerated development programs on manufacturing process development and regulatory requirements. Table members will propose and consider mechanisms to condense development timelines, align on best practices for regulatory engagement, and identify key areas for industry advocacy. BULLET POINTS FOR DISCUSSION:

1. What is the Table’s experience with innovative manufacturing approaches to reduce development timelines?

2. What are the best practices for early and frequent interactions with regulators? 3. How can we manage quality with an evolving process and a limited dataset? 4. When is the optimal time for agency buy-in: early in development, during review, or as

post-marketing commitments or change management protocols? 5. How should we engage with regulators as a community?

NOTES:

TABLE 9 TOPIC: Characterization of Complex Vaccines FACILITATOR: William Egan, GlaxoSmithKline SCRIBE: Dan Some, Wyatt Technology Corporation SCOPE: Various complexities confound the characterization of vaccines. There is an inherent complexity in the majority of single antigens, for example, the micro-heterogeneity of glyco-conjugate vaccines; there is a complexity arising from the presence of multiple components in vaccine formulations, such as with the multi-valent pneumococcal vaccines or with the combination vaccines, such as the various DTaP vaccines combined with HepB, IPV, or Hib components; there is a complexity that arises from the use of adjuvants, as might, for example, arise from the adsorption of vaccine antigens onto aluminum salt surfaces. This Roundtable will discuss the impact of these various complexities on the characterization and control of vaccines. BULLET POINTS FOR DISCUSSION:

1. Traditionally, complexity has resulted in a reliance on in vivo assays for vaccine characterization and control, for example, in vivo potency assays for product release. Where, if anywhere, does complexity still present a barrier to the use of in vitro methods relative to in vivo methods? How might these barriers be addressed?

2. With regard to single vaccine antigens, are there complexities that seem to preclude adequate characterization through chemical, physical-chemical, or immuno-chemical methodologies?

3. With therapeutic proteins, post-translational modifications, particularly glycosylation, are frequently critical quality attributes. Has this been the case for vaccines, particularly given the wide range of cell substrates used in the production of many vaccines?

NOTES:

TABLE 10

TOPIC: Accelerating Late-Stage Development FACILITATOR: Graham Tulloch, Merck SCRIBE: Markus Bluemel, Novartis SCOPE: In recent years, many promising new therapies have been granted breakthrough status and expedited regulatory review. This has often necessitated an acceleration of late-phase development activities to assure these drugs are made available to the patient as soon as possible. This impacts CMC activities in different ways, e.g. reduced number of drug substance batches manufactured, shorter time to assess stability properties and critical quality attributes of the drug product, reduced experience with analytical QC methods prior to validation, new QC methods may be required prior to submission. This table will discuss strategies for successfully accelerating late-stage development. BULLET POINTS FOR DISCUSSION:

1. What are the major challenges in accelerated development a. Analytical method development b. Characterization of drug substance/ drug product c. Stability programs d. Manufacturing process development and characterization e. Coordination of technical activities f. Other?

2. How have challenges been overcome a. Parallel work streams b. Application of platform methods c. Application of platform processes d. Application of risk-management business processes to streamline development

activities 3. Can elements of marketing applications be provisional (e.g. preliminary acceptance criteria

for selected release & stability tests)? Does this vary in different regions (e.g. USA vs. Europe)?

4. Approach to utilizing interaction with regulators to align on strategy and content of regulatory filings

NOTES:

TABLE 11

TOPIC: CMC Challenges for Breakthrough Programs FACILITATOR: Heidi Zhang, Genentech, a Member of the Roche Group SCRIBE: Kazumi Kobayashi, Biogen SCOPE: Breakthrough therapy designation is “intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of serous or life-threating conditions.” However, accelerated drug development under a breakthrough designation can pose significant challenges to the chemistry, manufacturing, and controls (CMC) area. This round table aims to discuss the CMC challenges for BT designated programs and brainstorms practical solutions for addressing them.

BULLET POINTS FOR DISCUSSION:

1. Where to do more and where to do less 2. Stability program, method validation, specification development 3. Prioritization of CMC efforts and tasks to meet shortened development timeline 4. Innovation through QbD, continuous manufacturing, real time release 5. Perspectives from small companies

NOTES:

TABLE 12 TOPIC: Biosimilars FACILITATOR: Emily Shacter, ThinkFDA SCRIBE: Chi-Ting Huang, BioAnalytix, Inc. SCOPE: Hot topics and common problems in Biosimilars development and approval BULLET POINTS FOR DISCUSSION:

1. What are some of the problems that you are facing in development of a biosimilar? 2. Are there communications from the FDA that are you having trouble understanding? 3. What the heck is FDA’s goal with their proposed Tiering system

NOTES:

TABLE 13 TOPIC: Biologics Process Control FACILITATOR: Bryan Silvey, Baxalta US Inc SCRIBE: St.John Skilton, SCIEX SCOPE: Biotherapeutics are complex chemical entities requiring equally complex manufacturing processes. Process control within the manufacturing setting is critical to high quality product and predicable supply of these therapies to patients. In this Roundtable we will discuss topics of relevance to process control and potential CMC content that supports product approval/post-approval changes. Control topics may include Target Product Profile (TPP), CQAs and CPPs, as the foundation blocks for manufacturing. Inclusive are analytics and methods of process monitoring (In-line, on-line, automation, etc.) that provide real-time control. CMC regulatory content strategies will be discussed for best practices. BULLET POINTS FOR DISCUSSION:

1. How does TPP translate into the process control design? What stage in process development is this final and is the ‘blue print’ for manufacturing?

2. What CQAs and CPPs selection process functions effectively in process control points for Manufacturing to use in the ‘real world’? Are these CMC / Established Conditions?

3. As Process knowledge increases with manufacturing experience, how does or if CPPs evolve? As patient experience with the product (post Approval) is gained, how do CQAs and associated process controls evolve?

4. Discussions: a. CMC changes and report ability challenges b. Incorporation of improvements in process monitoring for control, example in-

line/on-line analytics. Regulatory strategies and best practices c. Process analytics of the future – CMC strategies, and the value add to

Manufacturing 5. Process Impurity profile, upstream to downstream, - is it a CQA or CPP, or both!?

NOTES:

TABLE 14

TOPIC: Setting Phase Appropriate Specifications FACILITATOR: Samir Sane, Genentech, a Member of the Roche Group SCRIBE: Ping Hu, Janssen R&D LLC SCOPE: Drug Substance and Drug Product specifications are important components of overall control strategy to ensure safe and consistent product supply during different phases of clinical development. Specifications typically evolve during development as the sponsors gather more clinical experience, characterization data, and manufacturing experience. Participants at this table will exchange experiences and ideas related to setting product specifications at different phases of clinical development.

