Welcome to the CMC Strategy Forum Europe 2014 Improving Biopharmaceutical Product Quality: Moving Implementation Forward

Transcription

1 Welcome to the CMC Strategy Forum Europe 2014 Improving Biopharmaceutical Product Quality: Moving Implementation Forward The eighth annual CMC Strategy Forum Europe, organized by CASSS - An International Separation Science Society, will explore a number of critical topics focused on improving the quality in development and manufacturing of biopharmaceutical products. A series of plenary sessions and workshops led by experts from global regulatory agencies, academia and industry seek to explore emerging aspects of CMC technology and regulation in areas where existing modalities and systems are undergoing change. Plenary topics will include regulatory perspectives on the regulation of biopharmaceutical products and innovations and initiatives to accelerate product development and the regulatory implications. Workshops will provide the opportunity for in-depth discussions on comparability and similarity, quality assurance to ensure successful QbD submissions, regulatory guidance on biotech drug substance process validation and managing multi-site supply chains and registrations. The CMC Strategy Forum is designed to maximize dialog between participants. Presentations are relatively short and focused and set the agenda for the panel discussions to engage all the participants who have experience and expertise to share. It should be important for you to attend this event as we come together to discuss important issues on how to ensure product safety and efficacy for the patients we serve. Forum Co-Chairs: Niklas Ekman, Finnish Medicines Agency, Finland Jason Hampson, Amgen Limited, United Kingdom Martin Schiestl, Sandoz Biopharmaceuticals, Austria Scientific Organizing Committee: Brigitte Brake, Federal Institute for Drugs and Medical Devices (BfArM), Germany Emmanuelle Charton, EDQM, France John Dougherty, Eli Lilly and Company, USA (GSC Liaison) Chana Fuchs, CDER, FDA, USA Ralf Gleixner, F. Hoffmann-La Roche Ltd., Switzerland Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland Brendan Hughes, Bristol-Myers Squibb Company, USA Christopher Joneckis, CBER, FDA, USA Inger Mollerup, Novo Nordisk A/S, Denmark Enda Moran, Pfizer Ireland Pharmaceuticals, Ireland Ilona Reischl, BASG / AGES, Austria Mark Schenerman, MedImmune, USA (GSC Liaison) Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland Karin Sewerin, BioTech Development AB, Sweden Lance Smallshaw, UCB Biopharma srl, Belgium Paul Varley, MedImmune Limited, United Kingdom Jolanda Westerlaken, UCB Biopharma srl, Canada

2 The Scientific Organizing Committee gratefully acknowledges the program partners for their generous support of the CMC Strategy Forum Europe SUSTAINING DIAMOND PROGRAM PARTNER F. Hoffmann-La Roche Ltd. SUSTAINING PLATINUM PROGRAM PARTNER Biogen Idec SUSTAINING GOLD PROGRAM PARTNER AbbVie, Inc. SILVER PROGRAM PARTNERS Amgen Inc. Eli Lilly and Company MedImmune Novo Nordisk A/S BRONZE PROGRAM PARTNER Bristol-Myers Squibb Company

3 LEADING MEDIA PARTNERS BioProcess International International Pharmaceutical Quality MEDIA PARTNERS The Analytical Scientist BioProcessing Journal BioTech International Genetic Engineering & Biotechnology News LCGC North America separationsnow.com Technology Networks Limited Wiley / Journal of Separation Science

4 European Biopharmaceutical Enterprises (EBE) Satellite Session Monday, 5 May :00 09:00 Buffet Breakfast in Sala Sant Antonio 07:00 10:00 Buffet Breakfast (for accompanying guests) in Sala Sant Antonio 08:00 12:30 Registration in the Foyer Tritone 09:00 09:15 Welcome and Introduction to the European Biopharmaceutical Enterprises (EBE) Ongoing Activities and Initiatives in the Auditorium Tritone Enda Moran, Pfizer Ireland Pharmaceuticals, Ireland Concept Papers Update In the Auditorium Tritone Session Chairs: Ronald Imhoff, Janssen Biologics and Karin Sewerin, MedImmune Limited (consultant) 09:15 09:30 Draft Concept Paper on Forced Degradation Studies Annick Gervais, UCB Biopharma srl, Belgium 09:30 10:30 Panel Discussion Questions and Answers Stephane Cornen, Sanofi, France Annick Gervais, UCB Biopharma srl, Belgium John O Hara, UCB Biopharma srl, Belgium Mara Rossi, Merck-Serono, Germany Shahid Uddin, MedImmune Limited, United Kingdom 10:30 11:00 AM Break in the Foyer Tritone 11:00 11:15 Industry Perspectives on Visible Particle Requirements and Practices: An Overview of the EBE Position Paper Serge Mathonet, Sanofi, France 11:15 11:30 Case Studies for Control and Management of Visible Particles in Drug Product Andrew Lennard, Amgen Limited., United Kingdom 11:30 11:45 Semi-quantitative Method for Measuring Inherent Visible Particles in Protein Products Patricia Cash, MedImmune, USA

5 Monday, 5 May continued 11:45 12:15 Panel Discussion Questions and Answers Patricia Cash, MedImmune, USA Andrew Lennard, Amgen Limited, United Kingdom Hanns-Christian Mahler, F. Hoffmann-La Roche Ltd., Switzerland Serge Mathonet, Sanofi, France 12:15 12:30 Concluding Remarks Piers Allin, European Biopharmaceutical Enterprises (EBE), Belgium