 

BULLET POINTS FOR DISCUSSION:

1. Typical CoA assays for early stage and late stage programs 2. Rationale for starting with wider specifications in early development and tightening as

product moves to late stage and launch 3. Suitability of “report” as a specification 4. How to leverage “platform” level data while setting specifications? 5. What type of feedback/questions have sponsors received from health authorities on IND

applications and amendments? 6. Considerations for global filings - Pros and cons of having common control system for all

countries vs country/region-specific control system

NOTES:

TABLE 15

TOPIC: Identity Testing to Support Lot Release FACILITATOR: Mark Schenerman, MedImmune, A member of the AstraZeneca Group SCRIBE: Catherine Eakin, Seattle Genetics SCOPE: Identity testing is a key aspect of lot release testing because it verifies the protein being dosed is appropriate to the patient. In a multi-product fill/finish facility, it is particularly important to verify the identity of the biopharmaceutical product to ensure that the right product has been filled into the right vial/syringe. Many different approaches to identity testing are used including physicochemical, biophysical, and biological analysis or a combination of techniques. Rapid immunological approaches have also been used effectively in facilities that have limited testing equipment available. All identity testing must be validated to ensure that it is suitable for its intended use. Identity testing is also useful when working with law enforcement agencies to resolve investigations of “falsified medicines”. BULLET POINTS FOR DISCUSSION:

1. What approaches can be used for identity testing? 2. What challenges have been encountered and how were they resolved? 3. What is the experience with using “fingerprint” approaches such as peptide mapping? 4. What is the experience with using rapid immunological approaches? 5. What has been the regulatory agency feedback on identity testing? 6. What are the advantages/disadvantages to “platform testing” for identity? 7. What is the experience with validation of identity tests? 8. How can rapid identity testing be used to assist law enforcement investigations of falsified

medicines? 9. What other alternatives to current testing can be envisioned for the future?

NOTES:

TABLE 16

TOPIC: Raw Material Testing, Enough is Enough! Or is it? FACILITATOR: Joseph Siemiatkoski, Criterion Consulting SCRIBE: Shannon Holmes, Biogen SCOPE: This round table will attempt to answer the question: “How much characterization is required for a given raw material, really?” BULLET POINTS FOR DISCUSSION:

1. How do you stratify materials for level of incoming inspection? a. How many categories do you try to work with? b. What makes a material “critical”, “not so critical,” or “non-critical” for a given step

in the process? c. Which material innately require extra scrutiny?

2. How do you justify the testing for the different categories of material? a. Extensive characterization and process impact studies for critical materials? b. CoA review and identity testing for non-critical material?

3. How differently do you treat upstream materials from downstream materials? 4. How do you set acceptance limits if you have only used one or two lots of a given material?

a. Do you perform additional studies to better define ranges? b. What triggers those study – cost, perceived risk, something else?

5. Have you used Risk Assessment tools for raw material testing? 6. What would “phase appropriate” raw material testing plans look like?

NOTES:

TABLE 17 TOPIC: Control and Characterization of Host Cell Proteins and Residual DNA FACILITATOR: Tam Soden, Janssen R&D, a Member of the Johnson & Johnson Family SCRIBE: Demetra Macheras, AbbVie, Inc. SCOPE: Different host cells are used in the production of biological products (mammalian, insect, and plant cells). These host cells synthesize an entire repertoire of proteins which are essential for their own function and survival. Manufacturing processes are designed to produce recombinant therapeutics with a high degree of purity. This table aims, through open discussion amongst participants, to provide a scientific update on recent progress made in areas related to how these residual impurities (HCP and residual DNA) are being controlled and characterized.

BULLET POINTS FOR DISCUSSION:

1. Current technologies for detecting, and characterization of, residual impurities: a. What has been working and where is the need for better technology? b. Are you aiming for qualitative analysis or quantitative analysis? c. What is the LOD/LOQ of your methods, how low do you need to go, and for certain

technologies (i.e. LC-MS) how do you use the data since different runs and preparations will detect different numbers of HCPs with the same sample?

d. How do you identify ‘high risk’ residual impurities (i.e. that may co-purify with the product)?

e. Measuring the response of patients to residual impurities; clinical consequences 2. Approaches to control residual impurities during process development and manufacturing,

including purification, DP, and device development a. Where and how do you apply these assays during product development? b. How is the data used in setting specifications in the control system? c. Can they be dropped once process validation of the commercial process

demonstrates robust clearance; what are your success stories with different HAs? d. How do you monitor residual impurities during process development: continuous

on-line monitoring vs. periodic (or just end point) off-line monitoring? e. Setting limits for residual impurities: safety vs. manufacturing capability, targets,

trends and reject limits f. How do you approach comparability in light of your methods when you make

upstream and downstream process changes? 3. Demonstrating residual impurity clearance during process development and manufacturing

i.e. spike and challenge studies and material used for such studies 4. Incidence or examples that residual impurities are directly linked to imunogenicity, safety,

or tolerability of the product

TABLE 18

TOPIC: Low Endotoxin Recovery FACILITATOR: J.R. Dobbins, Eli Lilly and Company SCRIBE: Allison Torgesen, Seattle Genetics, Inc. SCOPE: Low endotoxin recovery (LER) is continuing to be a hot topic and is presenting challenges in the development of control strategies to support the commercialization of biological products. This round table will serve an interactive forum to discuss current issues and learning across industry and regulators as we continue to navigate the LER journey. BULLET POINTS FOR DISCUSSION:

1. What have we learned about the mechanism of LER? 2. What have we learned about the impact of the product matrix on LER? Impact of the

product, buffer, surfactant and other factors? 3. What have we learned about the endotoxin methodology? Have alternatives to USP <85>

been identified / implemented for routine testing? 4. What continues to be the major challenges associated with LER?

TABLE 19

TOPIC: Lessons learned from QbD FACILITATOR: Mia Kiistala, Biogen SCRIBE: Penny Davis, Biogen SCOPE: Quality by Design (QbD) has been defined as ‘a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management’. QbD concept has been applied to development and manufacture of biotherapeutics and biosimilar products. QbD can be applied at different stages of biological product development: during initial development stage, to establish a process design space, and for establishment of control strategy. This table discussion will seek to discuss recent experiences in QbD initiatives and lessons learned from them. How has QbD been applied at different stages of product development? What has worked with QbD and what were the lessons learned? BULLET POINTS FOR DISCUSSION:

1. Product design space for initial development. a. Setting the stage for later phases of QbD by intelligent molecular design. b. Lessons learned from application of QbD for biosimilar products that may be

beneficial in development of originator products. 2. Process design space for commercial manufacture

a. Models established for design space. Considerations for moving the models from small scale to commercial scale.

b. Implementation of process analytical technology for enhanced process control. 3. Control strategy for lot release and stability testing

a. Realizing the benefits of increased product and process understanding through reduced end product testing. Recent examples and lessons learned.

NOTES:

TABLE 20

TOPIC: Blood Analytics FACILITATOR: Laurent Siret, LFB USA SCRIBE: Max Fernandez, Baxalta SCOPE: The development of complex blood proteins, either plasma-derived or produced from recombinant DNA technology, requires an extensive panel of analytical techniques for their characterization and quality control. This table will be dedicated to the approach used to characterize and control these complex products, with focus on structural characterization, heterogeneity and purity assessment.

BULLET POINTS FOR DISCUSSION:

1. Criteria for establishing and testing the CQAs for blood products. 2. Key analytical technologies for blood products. 3. To which extent innovative analytical technologies developed for biotechnological blood

products could benefit to the characterization of plasma-derived products.

NOTES:

TABLE 21

TOPIC: Structure/Function Characterization FACILITATOR: Mike Lewis, Janssen R&D, LLC SCRIBE: William Matousek, Regeneron SCOPE: This table will discuss how to connect primary and higher order protein structure with biological function and clinical performance. In addition, how is this information utilized for critical quality attribute (CQA) assessment and analytical control strategy development. BULLET POINTS FOR DISCUSSION:

1. How do you establish protein structure/function relationships? How do you incorporate the information from mechanism of action, preclinical / clinical studies and immunogenicity assessment?

2. What challenges have you experienced in developing structure/function relationships? What novel approaches have you utilized to overcome these challenges?

3. What types of forced degradation studies are informative for CQA assessment? If significant changes are observed under forced degradation conditions, but no change is seen under intended storage conditions, how do you categorize and report those changes?

4. At what stage of development do you perform comprehensive S/F characterization? How do companies balance the desire to acquire more information on a new molecular entity with the need to limit resource investment prior to POC?

5. How do you incorporate this information into CQA assessment and control strategy development? What levels of details should be included in the filing?

6. What strategies are being used to the establish structure/function relationships for bispecific molecules, multi-domain proteins, ADCs or vaccines?

NOTES:

TABLE 22

TOPIC: Developing Bi-specifics FACILITATOR: Trevor Swartz, Genentech, a Member of the Roche Group SCRIBE: David Lee, Abbvie, Inc. SCOPE: Many bispecifics utilizing multiple formats are in varying stages of development. This session will focus on the development of bispecifics from early development to late stage development. Participants to discuss developing control strategies, developing characterization tools, and sharing unique challenges of developing bispecifics. BULLET POINTS FOR DISCUSSION:

1. Discuss various formats in development and challenges of these formats. Selection of molecule design (considerations for PK, immunogenicity, physicochemical properties, etc.).

2. Discuss bispecific analytical challenges (for example: impurities and associated analytical challenges, potency assay and control systems unique to bispecifics).

3. Discuss any unique characterization that is performed for bispecifics compared to standard mAbs during different stages of technical development.

4. Unique PC/PV challenges for bispecifics entering late stage development and/or accelerated clinical plans?

5. Clinical experience with bispecifics and any differentiating factors compared to the knowledge of mAbs in the industry.

6. Other bispecific challenges?

NOTES:

TABLE 23 TOPIC: Biopharmaceutical Knowledge and Data Management FACILITATOR: Dorian Zoumplis, MedImmune SCRIBE: Tim Schofield, MedImmune SCOPE: Information systems supporting the biotechnology industry have grown at a remarkable pace, while the cost of complex analytics decreases. This changing landscape provides faster, more comprehensive utilization of data-producing tools, but presents the challenge of managing all of those newly available data. Analyzing large amounts of data throughout the research, development, clinical and commercial lifecycle to derive meaning and drive decisions is an even bigger challenge. This table will discuss industry trends and challenges of managing, analyzing, and interpreting scientific data. BULLET POINTS FOR DISCUSSION:

1. Analytics of complex data sets a. Next Gen sequencing b. Structural/Visual c. Method & process development, performance, and improvement

2. Compliance a. Rounding b. Accuracy/Integrity c. Regulatory acceptance d. Alert, control, specification limit setting

3. Impact of costs (genome sequencing today vs. a decade ago) 4. Architecture & systems

a. Parallel interfaces b. Standardized formats c. System validation d. Infrastructure challenges of big data (e.g. file size) e. Hardware/cloud/accessibility and the importance of real-time data collection

5. Interpretation of data into meaning 6. Predictive vs. explanatory tools 7. Future capability and challenges

NOTES:

TABLE 24

TOPIC: Small Company Concerns FACILITATOR: Carol Krantz, ProNAi Therapeutics SCRIBE: Jeff Staecker, BioPhia Consulting Inc. SCOPE: The small company faces many challenges in the competitive landscape of product development. The primary one is the limited number and expertise of individuals forming the company which promotes a reliance on external resources. Not far behind is the challenge to capture the attention of and the funding from an executive committee that may not appreciate the advantage of understanding the process and product early in development and before clinical data may be available. This table discussion will seek to share best practices and solutions to the challenges of limited staff, limited funding, reliance on outside expertise which may also share the same issues. The goal is to establish some best practices that will help small companies streamline product and process development to support successful commercialization in standard and accelerated scenarios. BULLET POINTS FOR DISCUSSION:

1. How to make the case to spend on CMC before clinical data are in a. Risk-based approach to prioritize – what does this look like? b. How and to what extent to build in QbD when just starting up

2. What are the most cost effective, robust methods for Regulatory Intelligence? a. In-house regulatory specialists? b. Reg Intel services (e.g. Cortellis)? c. Consultants? d. Frequent meetings with Health Authorities? e. Combinations of any of the above and what would magic mix be?

3. Pipeline and Franchise expansion – when and how fast? a. What are critical elements to support bringing in new products and expanding the use

of the existing products? b. How to support late-stage/commercial and life cycle management?

4. The Challenges of Outsourcing a. What kind of staff are “must-haves” in-house and which staff can be contracted? b. What are benefits and pitfalls of technical expertise residing at CMO? c. What are pros and cons of centralizing test vs. testing at CMO? d. How to solve limitations on throughput? e. Are there any resources or software solutions that can facilitate outsource management

TABLE 25

TOPIC: Use of Public and Proprietary Databases when Characterizing Host Cell

Proteins with Mass Spectrometry FACILITATOR: Denise Krawitz, Genentech, a Member of the Roche Group SCRIBE: Jan Amstrup, Novo Nordisk SCOPE: Over the past decade, mass spectrometry has become an important tool in characterization of host cell proteins (HCP) during process development and in drug substance. Advances in genome sequencing have enabled this revolution in how we identify co-purifying HCP impurities. However, our ability to accurately identify and quantify HCPs is dependent on the quality of the database used for data searching. The quality of different genome databases varies significantly. For example, the E. coli genome database is fairly well characterized and annotated, and is a powerful tool for HCP characterization in E. coli-derived products. However, the CHO genome remains more of a challenge for industry due to heterogeneity, lack of annotation, and errors in the published genomes. This table will discuss how we are using databases industry-wide as part of HCP characterization with mass spectrometry. We will also discuss how comparative proteomics experiments can be evaluated when using genomes that have not been well annotated, such as CHO. BULLET POINTS FOR DISCUSSION:

1. How are searches conducted?

a. Software, databases b. Iterative searching?