6 12:30 13:45 Buffet Lunch in L Agrumeto Monday, 5 May continued CMC Strategy Forum Europe 2014 Scientific Program Summary 13:00 17:00 Registration in the Foyer Tritone 13:45 14:00 CASSS Welcome and Introductory Comments in the Auditorium Tritone John Dougherty, Eli Lilly and Company, USA Introduction / Welcome to the 8 th European CMC Strategy Forum Martin Schiestl, Sandoz Biopharmaceuticals, Austria Regulation of Biopharmaceutical Products: Regulatory Perspectives Plenary Session in the Auditorium Tritone Session Chairs: Jason Hampson, Amgen Limited and Martin Schiestl, Sandoz Biopharmaceuticals 14:00 14:30 Role of Official Medicines Control Laboratories (OMCL) in Assessing the Quality of Biologicals Carlo Pini, Istituto Superiore di Sanità, Italy 14:30 15:00 PMDA Perspective: Recent Trends in the Regulation of Biopharmaceuticals Takao Yamori, Pharmaceuticals and Medical Devices Agency (PMDA), Japan 15:00 15:30 FDA Perspective: Recent Trends in the Regulation of Biopharmaceuticals Sarah Kennett, CDER, FDA, USA 15:30 16:00 PM Break in the Foyer Tritone 16:00 16:30 FDA Perspective: Update on Vaccine Regulation Philip Krause, CBER, FDA, USA 16:30 17:00 Recent Regulatory Activities in Europe Ilona Reischl, BASG / AGES, Austria 17:00 18:00 Discussion - Questions and Answers 18:00 Adjourn 18:30 19:30 Hosted Networking Break in the Pagoda Pool Bar

7 Tuesday, 6 May :00 09:00 Buffet Breakfast in the Sala Sant Antonio 07:00 10:00 Buffet Breakfast (for accompanying guests) in the Sala Sant Antonio 08:30 17:00 Registration in the Foyer Tritone Comparability and Similarity A Practical Approach Workshop Session One in the Auditorium Tritone Session Chairs: Niklas Ekman, Finnish Medicines Agency and Thomas Schreitmüller, F. Hoffmann-La Roche Ltd. 09:00 09:05 Introduction 09:05 09:30 Comparability to Establish Biosimilarity Jan Visser, Sandoz Biopharmaceuticals, HEXAL AG, Germany 09:30 09:55 Justifying Manufacturing Changes for Established Products - The Comparability Approach Dieter Schmalzing, Genentech, a Member of the Roche Group, USA 09:55 10:20 EDQM Viewpoint on the Role of the Ph. Eur. in the Field of Biosimilars Mihaela Buda, EDQM, France 10:20 10:45 Comparability and Biosimilarity: An Assessor s View Martijn van der Plas, Medicines Evaluation Board, The Netherlands 10:45 11:15 AM Break in the Foyer Tritone 11:15 12:15 Panel Discussion Questions and Answers Mihaela Buda, EDQM, France John Dougherty, Eli Lilly and Company, USA Dieter Schmalzing, Genentech, a Member of the Roche Group, USA Martijn van der Plas, Medicines Evaluation Board, The Netherlands Jan Visser, Sandoz Biopharmaceuticals, HEXAL AG, Germany 12:15 13:30 Buffet Lunch in L Agrumeto The New Holistical Quality Assurance Philosophy: How Do We Ensure Successful QbD Submissions? Are There Regulatory and Legal Hurdles? Workshop Session Four in the Auditorium Tritone Session Chairs: Emmanuelle Charton, EDQM and Lance Smallshaw, UCB Biopharma srl 13:30 13:35 Introduction 13:35 14:00 Advancing the Promise of Analytics of the Future using Multi Attribute Methodology Anthony Mire-Sluis, Amgen Inc., USA

8 Tuesday, 6 May continued 14:00 14:25 The Impact of QbD on Quality Assurance and the Qualified Person Derek Murphy, MedImmune Limited, United Kingdom 14:25 14:50 How to Assure Quality and Consistency in an Evolving QbD Scenario: A Regulator s View Mats Welin, Medical Products Agency, Sweden 14:50 15:15 How the European Pharmacopoeia Provides the Framework to Implement QbD Principles Emmanuelle Charton, EDQM, France 15:15 15:45 PM Break in the Foyer Tritone 15:45 16:45 Panel Discussion Questions and Answers Brigitte Brake, Federal Institute for Drugs and Medical Devices (BfArM), Germany Sarah Kennett, CDER, FDA, USA Anthony Mire-Sluis, Amgen Inc., USA Derek Murphy, MedImmune Limited, United Kingdom John O Hara, UCB Biopharma srl, Belgium Mats Welin, Medical Products Agency, Sweden 16:45 Adjourn 17:30 21:30 Welcome and Networking Event at Francischiello Restaurant Transportation will be provided

9 Wednesday, 7 May :00 09:00 Buffet Breakfast in the Sala Sant Antonio 07:00 10:00 Buffet Breakfast (for accompanying guests) in the Sala Sant Antonio 08:30 17:00 Registration in the Foyer Tritone 08:45 09:00 Announcements by Jason Hampson, Amgen Limited The Continuing Evolution of Regulatory Guidance on Biotech Drug Substance Process Validation Workshop Session Two in the Auditorium Tritone Session Chairs: Brendan Hughes, Bristol-Myers Squibb Company and Mats Welin, Medical Products Agency 09:00 09:05 Introduction 09:05 09:30 EMA Guidance Documents on Process Validation Where Are We? Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark 09:30 09:55 Development of Integrated Control Strategies and PV Plans for US and European Filings Anthony Mire-Sluis, Amgen Inc., USA 09:55 10:20 Current Best Practices in the Definition of Process Parameters for Development of Control Strategies Ronald Bates, Bristol-Myers Squibb Company, USA 10:20 10:50 AM Break in the Foyer Tritone 10:50 11:50 Panel Discussion Questions and Answers Ronald Bates, Bristol-Myers Squibb Company, USA Robert Clemmitt, GlaxoSmithKline, United Kingdom Sarah Kennett, CDER, FDA, USA Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark Anthony Mire-Sluis, Amgen Inc., USA Preben Østfeldt, Novo Nordisk A/S, Denmark 12:00 13:15 Buffet Lunch in L Agrumeto Managing Complex, Multinational, Multi-site Supply Chains and Registrations Workshop Session in the Auditorium Tritone Session Chairs: Robert Lichtneckert, F. Hoffmann-La Roche Ltd. and Jolanda Westerlaken, UCB Pharma sprl 13:15 13:20 Introduction 13:20 13:45 The Effects of Supply Chains when Global Markets are Fragmented Reb Russell, Bristol-Myers Squibb Company, USA

10 Wednesday, 7 May continued 13:45 14:10 The Challenges of Global Reach for a Mid-size Biopharma Company Nathalie Forrer, UCB Biopharma srl, Belgium 14:10 14:35 The Ever-increasing Complexity of Biotech Changes A Pledge for Global Convergence Susanne Ausborn, F. Hoffmann-La Roche Ltd., Switzerland 14:35 15:00 PM Break in the Foyer Tritone 15:00 16:00 Panel Discussion Questions and Answers Susanne Ausborn, F. Hoffmann-La Roche Ltd., Switzerland Nathalie Forrer, UCB Biopharma srl, Belgium Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Reb Russell, Bristol-Myers Squibb Company, USA Annette Toft, Novo Nordisk A/S, Denmark Looking to the Future: Innovations and Initiatives to Accelerate Product Development and Regulatory Implications Plenary Session in the Auditorium Tritone Session Co-Chairs: Brigitte Brake, BfArM and Paul Varley, MedImmune Limited 16:00 16:05 Introduction 16:05 16:30 Accelerated Path to Probe the Biology through Deferred Cloning and Applying Platform Manufacturing Processes Rohini Deshpande, Amgen Inc., USA 16:30 16:55 Accelerating Clinical Evaluation of Biotherapeutics: Can Cost, Speed and Throughput be Improved without Compromising Quality? Tanya Shang, Pfizer Biotherapeutics Pharmaceutical Sciences, USA 16:55 17:20 Accelerating Drug Development to FTIH: Potential of New Expression Technologies Lekan Daramola, MedImmune Limited, United Kingdom 17:20 18:00 Panel Discussion Questions and Answers Louis Berth, Novo Nordisk A/S, Denmark Lekan Daramola, MedImmune Limited, United Kingdom Rohini Deshpande, Amgen Inc., USA Philip Krause, CBER, FDA, USA Tanya Shang, Pfizer Biotherapeutics Pharmaceutical Sciences, USA 18:00 18:15 Closing Remarks and Invitation to CMC Strategy Forum Europe 2015 Mark Schenerman, MedImmune, USA 18:15 Adjournment

11 EBE Satellite Session Concept Papers 2014 Update Draft Concept Paper on Forced Degradation Studies Annick Gervais UCB Biopharma srl, Belgium Forced Degradation Studies can be used to gain information for different purposes: to determine possible degradation pathways of a biotechnological/biological product by applying various stressing agents such as light, temperature, chemical or mechanical agents. This can therefore help understanding Critical Quality Attributes (CQA) of a Drug Substance or a Drug product to demonstrate specificity of stability indicating methods to characterize product-related species and product-related impurities to understand whether accidental exposures to conditions other than those proposed (eg during transportation, temperature excursions) are deleterious to the product Hence these studies are important to: select appropriate analytical methods help choosing a new molecule candidate from research understand manufacturing process development design formulation do comparability studies upon process changes A concept paper on forced degradation studies is being developed by members of EBE BioManufacturing Working Group with the aim to provide industry best practices in this field for therapeutic proteins. Despite guidance on forced degradation studies for biotechnology products is limited, this concept paper does not intend to define regulatory requirements but to share practical experience on how to deal with forced degradation studies. A summary of the concept paper will be presented together with specific case studies related to use of forced degradation studies e.g. for comparability studies, in the frame of understanding CQAs or the suitability of light stress to define precautions during handling and shipment.

12 Panel Discussion Questions and Answers Forced Degradation Studies Stephane Cornen, Sanofi, France Annick Gervais, UCB Biopharma srl, Belgium John O Hara, UCB Biopharma srl, Belgium Mara Rossi, Merck-Serono, Germany Shahid Uddin, MedImmune Limited, United Kingdom