2. Comparative proteomics a. Comparisons of large proteomic datasets- how is this accomplished using data from

different databases b. Publically available software tools c. Proprietary software tools

3. Identify what expression systems are used in addition to CHO and E. coli a. What public database resources are available? b. Is the quality of the database known/understood? c. Current research efforts to improve database quality

4. How does database quality limit ability to identify proteins by mass spectrometry a. Impact of annotation quality and errors b. Mechanisms to improve the database quality c. Public vs proprietary databases

Roundtables

Wednesday, January 27, 2016 15:45 – 16:30

We are excited about the expansion of the roundtable discussions for WCBP this year. The plan is for these to be active discussions, not presentations or lectures. There are 27 roundtable topics with 12 seats to a table. Seating will be on a first come, first serve basis. These roundtables will include a facilitator, whose role is to help assist the discussion and ensure a lively exchange, and a scribe, whose role is to make general, anonymous notes about the discussion so others can have a chance to view the discussion even if they could not participate. The discussion notes will be posted to the CASSS Website within a three week period after WCBP ends for all CASSS members to access. Listed Below is a quick view of the Roundtable Topics and the Designated Meeting Room. Roundtable Definition Scope, Facilitator and Scribe names for each table number are listed behind this sheet. Chinese Room

District Room East/State Room Palm Court Room

TABLE 1

TOPIC: Comparability Issues in Biological Products in Regards to Changes in Critical Raw Materials, Process and Assay

FACILITATOR: Steve Raso, Biogen SCRIBE: Fiona Cornel, Health Canada SCOPE: It is often necessary or highly desirable to make changes in critical raw materials, the manufacturing process or assay methods used in the production and testing of biological drug substances and drug products. Whenever such CMC changes are implemented, a comparability assessment must be performed to demonstrate that the product, pre and post-change, is the same with respect to quality, safety and efficacy. This assessment is prospectively planned and documented in a protocol that describes the process changes that are covered and specifies the testing plan, analytical methods and acceptance criteria used to demonstrate that the specified changes do not adversely affect the product. This table discussion will seek to elucidate the regulatory expectations of comparability assessments, and their respective protocols, with a goal toward an appropriate and uniform approach to such studies. BULLET POINTS FOR DISCUSSION:

4. How to determine the overall comparability plan a. Risk-based approach b. How to define scope of testing plan c. Comparability criteria vs. specifications d. At what stage should regulatory agencies be addressed/notified? Based on

significance of proposed change? 5. How to establish acceptance criteria/ranges

a. Statistical methods? b. What to do when historical data are limited? c. How to handle non-numeric results (e.g. spectroscopic data)?

6. Phase-appropriate comparability assessments a. How to support process changes during clinical trials? b. How to support late-stage/commercial and life cycle management?

NOTES:

TABLE 2 TOPIC: Control and Characterization of Biotherapeutic Glycosylation and Other

PTMs FACILITATOR: Philippe de Vilmorin, Biogen SCRIBE: Reed Harris, Genentech, a Member of the Roche Group SCOPE: Biotherapeutics are heterogeneous by nature, with variance in glycosylation one of the main sources of variation. During this session we’ll discuss strategies for characterizing and controlling PTMs. Characterization topics may include assay selection and timing, and how data is used to drive process development and establishment of a control strategy. Control topics may include choice of expression host, cell line selection, and cell culture/purification processes. BULLET POINTS FOR DISCUSSION:

6. What’s the basis for the target product profile with respect to PTMs? Theoretical biology, empirical biology, comparability, biosimilarity?

7. What metrics are used to summarize complex product quality attributes? Has the use of summary attributes masked variation or had other unintended consequences?

a. Site-specific vs. total for oxidation, glycation, etc. b. Glycosylation – Galactosylation, fucosylation, total high mannose, total sialic acid

8. Discuss strategies for controlling PTMs: a. Cell line development – host selection, host engineering, clone selection b. Cell culture process – additives, metabolic control, production step duration c. Downstream process – chromatography, synthetic modification

9. How early during development is information about PTMs obtained? Are there opportunities to inform molecule or clone selection based on this information?

10. How early during the manufacturing process is information about PTMs obtained? Are there opportunities for feed-back or feed-forward process control to minimize variation?

NOTES:

TABLE 4 TOPIC: Forced Degradation Studies: Best Practices & Strategies FACILITATOR: Charles Morgan, Genentech, a Member of the Roche Group SCRIBE: Karen Lee, Genzyme, A Sanofi Corporation SCOPE: A concept paper on forced degradation of therapeutic proteins was recently issued (Sep 2015) by a working group within the European Biopharmaceutical Enterprises. This roundtable will leverage this concept paper as a starting point for further discussion. Forced degradation studies (FDS) are performed to determine possible product degradation pathways under various physical and chemical stress conditions. Most frequently FDS are designed to achieve the following goals

• Selection of stability indicating analytical methods • Understanding of possible degradation pathways and impact to quality attributes • Selection of drug candidates in research • Formulation and manufacturing process development • Comparability assessments.

BULLET POINTS FOR DISCUSSION:

4. What is the purpose of conducting FDS? Where do they provide the most valuable information?

5. What are the common pitfalls and areas for improvement? a. If a high stress condition is required to induce a measureable change, does this say

anything meaningful about the likely degradation pathway under conditions for production, storage and transportation?

b. If no change is observed, is the molecule stable or is the analytical method insensitive?

c. Is the assessment limited to physical and chemical stress conditions or is there value in studying in vivo degradation routes (e.g. serum and plasma).

6. What are the regulatory perspectives and feedback on FDS? Where in the regulatory dossier is the information typically presented and at what phase of development?