13 Industry Perspectives on Visible Particle Requirements and Practices: An Overview of the EBE Position Paper Serge Mathonet Sanofi, France Therapeutic proteins such as monoclonal antibodies can exhibit a propensity for self-association leading to the formation of protein aggregates that range in size from nanometres (oligomers) to protein particles in the micrometre size range (subvisible and visible particles). The EP and USP monographs define a requirement for parenteral products, that they should be essentially/practically free of visible particles. The current EP monograph for Monoclonal Antibodies for human use (2031 revised in 2011) set the following expectations and QC requirements for Visible Particles for MABs: They are without visible particles, unless otherwise justified and authorised as compared to without visible particles in previous versions. This allows some level of intrinsic visible particles to be identified, characterized and qualified in pre-clinical or clinical studies that are thus shown not to be a quality or safety concern. The problem statement is that even for optimized formulations supported by excellent long term stability studies, having zero visible particles are an unrealistic expectation for release/shelf life testing of parenteral Drug Products containing protein active ingredients. In our view, as for other injectable biotech products, practically free of visible particles should be considered as an acceptance release and shelf life criteria in reference to both extrinsic and intrinsic particles.. The purpose of the position paper is to review best practices in the industry in terms of visual inspection process (100 % inspection followed by sampling inspection) and associated operator training, QC sampling, testing, setting acceptance criteria corresponding to practically free of visible particulates. It is also important to understand how to set acceptance criteria when inherent protein visible particles are unavoidable and intrinsic or extrinsic particles cannot be eliminated to the point of having zero defects.. Associated with the presence of particles, challenges such as particle characterization, patient safety assessment, visible particle defect categorization, inspection training and continuous process optimization are also addressed. The position paper applies to therapeutic protein, more specifically to monoclonal antibodies drug products in late stage development (Phase 3 clinical supplies) and those commercialized.

14 Case Studies for Control and Management of Visible Particles in Drug Product Andrew Lennard Amgen Limited, United Kingdom Visible particles may be classified as extrinsic (foreign, extraneous material), intrinsic (resulting from the manufacturing process, formulation or container) or inherent (derived from the protein product). When a product has no history of inherent particle formation and specified as practically free from particles, Batch Release to the specification and Stability testing can use AQL-based approaches during manufacture or from traditional QC testing Sampling plans are proposed to result in a maximum AQL of 0.65% following ANSI Z1.4 (ISO ) level 2. These criteria will harmonise the control of visible particles to the forthcoming USP <790>. A case study application of these proposals will be provided to illustrate how excessive sample size can be avoided while maintaining a valid sampling plan. Although the presence of visible particles is undesirable, the reality is that proteins are inherently sticky to form oligomers, aggregate, sub-visible particles and ultimately visible particles. The protein interactions forming visible particles can vary according to the conditions of stress under which they were generated and may be reversible and/or irreversible. Control of visible particles by formulation may be limited by drug concentration or route of administration. Regulatory agencies recognise that under some circumstances, on a case by case basis, the presence of inherent proteinaceous particles may be unavoidable and acceptable when appropriately justified, controlled and demonstrated as safe. Case studies are presented for products that may contain proteinaceous particles.

15 Semi-Quantitative Method for Measuring Inherent Visible Particles in Protein Products Patricia Cash; Maryam Mazaheri MedImmune, USA All protein solutions contain particles which vary greatly in size from invisible (sub-micron) to visible (millimeter). Visible Particles are sometimes observed in protein solutions, particularly in high concentration formulations. Biopharmaceutical companies are required to monitor and minimize the presence of visible and sub-visible particles in their products. A new, semi-quantitative method for assessing visible particles against standards will be presented.

16 Panel Discussion Questions and Answers Visible Particles Patricia Cash, MedImmune, USA Andrew Lennard, Amgen Limited, United Kingdom Hanns-Christian Mahler, F. Hoffmann-La Roche Ltd., Switzerland Serge Mathonet, Sanofi, France

17 Regulation of Biopharmaceutical Products: Regulatory Perspectives In this session regulators from the host country, EU and non-eu agencies present recent developments and relevant information for the field. The subsequent panel discussion provides a forum for further questions and the discussion of global developments.

18 Role of Official Medicines Control Laboratories (OMCL) in Assessing Quality of Biologicals Carlo Pini National Center for Immunobiologicals Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy The quality, safety and efficacy of medicines need to be carefully assessed before a given product is authorized for either clinical trials or commercialization. This assessment requires a multiple approach, based on documents assessment, inspections and analytical testing, either before and/or after that the use in patients has been authorized. Lack of this holistic approach, in the assessment of the MAA or during the whole lifecycle of the biological product, may cause incompleteness of assessment, and potential quality and safety issues might be either underestimated or even missed. In this context, an OMCL can assess quality of biologicals at various levels. For example, at the pre-marketing level, the quality of products to be used in clinical trials can be assessed from the dossiers but it can also be investigated by analytical methods. This would lead to the independent confirmation (or disproval) of data provided by the applicant. This could have some importance when impurities, whose level could influence the safety of the product under trial, are tested. In some other cases, for certain products, either permanent or temporary batch release is foreseen after the marketing authorization is granted. Finally, for products to be authorized for clinical trials or commercialization, inspections are regularly carried out. However, when novel methods are developed and used, their validation and performance on the field can be more comprehensively assessed by mixed GMP teams where experts from the OMCL are also included. Post marketing surveillance (PMS) is another area of activities where products can be sampled and analyzed from the market after the authorization has been granted. PMS can be also performed on centrally authorized products under the supervision of the EDQM. Finally, counterfeits and defective medicines are two other areas of activities where the role and the cooperation of the OMCL in supporting the Regulatory Agency are of paramount importance. Taken together, the above mentioned examples clearly support the idea that the overall quality of a medicinal products, including biologicals, relies upon a number of approaches where the analytical experience and capability plays an important role. From several points of view, cooperation between assessors, GMP inspectors and OMCL experts needs to be strengthened and improved, with the final common goal of a better quality and more controlled biological product.

19 PMDA Perspective: Recent Trends in the Regulation of Biopharmaceuticals Takao Yamori Pharmaceuticals and Medical Devices Agency (PMDA), Japan Abstract was not available at the time of printing.

20 FDA Perspective: Recent Trends in the Regulation of Biopharmaceuticals Sarah Kennett CDER, FDA, USA The success of marketed biopharmaceuticals has resulted in biopharmaceuticals representing an increasing proportion of drugs in development. Recent trends in protein product development include an increased use of novel and engineered structures, such as antibody-drug conjugates, bispecific and dual variable domain antibodies, single domain antibodies, and scfv molecules, an increase in numbers of fusion proteins and combination products, as well as increased engineering of antibody Fc regions. Biopharmaceutical product quality is critical, and impact on the TPP and patients should be considered when product quality decisions are made. Product quality aspects of FDA/CDER initiatives, such as the OBP QbD pilot program, process validation, breakthrough designation, biosimilar development, and the Office of Pharmaceutical Science reorganization, will be presented. Slides were not available at the time of printing.

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22 FDA Perspective: Update on Vaccine Regulation Philip Krause CBER, FDA, USA Topics discussed at a recent BIO-CBER vaccine roundtable meeting included expedited programs for serious conditions, refocusing the IND managed review process, and regulatory approaches to vaccines using novel adjuvants. As vaccines increasingly target rare serious conditions for which meaningful advantages over existing therapies can be achieved and for which pre-licensure clinical endpoint studies demonstrating an effect on irreversible morbidity and mortality are not feasible, it will be increasingly important to identify surrogate endpoints and intermediate clinical endpoints that can be used to predict a reasonable likelihood of benefit, permitting these products to be approved under the accelerated approval regulations. The new breakthrough therapy designation may also facilitate development of eligible products, for which preliminary clinical evidence supports substantial improvement on clinically significant endpoints against a serious condition. FDA's Office of Vaccines is exploring approaches to increase sponsor engagement during phase 2 and 3 in order to facilitate vaccine development and improve regulatory outcomes, including additional meetings and providing the option for discussions of potential issues earlier in the review cycle. There is continued keen interest in vaccines with novel adjuvants, as reflected by recent US advisory committee discussions on adjuvanted vaccines, as well as robust international discussion of the potential association between a pandemic influenza vaccine and narcolepsy. Adjuvants are important components of vaccines, but are not considered active ingredients under US regulations. While inclusion of an adjuvant in a vaccine should be justified, there are several approaches that can be used and clinical data is not always needed to make this determination. Consistent with recently issued WHO guidelines on nonclinical evaluation of vaccine adjuvants and adjuvanted vaccines, CBER does not require separate testing of components of combined adjuvants in preclinical studies or a preclinical immunogenicity dataset. Slides were not available at the time of printing.

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24 Recent Regulatory Activities in Europe Ilona Reischl BASG / AGES, Austria Regulatory activities during the last year of relevance for the development of biopharmaceuticals will be summarized in this presentation, stretching from the recently announced adaptive licensing pilot of EMA and the move and restructuring of the EMA to the close to finalized clinical trials regulation.

25 Regulation of Biopharmaceutical Products: Regulatory Perspectives Discussion Questions and Answers Sarah Kennett, CDER, FDA, USA Philip Krause, CBER, FDA, USA Carlo Pini, Istituto Superiore di Sanità, Italy Ilona Reischl, BASG / AGES, Austria Takao Yamori, Pharmaceuticals and Medical Devices Agency (PMDA), Japan

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27 Comparability and Similarity A Practical Approach In November 2004 with the finalization of ICH Q5E COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS SUBJECT TO CHANGES IN THEIR MANUFACTURING PROCESS, a global regulatory standard for the justification of manufacturing changes for biotech products became available and since then was officially and unofficially successfully applied by regulators and manufacturers in all regions of the world. This standard also can be considered as one of the driving principles for the development of Biosimilar Guidance starting 2005 in Europe and not ending but accumulating in a global WHO standard GUIDELINES ON EVALUATION OF SIMILAR BIOTHERAPEUTIC PRODUCTS (SBPs). Since the concepts of biosimilarity are discussed and respective guidance is developed the debate is cooking to what extent the comparability approach, outlined in Q5E and practically applied by regulators and industry since many years, is applicable during a biosimilar development.

28 Comparability to Establish Biosimilarity Jan Visser Sandoz Biopharmaceuticals, HEXAL AG, Germany Biologics are produced in living-systems resulting in inherent Quality Attribute (QA) variability. Sometimes changes in a manufacturing process of a biologic lead to a shift in QAs beyond the normally observed variability. To manage manufacturing changes and ensure they do not impact the efficacy and safety of biologics a comparability exercise is required by regulators. This comparability exercise, which is described in ICH Q5E, also formed the basis for biosimilar guidance as the comparability exercise to establish biosimilarity is using exactly the same scientific principles. The evaluation of biosimilarity is based on comparability at the analytical, non-clinical and clinical level. However, the comprehensive analytical comparability exercise forms the foundation as state-of-the-art analytical methods are very sensitive in detecting differences between QAs. At Sandoz biosimilars are systematically engineered to match their reference products, a concept in line with Quality by Design principles. The Quality Target Product Profile (QTPP) is one element driving directed biosimilar development and also includes ranges of reference product QAs - target specifications - which are established by analyzing a significant number of originator lots. The QA critically assessment is another element driving directed biosimilar development. QA criticality assessments are updated regularly and require process and product understanding. Biosimilars need to be as safe and efficacious as their reference product, meaning that the more critical QAs are, the more comparable they should be to the reference. Additionally, the more comparable a biosimilar is to its reference product the smaller the residual uncertainty and the more tailored the non-clinical and clinical program should be. During the life-time of a biosimilar development project several analytical comparability exercises are performed, culminating in the final comparability exercise. This exercise includes a very comprehensive head-to-head analysis of the proposed biosimilar and reference product, but also comparison to historic reference data and comparison of stability data under intended, accelerated and stress conditions. As for all biologics, the control strategy for biosimilars is a combination of QA criticality, process control and testing strategy. After approval in the EU a biosimilar is managed as an independent product, leading to a debate on to what extent divergence between the biosimilar and its reference product is a potential issue. However, to date there are no data showing divergence between biosimilars and their reference products or between interchangeably used originator biologics.