NOTES:

TABLE 5 TOPIC: Potency Assays: Cell Based vs. Non Cell Based Formats FACILITATOR: Sally Seaver, Seaver Associates LLC SCRIBE: Cheryl Blaise, Bristol-Myers Squibb Company SCOPE: A test for “potency” is one of the required, listed tests (21CFR610.10) and which “shall consist of either in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in 600.3(s). 21CFR600.3(s) defines “potency” as “the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.” In other words a potency test shows that the sample/lot/batch is “active”. Originally most potency tests were in vivo (animal based) but as biological/biotech products became “well characterized” in vivo tests were replaced with in vitro (cell based) tests. The later are more accurate, precise, faster and more reliable. Now many groups start with non-cell based assays such as binding to an antigen, receptor or other target molecule, which they find to be even more reliable (faster, more accurate and precise). Many regulators consider the non cell based test not a true test of potency. BULLET POINTS FOR DISCUSSION:

6. Does your company have platform formats for potency tests whether cell and non-cell based? How many formats does your company consider for binding tests? For cell based tests?

7. When do you start work on cell based potency tests? Non-cell based tests. How do you show (or do you show) that the binding test leads to a desired therapeutic action?

8. If you have several cell or non-cell based tests, how do you choose which one(s) a. To qualify toxicology material? b. For early clinical material? c. For pivotal clinical trial material? d. To submit for approved product material?

9. As you transition between cell based and non-cell based formats, what does your company do to show the comparability of the old and new formats?

a. Before tox lots b. Before clinical lots c. Before pivotal clinical lots d. After approval

10. How does the qualification of operators for the specific test formats change? a. Before tox lots b. Before clinical lots

c. Before pivotal clinical lots d. After approval

NOTES:

TABLE 6 TOPIC: The Holy Grail: Global Specifications FACILITATOR: Roberto Rodriguez, Bristol-Myers Squibb Company SCRIBE: Helena Madden, Biogen SCOPE: From its inception, the International Conference for Harmonization (ICH) has provided a more consistent approach to most aspects of pharmaceutical and biopharmaceutical development. The efforts of the committee, among many other achievements, have resulted in significant progress towards a reduction in the variability for Health Authority (HA) requirements from country-to-country and a more homogeneous, risk-based approach to development and manufacturing of medicines across the industry. A key element of the published ICH guidances is the idea that product development should generate the process and product knowledge required to establish the safety and efficacy of a product, and its consistent manufacturing. Both the product and process knowledge play key roles in the generation of commercial specifications at the end of development through the identification of product Critical Quality Attributes (CQAs) and the process parameters that affect them. A robust battery of tests should be in place to monitor the quality and stability of the product with particular emphasis on the CQAs. Appropriate limits justified with data are selected and negotiated with Health Authorities. Too frequently, however, the requirements for specifications introduce discrepancies in the release and storage of product when intended for multiple markets. Even minor differences on specifications can introduce significant complexity to areas such as manufacturing, supply management and regulatory filings. The round table on “The Holy Grail: Global Specifications” will provide a (small) forum to identify and discuss the most common differences on specifications requirements, the resulting challenges, and approaches commonly used to remain complaint in a global market. The questions below are intended to stimulate discussion by the participants. BULLET POINTS FOR DISCUSSION:

6. What are the most common differences in specification limits and justification required for global products during development and at licensure?

7. What are the most common/problematic dissimilarities in tests/methodology required by the different HAs?

a. Are there any (MUST have) tests that apply to some countries/regions and not others?

b. Are there significant differences in justifying removal of tests? c. Are there differences on acceptable methodology (e.g. identity test by peptide

mapping vs. other approaches)? 8. Are there major differences on acceptability of control strategy (when and where in the

process tests are performed)? 9. Are there significant differences on life-cycle management? Is the bar higher in some

countries/regions when specification changes are needed? What common approaches are

used to manage supply when specification changes approval in multiple countries is required?

10. What are the main differences on shelf-life assignment? Are different shelf-life (or use periods) provided when the same stability package is presented to HAs?

NOTES:

TABLE 7

TOPIC: Trends in Regulatory Inspections and Best Practices FACILITATOR: Jessica Snow, Bristol Myers Squibb Company SCRIBE: Ken Miller, MedImmune, a Member of the AstraZeneca group SCOPE: Regulatory inspections of GMP facilities is a routine part of doing business. The global regulatory landscape is evolving, as evidenced in shifting inspectional focus, joint inspections and revised guidelines. This discussion will provide an opportunity to evaluate current trends and focus topics from recent GMP inspections as well as to consider best practices for managing the inspection process (from preparation through response). The following questions are intended start and guide the discussion by the participants, with a goal of shared understanding of key learnings. BULLET POINTS FOR DISCUSSION:

5. Trends and emerging inspectional themes from HAs a. Different approaches and area of focus depending on the HA? b. Is there greater collaboration between HAs? c. Different focus depending on product and type of inspection?

6. Changes to HA requirements and guidelines (e.g. EMA) and impact on inspectional focus a. Have these revisions emerged as key topics during inspections? b. What are strategies for demonstrating data integrity? c. How are companies demonstrating their assessments of regulations and guidelines? d. Any challenges with compliance to revisions (e.g. EMA GMP guidelines)?

7. Inspection best practices (prior to and during inspections) a. What are effective logistics processes? Do these vary based on the HA? b. Pros and cons of real-time corrections during inspections c. What approaches have been successful in ensuring site readiness? d. What inspection support / prep is provided to contract labs and TPMs utilized?

8. Inspection knowledge management to ensure continuous learning a. How do we improve readiness? b. Best practices for learning from near misses? c. How is right first time achieved during the observation response process? d. How is inspection experience shared within the company, across industry, and from

our raw material suppliers, contract labs, TPMs? e. Appropriate metrics to measure inspectional success? What’s the benchmark?

NOTES:

TABLE 8

TOPIC: Accelerated Development (Global Considerations) FACILITATOR: Catherine Anderson, Biogen SCRIBE: Lesley Redfern, AbbVie, Inc. SCOPE: Global regulatory convergence towards reduced development and approval time for potentially life-changing therapies is intended to enable earlier patient access. However, these reduced timelines also drive an urgent need to streamline pharmaceutical development and will require increased flexibility from both manufacturers and regulators. This Table will discuss the impact of global accelerated development programs on manufacturing process development and regulatory requirements. Table members will propose and consider mechanisms to condense development timelines, align on best practices for regulatory engagement, and identify key areas for industry advocacy. BULLET POINTS FOR DISCUSSION:

6. What is the Table’s experience with innovative manufacturing approaches to reduce development timelines?

7. What are the best practices for early and frequent interactions with regulators? 8. How can we manage quality with an evolving process and a limited dataset? 9. When is the optimal time for agency buy-in: early in development, during review, or as

post-marketing commitments or change management protocols? 10. How should we engage with regulators as a community?