29 Justifying Manufacturing Changes for Established Products - The Comparability Approach Dieter Schmalzing Genentech, a Member of the Roche Group, South San Francisco, CA, USA Comparability exercises to support manufacturing changes are critical and frequent activities in the lifecycle of any biotechnological product from stage of concept through post-approval. This presentation will talk about the risk-based approach used by Roche/ Genentech to select and rationalize the appropriate tools for these exercises, depending on the criticality of the change. It will outline the underlying principles that guide this approach. The presentation will also talk about key components, such as lot selection, how acceptance criteria for comparability are set and which databases and statistical tools are employed and why. Finally, it will touch upon compendial standards (written and physical) and how they contribute to comparability assessments. Slides were not available at the time of printing.

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31 EDQM Viewpoint on the Role of the Ph. Eur. in the Field of Biosimilars Mihaela Buda EDQM, Strasbourg, France The European Pharmacopoeia (Ph. Eur.), which is now in its 8 th Edition, is a reference for quality in the field of biological medicinal products monographs for biologicals have been used as quality standards for decades. With the rapidly growing number of biologicals on the market and of similar biological products authorized via the centralized procedure, the role of the Ph. Eur. is becoming increasingly complex in providing support for harmonized approaches to product quality and public standards. Joint efforts are deemed necessary to ensure that Ph. Eur. monographs continue to meet the requirements of both industrial and regulatory stakeholders engaged in the development of quality standards for biologicals and biosimilars. This presentation aims at defining the place of the Ph. Eur. monographs in the biosimilarity landscape and will focus on: role and requirements of the Ph. Eur. reference materials, namely Chemical Reference Standards and Biological Reference Preparations, to support monographs for biologicals as well as method qualification for the purpose of comparability; flexibility of monographs in the field of biologicals and the need to remain updated in order to cover the quality of a biosimilar product the recently adopted Ph. Eur. monograph Human coagulation factor IX (rdna) concentrated solution (2522) will be presented as a case study.

32 Comparability and Biosimilarity: An Assessor s View Martijn van der Plas Medicines Evaluation Board, The Netherlands Abstract was not available at the time of printing. Slides were not available at the time of printing.

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34 Comparability and Similarity A Practical Approach Panel Discussion Questions and Answers Mihaela Buda, EDQM, France John Dougherty, Eli Lilly and Company, USA Dieter Schmalzing, Genentech, a Member of the Roche Group, USA Martijn van der Plas, Medicines Evaluation Board, The Netherlands Jan Visser, Sandoz Biopharmaceuticals, HEXAL AG, Germany Questions to be discussed: What are the databases used when establishing comparability after a manufacturing change versus establishing biosimilarity? What means a product is analytically comparable versus a product is highly similar? How do manufacturer define target acceptance criteria/ranges for a comparability assessment after a manufacturing change versus when establishing biosimilarity? How to assess the criticality of differences between pre- and post-change materials versus the biosimilar and the reference product? What is the role of the QTTP in the context of a comparability exercise versus developing a biosimilar? To what extent product specific monographs or general monographs from Pharmacopoeias as well as publicly available reference standards can facilitate or hinder both types of assessments? What can be the role/value of statistics when doing these comparative assessments? What questions should we ask and what do we do with the answers? What tools do we use and for what purpose do we use them?

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36 The New Holistical Quality Assurance Philosophy: How Do We Ensure Successful QbD Submissions? Are There Regulatory and Legal Hurdles? Regulatory agencies around the world are testing DPs, in addition to testing performed by industry. Some regions (eg. EU) require testing to be performed inside their region. Explicit demonstration of compliance with monographs is written into the law in many regions. As industry moves toward building quality into processes, on-line testing and use of new technologies such as MS, this will reduce the amount of end product testing required and the resulting DP specification is likely to look very different to the "traditional" DP specification.

37 Advancing the Promise of Analytics of the Future using Multi Attribute Methodology Anthony Mire-Sluis Amgen Inc., USA Analytical technology is providing ever increasingly powerful tools in the characterization and lot release of biotechnology products. Analytics of the future should allow for much more real time control of the process and less reliance on lot release assays, as well as driving more testing onto the manufacturing floor and reducing the costly footprint of the Quality Control Laboratories. For example, Mass spectrometry can be used to detect multiple and specific product attributes as opposed to the current chromatography description of peaks containing a variety of product variants. In addition, such technology can distinguish product attributes for certain products (e.g. conjugated antibodies) that conventional technology is unable to do so. The ability to detect specific product attributes rather than peaks provides a more real time ability to influence the manufacturing process and control product quality. However, this increasing depth of analysis comes with a price - how to analyze such data and work out what information is actually useful and relevant for safety and efficacy or lot to lot consistency. Ever complicated spectroscopic profiles also require the time and expertise to understand the exact nature of what is being reported as well as efforts to ensure that the methodology itself is appropriately qualified or validated. NOTES