NOTES:

TABLE 9 TOPIC: Characterization of Complex Vaccines FACILITATOR: William Egan, GlaxoSmithKline SCRIBE: Dan Some, Wyatt Technology Corporation SCOPE: Various complexities confound the characterization of vaccines. There is an inherent complexity in the majority of single antigens, for example, the micro-heterogeneity of glyco-conjugate vaccines; there is a complexity arising from the presence of multiple components in vaccine formulations, such as with the multi-valent pneumococcal vaccines or with the combination vaccines, such as the various DTaP vaccines combined with HepB, IPV, or Hib components; there is a complexity that arises from the use of adjuvants, as might, for example, arise from the adsorption of vaccine antigens onto aluminum salt surfaces. This Roundtable will discuss the impact of these various complexities on the characterization and control of vaccines. BULLET POINTS FOR DISCUSSION:

4. Traditionally, complexity has resulted in a reliance on in vivo assays for vaccine characterization and control, for example, in vivo potency assays for product release. Where, if anywhere, does complexity still present a barrier to the use of in vitro methods relative to in vivo methods? How might these barriers be addressed?

5. With regard to single vaccine antigens, are there complexities that seem to preclude adequate characterization through chemical, physical-chemical, or immuno-chemical methodologies?

6. With therapeutic proteins, post-translational modifications, particularly glycosylation, are frequently critical quality attributes. Has this been the case for vaccines, particularly given the wide range of cell substrates used in the production of many vaccines?

NOTES:

TABLE 10

TOPIC: Accelerating Late-Stage Development FACILITATOR: Graham Tulloch, Merck SCRIBE: Markus Bluemel, Novartis SCOPE: In recent years, many promising new therapies have been granted breakthrough status and expedited regulatory review. This has often necessitated an acceleration of late-phase development activities to assure these drugs are made available to the patient as soon as possible. This impacts CMC activities in different ways, e.g. reduced number of drug substance batches manufactured, shorter time to assess stability properties and critical quality attributes of the drug product, reduced experience with analytical QC methods prior to validation, new QC methods may be required prior to submission. This table will discuss strategies for successfully accelerating late-stage development. BULLET POINTS FOR DISCUSSION:

5. What are the major challenges in accelerated development a. Analytical method development b. Characterization of drug substance/ drug product c. Stability programs d. Manufacturing process development and characterization e. Coordination of technical activities f. Other?

6. How have challenges been overcome a. Parallel work streams b. Application of platform methods c. Application of platform processes d. Application of risk-management business processes to streamline development

activities 7. Can elements of marketing applications be provisional (e.g. preliminary acceptance criteria

for selected release & stability tests)? Does this vary in different regions (e.g. USA vs. Europe)?

8. Approach to utilizing interaction with regulators to align on strategy and content of regulatory filings

NOTES:

TABLE 11

TOPIC: CMC Challenges for Breakthrough Programs FACILITATOR: Heidi Zhang, Genentech, a Member of the Roche Group SCRIBE: Kazumi Kobayashi, Biogen SCOPE: Breakthrough therapy designation is “intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of serous or life-threating conditions.” However, accelerated drug development under a breakthrough designation can pose significant challenges to the chemistry, manufacturing, and controls (CMC) area. This round table aims to discuss the CMC challenges for BT designated programs and brainstorms practical solutions for addressing them.

BULLET POINTS FOR DISCUSSION:

6. Where to do more and where to do less 7. Stability program, method validation, specification development 8. Prioritization of CMC efforts and tasks to meet shortened development timeline 9. Innovation through QbD, continuous manufacturing, real time release 10. Perspectives from small companies

NOTES:

TABLE 12 TOPIC: Biosimilars FACILITATOR: Emily Shacter, ThinkFDA SCRIBE: Chi-Ting Huang, BioAnalytix, Inc. SCOPE: Hot topics and common problems in Biosimilars development and approval BULLET POINTS FOR DISCUSSION:

4. What are some of the problems that you are facing in development of a biosimilar? 5. Are there communications from the FDA that are you having trouble understanding? 6. What the heck is FDA’s goal with their proposed Tiering system

NOTES:

TABLE 26

TOPIC: Expectations for Control of Non-CQA (low risk) Attributes FACILITATOR: Sarah Demmon, Eli Lilly and Company SCRIBE: Daisy Richardson, Merck SCOPE: The analytical control strategy for bioproducts is highly complex and is centered primarily around critical quality attributes (CQA’s) of the product. There are a few properties such as charge heterogeneity and product related substances that may not be classified as a CQA, yet strict controls are often imposed by regulatory authorities. The goal of this table is to have an open discussion on the role of low risk quality attributes in the analytical control strategy and possible approaches to demonstrating control and understanding without strict routine release testing commitments.

BULLET POINTS FOR DISCUSSION:

1. Are there quality attributes that are routinely classified as low risk? Identify low risk attributes for further discussion.

2. Discuss examples of low risk quality attributes with tight controls (either self-imposed or through regulatory interactions)

3. What elements of the control strategy are used for assessing low risk attributes? How does the strategy change as the product progresses through the development lifecycle? (e.g., release testing, in-process testing, in-process controls, comparability, process validation, etc.)

4. Discuss charge heterogeneity and role in the analytical control strategy (measurement of process consistency vs. control individual variants). Are the properties of total acidic and total basic variants always viewed by regulators as CQA’s or is it molecule/indication specific? Do regulators tend to treat charge heterogeneity as more of a purity property rather than a measure of process consistency?

5. Early phase specification setting expectations – recent trend of being asked to set specifications on charge variants at early phase with limited batch experience

6. Discuss the pros and cons of gathering data on non-CQA properties during process development studies – necessary or a waste of valuable resources? Does this help the cause?

NOTES:

TABLE 27

TOPIC: Specifications for Combination Products FACILITATOR: Jamie Moore, Genentech, A Member of the Roche Group SCRIBE: Peter Johnson, 3M Drug Delivery SCOPE: This table will focus on specifications and strategies to develop control systems for combination products. BULLET POINTS FOR DISCUSSION:

7. Is it common to have control strategies for both drug and device? 8. Is the process for determining the control strategy for device the same as that for their drug

product? 9. What are notable similarities, differences and challenges (e.g. for determining CQA’s or

criteria for controls)? 10. How have companies reconciled the differences in device development (design controls

per 21 CFR 820 and risk management according to ISO14971) with drug development (pharmaceutical controls per ICH Q8 and risk management per ICH Q9) to establish their final control strategy of the drug-device combination product?

11. Does the device control strategy integrate well with traditional design controls req’d for the combination product?

12. Have companies submitted single integrated control strategies for the combination product (why or why not? challenges, advantages) and what are HA reactions/difficulties in looking at an integrated process and strategy.

13. What approaches for pCCI testing are used for Autoinjectors and PFS-NSDs? 14. When using 510(k) cleared and or CE marked devices, is there a focus on establishing a

control strategy for the finished combination product, and rely on their purchasing controls to confirm the device company has implemented the appropriate controls for the manufacture of the device specific components?

NOTES:

TABLE 28

TOPIC: Disposable Technologies FACILITATOR: Allison Lehtinen, Biogen SCRIBE: Patsy Lewis, Seattle Genetics SCOPE: FDA approved the first all sing-use/disposable facility (Shire facility in Lexington, MA USA) in early 2014. This table will discuss the benefits and challenges of using disposable technology, including the expectations from FDA. Participants will be asked to share how disposables are being used in their facilities and where expansion is occurring. QUESTIONS FOR DISCUSSION:

1. Are there areas where disposables are being scaled back/not considered? Why? Are there areas where they should not be employed?

2. Leachables and extractables studies are expectations. What studies have you done to look at leachables and extractables? Are you just relying on vendor data – how does that apply to what you are doing? What is the toxicity of the components found?

3. What studies have been done to demonstrate compatibility of the container with your materials?

4. What is the potential impact on stability of material; suitability for use – related to compatibility, what data supports the stability of the material being stored in the container? What data package is needed?

5. What is the impact of changes in polymer production process – are you seeing change controls from your vendor? How are you assessing that impact – risk assessment, technical studies, etc.?

6. With regard to availability of containers – what methods are you doing to qualify your suppliers and to ensure that there is sufficient supply for your production needs?

7. Are you changing from stainless steel to disposables? What information are you submitting to support the changes? What questions are you getting from regulators?

NOTES:

TABLE 29

TOPIC: Multi-Attribute Methods FACILITATOR: Zoran Sosic, Biogen SCRIBE: Scott Berger, Waters Corporation. SCOPE: This Table will discuss state of the art methods for multi-attribute monitoring for QC release and for on-line monitoring with feedback control using process analytical technology (PAT). Table members will discuss strategies for the introduction of new methods for advanced process control (APC) of biopharmaceutical manufacturing, as well as potential challenges in implementing novel analytical tools in manufacturing and QC environment. BULLET POINTS FOR DISCUSSION:

1. Identify requirements for selection of multi-attribute methods intended for QC release and those used for PAT monitoring within manufacturing facility

2. How knowledge of product critical quality attributes and manufacturing process can help with timely development and implementation of appropriate methods for advanced process control as applied to real time release testing.

3. How use of mathematical, predictive models based on quality by design principles can shift testing earlier in the manufacturing process and minimize number of classical, end-product release tests.

4. What are some of examples of analytical, multi-attribute methods or other informative methods that can be used for real time release testing?

NOTES:

TABLE 30

TOPIC: The Voyage of the BLA FACILITATOR: Kim Wolfram, Biogen SCRIBE: David Lee, AbbVie, Inc. SCOPE: Writing a Biological License Application (BLA) is an enormous task that takes many years of dedicated work by a large group of experts. Prior to embarking on the authoring process, it is imperative to have a detailed strategic plan to account for both planned and unanticipated events. During this session we will discuss best practices and pitfalls that have been identified during BLA preparations. Please come prepared with a list of challenges that you and your team have faced and how you overcome these obstacles. Please also share new ideas to increase efficiency and quality of the application. Of specific interest are strategies to meet the demands of expedited development, post-approval flexibility, and novel products. BULLET POINTS FOR DISCUSSION:

1. What data and information do you need prior to writing the BLA? What information do you add during the authoring?

a. Analytical method validation- b. Characterization and comparability data c. Stability how does your team account for ongoing studies? d. Process Validation- how does the team adjust to changing timelines? e. Other?

2. What are you biggest challenges with authoring in parallel to data collection? a. Have you overcome a poor reference standard strategy or non-representative

reference? b. When do you confirm your bioassay strategy? c. Did you identify missing tests during the review? d. How do you set specifications based on a limited data set? e. How have you minimized the impact of surprising comparability/analytical results?

3. What issues have resulted in delays to the review approval and/or significant post-market commitments? Does this vary in different regions (e.g. USA vs. Europe)?

4. How are you best utilizing pre-filing meetings to gain agreement on the data package and data gaps?

5. What are current reviewer pet peeves and/or trends that should be changed?

NOTES:

TABLE 31

TOPIC: How do you Define Ranges for Specifications and Comparability for Glycosylation Attributes in the Midst of Micro-heterogeneity?

FACILITATOR: Sean Evans, LFB USA, Inc. SCRIBE: Tim Schofield, Medimmune, A member of the AstraZeneca group SCOPE: The various glycan moieties, sialic acids, alpha 1,3-glycans, and afucosylation make it that there are no two batches that are identical.

BULLET POINTS FOR DISCUSSION:

1. Glycoprotein Analysis that may vary depending on the purpose: a. R&D process development b. Product characterization and comparability c. Release and stability testing

2. Modes of Glycoprotein Analysis a. Profile analysis b. Quantification of micro-heterogeineity c. Validation of modes of analysis

3. Link between glycoforms and biological activity, product safety and PK, based on overall nonclinical and clinical experience (CQA’s)

a. Antibody-dependent cell-mediated cytotoxicity (ADCC) b. Binding affinity c. Immunogenicity

4. Link between process and glycoform micro-heterogeneity a. Identification of Critical Process Parameters (CPP’s) & Robustness b. Process capabilities

5. ICH guidelines Q6B and Q5E, a. Micro-heterogeneity of 50iopharma products and regulatory expectations b. Justification of specifications and comparability acceptance criteria

NOTES:

TABLE 32 TOPIC: Viral Clearance and the Use of Advanced Technologies Such as NGS in the

Detection of Adventitious Agents in Biologics FACILITOR: Jeri Ann Boose, Eurofins Lancaster Laboratories, Inc. SCRIBE: Maura Kibbey, U.S. Pharmacopeia SCOPE: How to demonstrate viral clearance in the manufacturing process and the use of NGS to ensure absence of adventitious agents in the product. BULLET POINTS FOR DISCUSSION:

1. Current topics in Viral Clearance: a. The selection of worst-case virus models for viral clearance studies b. How much virus spike is appropriate? c. How pure should the virus spike be? d. Design space studies for viral clearance

2. NGS: a. Is NGS appropriate for use as a GMP lot release test? b. Cost and time required for use of NGS as a screening assay? c. Interpretation of results if only partial genomic fragments are found d. Qualification of testing labs and data analysis

NOTES:

TABLE 33

TOPIC: New Product Introduction (NPI) strategies at CMOs FACILITATOR: Ilona Reischl, AGES SCRIBE: St. John Skilton, SCIEX SCOPE: CMOs have multi-product lines. In many cases not all the equipment used is disposable. In addition, not all simple ID assays (short of a peptide map), are clearly demonstrated to be product specific against the world of other proteins which may be introduced onto the line. This table discussion will elaborate on how the industry addresses NPI with respect to identity testing. BULLET POINTS FOR DISCUSSION:

1. Who knows what? 3. Where is the overall information on manufactured products held? 4. How much information is given to clients, regulators by the CMO? 5. How much information is needed by clients, regulators? 6. How does multi-product manufacture impact on product specific manufacturing

information? 7. How does NPI impact on manufacturing information for existing products? 8. Overall strategy: 9. Measures to avoid contamination. 10. Facility design. Leaning validation. 11. Analytical control strategy. 12. Measures ahead of starting a new campaign. 13. Control measures during manufacture.