38 The Impact of QbD on Quality Assurance and the Qualified Person Derek Murphy MedImmune Limited, United Kingdom As can be seen by the resent draft version of Annex 15 to Part 1 of the EU GMPs, Quality by Design (QBD) principles are becoming more widely accepted and used within the Bio/Pharmaceutical industry. One of the key advantages highlighted to adopting a QbD approach is that a greater understanding of the impact of variations in process parameters which can then be used to better understand changes and deviations to manufacturing conditions, a major benefit to GMP Quality Assurance and the Qualified Person and also making them a key stakeholder in the process design and control. As process control strategies move from the classic approach based upon parameters fixed during process validation runs to a QbD approach this does also present challenges to QA and the QP. For example the data used to support processes will be generated will most likely look different and the knowledge base required to apply the information logically will be different. Also the role of QA across functions is likely to change as is the relationship between the QP and the regulatory authorities if we are to deliver the identified benefits. Another recent reworking of part one of the EU GMPs, Annex 16, has provided some very helpful guidance as to what types of variance to a filing a QP can accept without the company having to inform the competent authority. What is also noticeable is the reliance upon compliance to specifications. As the control strategies move away from end product testing, how will competent authorities react to this change and what scope will they allow the company/qp to assess such variations? Will Competent Authorities actually allow companies to remove certain tests from specifications or will they still be expected to be listed? In order to be able to understand these issues and develop quality systems to cope, QA and the QP must engage positively with other key stakeholders, for example Development and Regulatory Affairs, to understand the new paradigm and how the information generated can be used to assure safer products through the clinical development process and in to manufacturing. This dialogue also has to extend beyond the company and involve open dialogue with the regulatory agencies to ensure that the full benefits of QbD are delivered to the patient.

39 How to Assure Quality and Consistency in an Evolving QbD Scenario: A Regulator s View Mats Welin Medical Products Agency, Uppsala, Sweden The introduction of QbD will shift the focus from end product testing to establishment of robust processes and monitoring these processes. With evolving analytical technologies real time release testing will be an option. The way the necessary regulatory oversight is executed will consequently have to adapt to these changes. To reach a preferred state in line with Q8-11, assessment and inspection services need to work more closely together to be able to take a holistic approach to an application, both considering what is in the file and also GMP related issues. This will likely require more product related inspections which is likely more labour intense as it is expected that inspectors need to be joined by assessors and it will take time before this can be run in full scale which will have effect on the potential flexibility to be gained. Linked with these issues is the way the manufacturing process is described in the dossier as this is one major part of what is inspected. In particular what is a non-critical parameter and how these should be handled are heavily discussed between industry and assessors. There is a need to reach an agreement on these issues and to find a balance of the level of detail in the process description that allows regulators to understand the full process and allow sufficient regulatory oversight while still allow for improvement of the processes. As mentioned more on-line measurements leads to less need for product testing and introduction of new methods will provide new opportunities for detailed analysis compared to current methodologies. Alternative methods to Ph Eur official methods are accepted provided they are shown to be comparable or better. However it may not be straightforward to transfer compendial requirements written based on certain separation technologies (molecular size, charge etc.) to the output of novel technologies. It may also be difficult to show similarity to a variable old method and it should be further discussed what is needed to support the use of alternative methods.

40 How the European Pharmacopoeia Provides the Framework to Implement QbD Principles Emmanuelle Charton EDQM, France Abstract was not available at the time of printing. Slides were not available at the time of printing.

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42 The New Holistical Quality Assurance Philosophy: How Do We Ensure Successful QbD Submissions? Are There Regulatory and Legal Hurdles? Panel Discussion Questions and Answers Brigitte Brake, Federal Institute for Drugs and Medical Devices (BfArM), Germany Sarah Kennett, CDER, FDA, USA Anthony Mire-Sluis, Amgen Inc., USA Derek Murphy, MedImmune Limited, United Kingdom John O Hara, UCB Biopharma srl, Belgium Mats Welin, Medical Products Agency, Sweden Questions to be discussed: Will Industry need to develop and validate a duplicate set of traditional analytical methods and set specifications for such methods? Is it globally acceptable that the product may comply if tested to a monograph, rather than having to perform the monograph tests? How can upstream testing or validation be used to minimize end testing, i.e. real time release testing In some markets, compliance with eg PhEur is written into the law, so could there be the potential for legal barriers to implementation, even if the approach is scientifically robust? Does PhEur and other pharmacopoeiae need to consider changes to monographs, new methods etc to reflect this emerging technology? Technologies such as MS require fairly specialized equipment which may not be available broadly. For markets where local import testing is performed (periodically or each batch), how would the test laboratory perform the test per the submitted specification? To what extent would the applicant need to cross-validate new technologies against established methods to enable testing by third parties? Would this mean a different specification for third party testing purposes?

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44 The Continuing Evolution of Regulatory Guidance on Biotech Drug Substance Process Validation This session will consider the impact of the emerging EMA Guidance, areas of consistency and divergence with FDA Guidance and practical aspects of implementation in preparation of control strategy development, PV plans, dossier preparation and ongoing manufacturing. Regulatory agency speakers will provide an update on the EMA Guidance document and the incorporation of the discussions from the March 2013 EMA Workshop on PV. Industry speakers will discuss the development of control strategies in the context of this new guideline and will also describe how this is being incorporated into regulatory submissions in Europe. Industry presentations will also provide an assessment of the similarities and divergences of expectations between current FDA and EMA Guidance in terms of control strategy development and implementation during routine manufacturing.

45 EMA Guidance Documents on Process Validation - Where are We? Nanna Aaby Kruse Danish Health and Medicines Authority, Denmark On 15 th January 2014, EMA published on their website the guideline: Guideline on process validation for finished products - information and data to be provided in regulatory submissions. This guidelines cover aspect relating to process validation for finished products. Its main scope is chemicals/small molecules but the principles described are also applicable to biological medicinal products on a case by case basis. This guideline is primarily developed by QWP, but with contributions from BWP. In May 2011, CHMP s Biologics Working Party issued a concept paper that stipulates the need for a guideline on process validation for the manufacture of biotechnology-derived active substances. This request was based on the lack of detailed guidance on this topic and the need to provide practical recommendations on data requirements in the context of an initial Marketing Authorisation Application (MAA) for a biotech product. In April 2013 BWP held a one-day stakeholder workshop on biotech manufacturing process validation to discuss and exchange ideas for the guideline to be developed. One year later, in April 2014, BWP may succeed in adopting the guideline worked on since the stakeholder workshop. Once the guideline is adopted, it will go out for public consultation and comments are kindly requested. This talk will illustrate the main points from the two guidelines and outline issues where BWP still would like to hear and discuss the stakeholders perspectives on the principles found in the guideline for process validation of a biotech product.

46 Development of Integrated Control Strategies and PV Plans for US and European Filings Anthony Mire-Sluis Amgen Inc., USA Abstract was not available at the time of printing.

47 Current Best Practices in the Definition of Process Parameters for Development of Control Strategies Ronald Bates Bristol-Myers Squibb Company, USA One of the most important aspects of biotherapeutic manufacturing processes is the in-process control (IPC) strategy. These strategies are often the result of years of development effort combined with significant experience during clinical manufacturing. IPC strategy documents are used to facilitate technical transfer and authoring of master batch records, SOPs, validation protocols, and regulatory documents. IPC nomenclature is far from standard across the industry with numerous sources for manufacturers to draw from, including PDA TR 42, the A-Mab case study, and ICH guidance documents to name a few. This presentation will examine past terminologies and incorporate recent regulatory guidance to develop a simple, multi-tiered IPC nomenclature.

48 The Continuing Evolution of Regulatory Guidance on Biotech Drug Substance Process Validation Panel Discussion Questions and Answers Ronald Bates, Bristol-Myers Squibb Company, USA Robert Clemmitt, GlaxoSmithKline, United Kingdom Sarah Kennett, CDER, FDA, USA Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark Anthony Mire-Sluis, Amgen Inc., USA Preben Østfeldt, Novo Nordisk A/S, Denmark Questions to be discussed: What are the key differences in expectations in the role played by ongoing process monitoring in process validation filings in the EMA and FDA regulations? Is there consensus now for the definitions of Process Parameters (Critical, Key, Non-Key) in industry and with regulators? What experiences are companies having during inspections with respect to implementation of control strategies and process monitoring? Are companies able to design and describe single integrated control strategies and process validation plans which meet the needs of EMA and FDA.

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50 Managing Complex, Multinational, Multi-site Supply Chains and Registrations The global regulatory landscape is evolving, and launching new biopharmaceuticals has become technically challenging. In addition, the fragmented, world-wide post-approval regulatory landscape has resulted in increasing complexities and difficulties maintaining a compliant supply of biopharmaceuticals to patients. A global supply chain today may involve the management of multiple specifications and acceptance criteria, technology transfers and managing two or more manufacturing sites, multiple in-country testing laboratories. Different countries receive different batches that have different specifications and attributes. Except broad ICH guidelines, there is little harmonization of expectations in health authorities worldwide regarding post-approval regulatory changes and each market has different requirements and associated timelines. Post-approval changes for biotechnology derived drug substances or related drug products have elevated requirements in highly regulated countries such as the US or the EU. These requirements influence the timelines for final implementation of changes in a global environment only to a very limited extent as the implementation of a change is limited by the last of the global approvals. The last approval in turn is influenced by factors such as: The need to provide a Certificate of the Pharmaceutical Product of reference countries in a large number of countries; The need for inspections; The long timelines to approval in a few countries; Provisions of QC samples for in country registration testing; The need to provide Certificates of Analysis for a large number of consecutive commercial batches in some CPP countries. Comparison of representative and typical post-approval changes show that the same change may be classified differently by country, for example as minor or major changes or even new registration. In addition, many countries have specific dossier requirements resulting in a high complexity in dossier generation. This lack of harmonisation in classification, review timelines and dossier requirements is a main cause for long implementation timelines causing a very complex supply chain and potential drug shortage. Approved products fragmentation is exacerbated when changes are implemented before cluster markets have all approved. Development of global classification and procedural guidance coordinated by the WHO or the ICH global coordination group could positively influence the timely implementation of global changes. The complexity of the supporting documentation would be minimized by harmonizing the documentation requirements. The number of changes could also be greatly reduced by removing GMP elements such as analytical SOPs, batch records from the scientific documentation and verify these elements in inspections. The current conservative assessment schemes stifle innovation as they hinder the implementation of innovation and improvements to the quality of medicinal products. However, these changes should be fast tracked to drive progress and categorization should be driven by their potential to influence patient safety and efficacy.