NOTES:

TABLE 34

TOPIC: Legacy Products and the Implementation of QbD FACILITATOR: Roman Drews, LFB USA SCRIBE: Paulien Groll, Baxalta SCOPE: Quality by design (QbD) is a science and risk based approach to product development, as described in the ICH guidance documents Q8, 9, 10, and 11. For legacy products, the development stages have been already finalized and the manufacturing processes established when QbD approach was recommended by the regulatory agencies and implemented by the industry. However, for most of these products a large quantity of historical data is available deriving from the commercial production of multiple lots. This includes variety of changes implemented into the process over time. In most cases, the impact of these changes on processes and products has been well documented. The captured knowledge from the routine manufacturing and process improvements allows better understanding of the relations between capability of the process, adequacy of the applied control strategy, and product quality attributes. This table discussion will focus how the QbD tools can be used to leverage historical manufacturing data to strengthen quality of final product and process consistency and facilitate continuous improvement over product life cycle. BULLET POINTS FOR DISCUSSION:

1. What are the most effective practices to collect and analyze product and process data? 2. How the implementation of “Continued Process Verification” (Validation Stage III)

program recommended by the FDA Process Validation guidance help to leverage the historical data to:

a. continuously update Control Strategy b. help assess Criticality c. improve process performance and product quality

3. Is the prior knowledge about the product and manufacturing process sufficient to identify criticality of product quality attributes and process parameters and to demonstrate link between them?

4. Could the applicability of QbD principles be limited by a class of a legacy product, e.g. complex plasma derived product vs. well characterized recombinant protein?

5. How implementation of Process Analytical Technology (PAT) to in–process measurements may facilitate implementation of QbD principles to better understand and control the manufacturing process?

NOTES:

TABLE 35

TOPIC: Analytical Challenges Related to Antibody-drug Conjugates

Characterization and Specifications FACILITATOR: Oscar Salas-Solano, Seattle Genetics SCRIBE: Brian Dipollo, AbbVie, Inc. SCOPE: Antibody-drug conjugates (ADCs) are becoming increasingly important therapeutic agents. ADCs are manufactured through the chemical linkage of a potent cytotoxic drug to a monoclonal antibody (mAb). As a result, ADCs leverage the selectivity of monoclonal antibodies (mAb) for targeted delivery of the cytotoxic drug while minimizing exposure to normal tissues. Generally, the conjugation process generates more complex and heterogeneous ADC structures than the corresponding parent mAb. ADC’s heterogeneity presents challenges to both the analysis of product quality attributes and setting of specifications. This table will discuss strategies to advance ADC characterization and facilitate the setting of specifications. BULLET POINTS FOR DISCUSSION:

1. The selection of appropriate analytical methods for a specific ADC depends on the properties of the drug-linker and the conjugation site (inter-chain cysteines, lysines, engineered cysteines, Fc glycans, etc.).

2. What quality attributes are relevant for ADCs? 3. How are you overcoming the characterization challenges of ADCs? 4. What novel methodologies can be applied to advance the physicochemical and biological

characterization of ADCs? 5. Which ADC attributes should be captured as part of the certificate of analysis verses

characterization and comparability?

NOTES:

TABLE 36

TOPIC: Validation of Rapid Microbiology Methods FACILITATOR: Stephanie Ramsey, Baxalta SCRIBE: Allison Torgesen, Seattle Genetics SCOPE: Rapid Microbiology methods are slowly being developed, validated and approved for use with products. The session will discuss strategies for approval and demonstration of suitability as compared to traditional approaches. BULLET POINTS FOR DISCUSSION:

1. Besides USP <1223>, Validation of Alternative Microbiological Methods, EP Chapter

5.1.6. Alternative methods for control of microbiological quality and PDA TR 33, Evaluation, Validation and Implementation of New Microbiological Testing Methods, are there any other standards industry is expected to use?

2. Regarding Comparability Studies, a. How is limit of detection handled? b. For RMMs that are qualitative –e.g. detection via fluorescence/particle size how do

you appropriately set your baseline levels? c. Regarding in-house isolates, is there an expectation to use more for RMM studies?

If so, how many more? d. Are stressed organisms required to be used as part of the study? e. Is there an expectation to always run traditional methods in parallel for a period of

time? f. What are some of the lessons learned from studies?

3. What are the key validation elements needed to have a successful submission? a. What are the requirements? b. What does a good submission look like?

4. Is it possible to eliminate “grab samples” if an on-line RMM system is implemented (i.e. on-line water system for bioburden)?

NOTES:

TABLE 37

TABLE 38

TOPIC: How to Characterize Polyclonal Products for Infectious Diseases. FACILITATOR: Jeffrey Staecker, BioPhia Consulting, Inc. SCRIBE: Catherine Eakin, Seattle Genetics SCOPE: Polyclonal products (intravenous immunoglobulins or IVIgs) that combat infectious diseases include new products where speed in development/production is critical to treat diseases such as Ebola to more established products used in treating primary immunodeficiency disease, influenza, Hepatitis B and other diseases. Critical characterization of these products may be donor selection and/or characterization of blood products from donors that might include pooling, purification, modification, and other manufacturing steps. Safety considerations may evaluation of donors, blood products, or processed material. Characterization utilized in preparation of materials for clinical evaluation may provide different information than what is needed for established products where identification of critical quality attributes are well understood relative to clinical efficacy. Examples provided below will be used to initiate discussion. BULLET POINTS FOR DISCUSSION:

1. Convalescent whole blood/plasma used for acute crisis such as Ebola outbreak. a. Identification of suitable donors. b. Donor information, consent and selection c. Donor’s blood grouping and screening for infections

2. Preparation of IVIG to influenza: a. Donor identification and plasma collection b. Quantification of antibody activity using laboratory assays c. Animal (mouse) studies d. Characterization of antibody specificity

3. Characterization of Hepatitis B Immune Globulin: a. Donor identification b. Screening of plasma for HBV, HBsAg, HIV, and HCV c. Final release testing for potency, total protein, pH, and sterility. d. Potency (international units) by comparison to WHO standard.

4. General considerations in characterizing polyclonal antibodies: a. Specificity b. Potency (cell-based or immunologic method) c. Importance of reference materials

NOTES: