Welcome to the CMC Strategy Forum Europe 2009: CMC Perspectives on Biological Investigational Medicinal Products in Clinical Trials

Transcription

1 Welcome to the CMC Strategy Forum Europe 2009: CMC Perspectives on Biological Investigational Medicinal Products in Clinical Trials The organizers of the CMC Strategy Forum Europe, sponsored by CASSS, An International Separation Science Society (formerly the California Separation Science Society), and co-sponsored by the United States Food and Drug Administration (FDA), invite you to attend and participate in its third annual conference. This year s meeting will open with a half day workshop expanding on recent regulatory agency and industry interactions regarding Quality by Design for Biopharmaceuticals. This will be followed by three workshops focused on the EMEA draft guideline on Chemical and Pharmaceutical Quality Documentation Concerning Biological Investigational Medicinal Products in Clinical Trials. Topics to be explored include comparability during clinical development, control strategy development, and the requirements for stability data. The final workshop of the conference will focus on the practical implementation aspects of the new EMEA Guideline on Production and Quality Control of Monoclonal Antibodies and Related Substances. Regulatory agency presentations and industry case studies will serve as a backdrop for in depth discussions on the scientific and regulatory expectations for these important topics. Each workshop will utilize a series of questions and points to consider as a framework for facilitating the discussions. Government regulatory and industry professionals from the development, quality assurance, and regulatory affairs functions are encouraged to attend these important discussions. Program Co-Chairs: Brigitte Brake, Federal Institute for Drugs (BfArM), Germany Karin Sewerin, NDA Regulatory Services AB, Sweden Mats Welin, Medical Products Agency, Sweden Hannelore Willkommen, RBS-Consulting, Germany Forum Co-Chairs: John Dougherty, Eli Lilly and Company, USA (PAC Liaison) Wassim Nashabeh, Genentech, Inc., USA (PAC Liaison) Scientific Organizing Committee: Brigitte Brake, Federal Institute for Drugs (BfArM), Germany John Dougherty, Eli Lilly and Company, USA (PAC Liaison) Kowid Ho, AFSSAPS, France Brendan Hughes, Wyeth BioPharma, Ireland Christopher Joneckis, CBER, FDA, USA Anneke Koole, Schering-Plough Corporation, The Netherlands Inger Mollerup, Novo Nordisk A/S, Denmark Gene Murano, Genentech, Inc., USA Wassim Nashabeh, Genentech, Inc., USA (PAC Liaison) Ilona Reischl, AGES PharmMed, Austria Martin Schiestl, Sandoz GmbH, Austria Thomas Schreitmüller, F. Hoffmann-LaRoche Ltd., Switzerland Karin Sewerin, NDA Regulatory Services AB, Sweden Lance Smallshaw, Eli Lilly and Company Ltd, United Kingdom Keith Webber, CDER, FDA, USA Mats Welin, Medical Products Agency, Sweden Hannelore Willkommen, RBS-Consulting, Germany

2 The Scientific Organizing Committee gratefully acknowledges the program partners for their generous support of the CMC Strategy Forum Europe PLATINUM PROGRAM PARTNER Genentech, Inc. GOLD PROGRAM PARTNERS Eli Lilly and Company MedImmune Novartis Pharma GmbH SILVER PROGRAM PARTNER Genzyme Corporation BRONZE PROGRAM PARTNER F. Hoffmann-La Roche Ltd. Novo Nordisk A/S FRIEND OF CASSS PROGRAM PARTNER Biologics Consulting Group, Inc. Wyeth BioPharma

3 CMC Strategy Forum Europe 2009 Scientific Program Summary Monday, 27 April :30 18:00 Registration in the Castelo Foyer 12:00 13:45 Hosted Lunch in the Contemporâneo Restaurant 13:45 14:00 Introduction / Welcome to the 3 rd European CMC Strategy Forum John Dougherty, Eli Lilly and Company, Indianapolis, IN USA QbD for Biotech: European Update Plenary Session in the Castelo I / II Room Session Chairs: Siddharth Advant, Tunnell Consulting and Brendan Hughes, Wyeth BioPharma 14:00 14:25 EMEA PAT Team Activities Kowid Ho, AFSSAPS, Saint Denis Cedex, France 14:25 14:50 CMC Bio Working Group Case Study for A-Mab Kenneth Seamon, University of Cambridge, Cambridge, United Kingdom 14:50 15:15 EFPIA Mock S2 Document for Biotech Status and Path Forward Margaret Leahey, Wyeth Biotech, Grange Castle, Dublin, Ireland 15:15 15:45 PM Break in the Castelo Foyer 15:45 17:15 Panel Discussion Lina Ertle, AFSSAPS, France Mette Kræmmer Hansen, Novo Nordisk A/S, Denmark Kowid Ho, AFSSAPS, France Margaret Leahey, Wyeth Biotech, Ireland Kenneth Seamon, University of Cambridge, United Kingdom Patrick Swann, CDER, FDA, USA Mats Welin, Medical Products Agency, Sweden 17:30 19:00 Welcome Reception in the Castelo IX Room

4 Tuesday, 28 April :30 08:30 Buffet Breakfast in the Contemporâneo Restaurant 08:00 17:00 Registration in the Castelo Foyer EMEA Guidelines on CMC Regulatory Expectations Plenary Session in the Castelo I / II Room Session Chairs: Brigitte Brake, Federal Institute for Drugs (BfArM), Karin Sewerin, NDA Regulatory Services AB and Hannelore Willkommen, RBS-Consulting 08:30 08:45 Brief Overview of Clinical Trials in Portugal - Welcome! Margarida Menezes Ferreira, National Authority of Medicines and Health Products (INFARMED, I.P.), Lisbon, Portugal 08:45 09:00 Harmonized Quality Requirements for Biotech Investigational Medicinal Products - A Regulator's View Brigitte Brake, Federal Institute for Drugs (BfArM), Bonn, Germany 09:00 09:30 Biologics EU Regulatory Framework: An Industry Perspective of Needs Brian Withers, Abbott Laboratories Ltd., Kent, United Kingdom 09:30 10:00 The Voluntary Harmonisation Procedure (VHP) for the Assessment of Multinational Clinical Trial Applications in the EU Hartmut Krafft, Paul-Ehrlich-Institute, Langen, Germany 10:00 10:30 AM Break in the Castelo Foyer 10:30 11:00 Risk-Based Regulation of Quality During Clinical Development Keith Webber, CDER, FDA, Silver Spring, MD USA 11:00 11:30 Panel Discussion Questions and Answers Comparability During Clinical Development Workshop Session One in the Castelo I / II Room Session Chairs: Brigitte Brake, Federal Institute for (BfArM) and Jason Hampson, Amgen Ltd. 11:30 11:50 Comparability - Regulatory Considerations and Expectations During Clinical Development Birgit Schmauser, Federal Institute for Drugs (BfArM), Bonn, Germany 11:50 12:10 Comparability During Clinical Development Anthony Mire-Sluis, Amgen, Inc., Thousand Oaks, CA USA 12:15 13:45 Hosted Lunch in the Contemporâneo Restaurant

5 Tuesday, 28 April 2009 continued Open Forum Panel Discussion: Workshop Session One: Comparability During Clinical Development In the Castelo I / II Room Session Chairs: Brigitte Brake, BfArM and Jason Hampson, Amgen Ltd. 13:45 15:15 Panel Discussion Kathleen Francissen, Genentech, Inc., USA Elisabeth Kirchisner, Roche Diagnostics GmbH, Germany Emanuela Lacana, CDER, FDA, USA Graham McCartney, Eli Lilly and Company, Ireland Claudia Meyer, Human Genome Sciences Europe GmbH, Germany Anthony Mire-Sluis, Amgen, Inc., USA Birgit Schmauser, Federal Institute for Drugs (BfArM), Germany 15:15 15:45 PM Break in the Castelo Foyer Control Strategies for Products in Clinical Development Workshop Session Two in the Castelo I / II Room Session Chairs: Karin Sewerin, NDA Regulatory Services AB and Carlo Pini, Instituto Superiore di Sanita 15:45 16:00 Control Strategies for Investigational Medicinal Products in Clinical Trials - An Assessor's View Niklas Ekman, National Agency for Medicines, Helsinki, Finland 16:00 16:15 Control of Process and Product During the IND Stages: Regulatory Considerations Roman Drews, CBER, FDA, Rockville, MD USA 16:15 16:30 What Characterizes a Biologically Relevant in vitro Assay? Bettina Lundin Brockdorff, Novo Nordisk A/S, Copenhagen, Denmark Open Forum Panel Discussion: Workshop Session Two: Control Strategies for Products in Clinical Development In the Castelo I / II Room Session Chairs: Karin Sewerin, NDA Regulatory Services AB and Carlo Pini, Instituto Superiore di Sanita 16:30 18:00 Panel Discussion Roman Drews, CBER, FDA, USA Niklas Ekman, National Agency for Medicines, Finland Bernard Hilger, F.Hoffman-La Roche Ltd., Germany Silke Møller Larsen, Novo Nordisk A/S, Denmark Dieter Schmalzing, Genentech, Inc., USA Carina Sonnega, France Hannelore Willkommen, RBS-Consulting, Germany 18:45 23:00 Networking Reception Boat Cruise on the Tagus River Transportation is provided to the boat

6 Wednesday, 29 April :00 09:00 Buffet Breakfast in the Contemporâneo Restaurant 08:30 17:00 Registration in the Castelo Foyer Stability Requirements for Products in Clinical Development Workshop Session Three in the Castelo I / II Room Session Chairs: Ilona Reischl, AGES PharmMed and Thomas Schreitmüller, F. Hoffman-La Roche Ltd. 09:00 09:20 Considerations and Expectations on Stability Data During Clinical Development Ivana Haunerova, State Institute for Drug Control, Prague, Czech Republic 09:20 09:40 How to Ensure the Stability of Products in Clinical Trials - An Industry Perspective Volker Schnaible, F. Hoffmann-La Roche Ltd., Basel, Switzerland 09:45 10:15 AM Break in the Castelo Foyer Open Forum Panel Discussion: Workshop Session Three: Stability Requirements for Products in Clinical Development In the Castelo I / II Room Session Chairs: Ilona Reischl, AGES PharmMed and Thomas Schreitmüller, F. Hoffman-La Roche Ltd. 10:15 11:45 Panel Discussion Stefan Christians, Paul-Ehrlich-Institute, Germany Roland Guenther, Novartis, Switzerland Ivana Haunerova, Czech Republic Michelle Frazier-Jessen, MedImmune, USA Anna Lafi, Biogen Idec Inc., United Kingdom Kathy Lee, CDER, FDA, USA Volker Schnaible, Switzerland Pierrette Zorzi, AFSSAPS, France 12:00 13:30 Hosted Lunch in the Contemporâneo Restaurant 13:30 14:00 RECAP: CMC Perspectives on Biological Investigational Medicinal Products in Clinical Trials John Dougherty, Eli Lilly and Company, USA and Wassim Nashabeh, Genentech, Inc., USA EU Guidance on Monoclonal Antibody: Practical Implementation Aspects Workshop Session Four in the Castelo I / II Room Session Chairs: Kowid Ho, AFSSAPS and Paul Varley, MedImmune Limited 14:00 14:15 The CHMP Guideline on Monoclonal Antibodies for in vivo Use in Humans Robin Thorpe, National Institute for Biological Standards & Control, Potters Bar, United Kingdom

7 Wednesday, 29 April 2009 continued 14:15 14:30 Monoclonal Antibodies for Human Use 2031 Guy Rautmann, European Directorate for the Quality of Medicines Council of Europe (EDQM), Strasbourg, France 14:30 14:45 Requirements and Challenges for Particulates Testing Paul Varley, MedImmune Limited, Cambridge, United Kingdom 14:45 14:55 TITLE TBD Ron Taticek, Genentech, Inc., South San Francisco, CA USA 14:55 15:15 A Risk-based Strategy for Characterization of Effector Functions of Therapeutic Antibodies Xu-Rong Jiang, MedImmune, Gaithersburg, MD USA 15:15 15:30 PM Break in the Castelo Foyer Open Forum Panel Discussion: Workshop Session Four: EU Guidance on Monoclonal Antibody: Practical Implementation Aspects In the Castelo I / II Room Session Chairs: Kowid Ho, AFSSAPS and Paul Varley, MedImmune Limited 15:30 17:00 Panel Discussion Paul Chamberlain, Biologica Consulting, France Simon Hotchin, Amgen Ltd., United Kingdom Xu-Rong Jiang, MedImmune, USA Valérie Pimpaneau, Voisin Consulting, France Guy Rautmann, EDQM, France Ron Taticek, Genentech, Inc., USA Robin Thorpe, NIBSC, United Kingdom Patrick Swann, CDER, FDA, USA 17:00 17:15 Closing Remarks and Invitation to CMC Strategy Forum Europe 2010 Ilona Reischl, AGES PharmMed, Vienna, Austria 17:15 Adjournment

8 QbD FOR BIOTECH: EUROPEAN UPDATE SESSION ABSTRACT This session will provide participants with an opportunity to catch up on some of the key activities underway in Europe in the area of QbD for biotech. The current status of the EFPIA Mock S2 document will be presented and participants will be invited to provide commentary and discuss the approach taken in this document. The progress and direction of the US based Conformia-sponsored Mock S2 group will also be presented and discussed at this session. The EMEA PAT Working party will also be represented at the meeting and members of that group will provide updates on recent Mock Inspections and other aspects of the group s work. Participants will be invited to discuss the issues emerging from the work of the PAT group with Regulators and Industry representatives on the panel. Questions to be addressed: 1. What is the status of the European Mock S2 document? Do we know what we need to put in the filing and what is maintained on site for inspection? 2. What are the differences in approach between the US Conformia Mock Document and the European effort? 3. How do we address quality attributes for which we cannot assign criticality? Must we assume they default to critical status? 4. Are there QbD filings already submitted in Europe? 5. How are companies addressing Q10 in the context of QbD filings in terms of Knowledge Management Transfer and Quality systems for R&D activities?

9 EMEA PAT Team Activities Kowid Ho AFSSAPS, Saint Denis Cedex, France Abstract is not available at time of printing. QbD FOR BIOTECH: EUROPEAN UPDATE PRESENTER ABSTRACTS

10 CMC Bio Working Group Case Study for A-Mab Kenneth Seamon University of Cambridge, Cambridge, United Kingdom Abstract is not available at time of printing.

11 EFPIA Mock S2 Document for Biotech Status and Path Forward Margaret Leahey Wyeth Biotech, Grange Castle, Dublin, Ireland Abstract is not available at time of printing.

12

13 EMEA GUIDELINES ON CMC REGULATORY EXPECTATIONS PLENARY SESSION ABSTRACTS Brief Overview of Clinical Trials in Portugal Welcome! Margarida Menezes Ferreira National Authority of Medicines and Health Products (INFARMED, I.P.), Lisbon, Portugal Abstract is not available at time of printing.

14 Harmonized Quality Requirements for Biotech Investigational Medicinal Products A Regulator s View Brigitte Brake Federal Institute for Drugs (BfArM), Bonn, Germany Approval of clinical trials is the responsibility of individual EU Member States, who are evaluating the products used in clinical studies. In view of the current lack of common reference guidance on which to base the assessment of quality of biological/biotech clinical trial material and the difference in experience among sponsors and competent authorities, there is a need to promote a harmonised approach throughout the European Union. The progress to draft guidance in this area will be discussed. Sharing views, experience and expectations of regulators and representatives from industry will be a valuable contribution to define quality requirements and the amount and type of data deemed to be appropriate. Potentially contentious issues like comparability, validation of analytical methods, setting meaningful specifications, stability data and shelf life extension deserve closer discussion.

15 Biologics EU Regulatory Framework: An Industry Perspective of Needs Brian Withers Abbott Laboratories Ltd., Kent, United Kingdom The discussion will focus on an industry view of how changes in the regulatory framework can facilitate development; the implementation of product and process improvements and the application of QbD for biotech products.

16 The Voluntary Harmonisation Procedure (VHP) for the Assessment of Multinational Clinical Trial Applications in the EU Hartmut Krafft Paul-Ehrlich-Institute, Langen, Germany Following the implementation of the Clinical Trials Directive 2001/20/EC in May 2004 the EU Heads of Medicines Agencies established a Clinical Trials Facilitation Group (CTFG) to improve the harmonisation of the assessment decisions and the administrative procedures for clinical trials across the EU. With the translation of the clinical trials (CT) Directive into national laws and regulations, divergent practices between the different Member States remain, in areas such as: Distribution of duties between the National Competent Authorities and the Ethics Committees Content, format or language requirements Timelines for the review of a Clinical Trial Application (CTA) Different application dates by the sponsor in the different MS Regarding multinational CT for which an application is filed in several Member States, since the authorisation of a CT is subject to national legislations, the assessment of the same CTA for a given CT might result in varying final decisions. Country-specific modifications might occur due to changes requested by the different National Competent Authorities and Ethics Committees; a CT might even be approved in one member state and rejected in another. In order to harmonise multinational CT in Europe and to ensure the same protection of the participants as well as the scientific value of clinical trials, the CTFG developed a Voluntary Harmonisation Procedure (VHP). In the VHP the critical issues of the multinational scientific assessment will be discussed by the named MS after a voluntary submission by the applicant and before the national application of the CT. The pilot phase of the VHP consists of three steps: Choosing suitable CTs according to the VHP criteria Joint assessment of the CT documents (Protocol, IB, IMPD) by the MS / Communication of the results to the applicant National application by the applicant and rapid approval by CA The time lines for the VHP are ambitious and foresee the completion of a VHP within 60 Calendar days and a subsequent national application within 20 and an approval within 10 days, resulting in approval times for multinational CT in the EU of 90 days after the start of the VHP. Details of the VHP can be found in the CTFG Guideline on the VHP under

17 Risk-Based Regulation of Quality During Clinical Development Keith Webber CDER, FDA, Silver Spring, MD USA Although the principles of risk management have been used by a variety of industries, including pharmaceutical companies, publication of the International Conference on Harmonisation Q9 guideline on Quality Risk Management in 2005 was a milestone in the establishment of risk management as a foundation for decisionmaking during drug development and manufacturing. During pre-clinical and clinical development, the probability of successfully producing an approvable product can be increased by considering the recognizable hazards that could impede development or lead to outright failure and taking step to minimize the probability of their occurrence. As the goals of each stage of clinical development progress from initial safety evaluation of the active to demonstration of safety and efficacy for a final formulated product, the goals of the risk management plan, from the regulatory perspective, change in parallel. When entering Phase 1 trials, before any clinical safety or efficacy data has been gathered for the prospective product, the focus is primarily on patient safety. Hazards related to product quality, at this stage, include adventitious agents and potential toxicities due to product- or process-related impurities. In addition, the absence of a reliable potency assay may be considered a hazard with regard to the ability to administer predictable doses when more than one lot of product is to be used. As the product moves through Phase 2 and Phase 3 clinical trials, it becomes increasingly important to understand the relationships between structural characteristics and functional attributes in order to assess the risks that structural variability may have on clinical effect and justify the proposed product specifications. No less important, as one moves toward licensure (and beyond), is the understanding of the impact that changes in manufacturing process parameters have on the product s quality attributes, so that appropriate, risk-based controls can be applied during manufacturing.

18 COMPARABILITY DURING CLINICAL DEVELOPMENT SESSION ABSTRACT During the phases of non-clinical and clinical development, it is expected that the manufacturing process for a biological drug substance evolves in a stepwise manner to provide adequate yields, appropriate product quality for the phase of development, and to deliver the process robustness required of the final commercial process. Such improvements in the manufacturing process have the potential to produce clinical trial materials possessing detectably different quality profiles compared to materials from previous clinical or toxicology batches. Establishing the necessary degree of comparability of pre-and post-change materials, relevant to the stage of development, and understanding the importance and impact of such differences on patient safety and product efficacy can be challenging. This workshop will compare and contrast industry approaches to establishing comparability during clinical development, and will examine evolving regulatory expectations. Plenary presentations and the questions below will serve as a framework for interactive discussions led by a panel of international regulatory and industry experts. To what extent are the concepts described in Q5E applicable to manufacturing/analytical changes during clinical development? o Should the paradigm be more focused on establishing the fitness for use of the post change material (i.e., safe and efficacious) in ongoing clinical trials, rather than comparability with previous process material? o To what extent would drug product data be required as part of the drug substance comparability exercise? What differences are there, if any, in the assessment of comparability at the various stages of development? o Material used in non-clinical studies vs. First into Man material? o First into Man material vs. Material used in pivotal (Phase III) studies? Which quality attributes should be included in the comparability assessment? What types of changes, or what types of differences in analytical comparability data, should trigger the need to conduct additional pre-clinical/ clinical studies as part of the overall comparability exercise? What data/information needs to be provided to sufficiently assure regulators that the post-change material is suitable for forthcoming clinical trials and will not raise patient safety concerns? o Is it sufficient to compare only to the previous process? o When would it be necessary/appropriate to compare all process generations side-by-side? How are sponsors assuring that the analytical methods used to support the comparability assessment are suitable for their intended use? How are sponsors establishing pre-determined acceptance criteria for comparability assessments? What approaches are sponsors taking to address the failure to meet the pre-determined acceptance criteria?

19 COMPARABILITY DURING CLINICAL DEVELOPMENT PRESENTER ABSTRACTS Comparability Regulatory Considerations and Expectations During Clinical Development Birgit Schmauser Federal Institute for Drugs (BfArM), Bonn, Germany During development the manufacturing process of a biological substance is expected to require continuous adaptations and changes in order to satisfy increasing demands of the substance at increasingly predictable quality standards. Concurrently appropriate filiation of batches is considered essential to ensure a suitable performance throughout the preclinical/clinical phases. To balance all needs comparability investigations should be performed whenever process changes are introduced that are likely to impact quality characteristics. The comparability investigations link applied process parameters with resulting product characteristics and as such should help to conclude on product consistency. The challenge to evaluate these comparability data will depend on the complexity of the biological substance itself as well as on the methods used to assess the quality characteristics. The main purpose of a comparability evaluation of quality characteristics should be to ensure the representativeness of the biological substance from one stage of clinical development to the other. It should be discussed which data is needed to provide sufficient evidence that the post-change product is suitable for the forthcoming clinical trials and will not raise any safety concerns for patients included in the clinical trial. Depending on the outcome of quality comparison it may be necessary to bridge observed differences by additional pre-clinical and clinical studies. A decision in this respect will always include the knowledge of the particular substance in the context of clinical performance and the potential of these studies to provide the necessary information.

20 Comparability During Clinical Development Anthony Mire-Sluis Amgen, Inc., Thousand Oaks, CA USA It is expected that changes to the manufacturing process are going to occur during the clinical development of a biotechnology product. Changes occur for many reasons, including scale, site, efficiency and increased robustness. It is therefore essential to ensure that process changes do not impact the quality attributes of a product so that previous nonclinical and clinical study data remain applicable to product moving forward. Thus, a risk based and timeline appropriate comparability program should be developed to monitor product quality attributes during development. The extent of testing (analytical, nonclinical or clinical) and acceptance criteria for such studies will depend on the stage of development, the type of change and the nature of the product. In addition, what one does should one fail analytical comparability needs consideration. One must also assure that data collected is archived in a way such that it can be used to create a product development history that is eventually filed in a marketing application.

21

22 CONTROL STRATEGIES FOR PRODUCTS IN CLINICAL DEVELOPMENT SESSION ABSTRACT The strategy for design of a control system including relevant in process controls, and specifications for products in clinical development from Tox to Phase 3 and market will be discussed in this session. The topics listed below will be discussed by the panel, representing both industry and agency from Europe and USA. However, any question can be discussed that extends the knowledge and understanding between the industry and agency. What constitutes a scientifically sufficient amount of structural characterization data throughout clinical development? At what point during the development is it appropriate to characterize porcess and product related impurities? What are regulatory expectations (industry and agency) for the evolution of qualitative specifications (FIO) on process related impurities and product related variants? How do industry approaches to the development of process control strategies compare to the evolveing global regulatory expectations?

23 CONTROL STRATEGIES FOR PRODUCTS IN CLINICAL DEVELOPMENT PRESENTER ABSTRACTS Control Strategies for Investigational Medicinal Products in Clinical Trials An Assessor s View Niklas Ekman National Agency for Medicines, Helsinki, Finland The approval of an investigational medicinal product (IMP) for clinical trials is based on balancing between the foreseeable risks against the anticipated benefits for trial subjects. In order to minimise the risks, the quality of the IMP must be properly controlled. This is achieved at multiple levels, including control of the raw materials, with emphasis on the safety of any materials of biological origin, by the use of a qualified and suitable manufacturing process with critical manufacturing steps and intermediates identified, and by proper characterisation of the IMP allowing the Company to set adequate drug substance and drug product specifications. The regulatory expectations for the control strategies will be discussed.

24 Control of Process and Product During the IND Stages: Regulatory Considerations Roman Drews CBER, FDA, Rockville, MD USA Abstract is not available at time of printing.

25 What Characterizes a Biologically Relevant in vitro Assay? Bettina Lundin Brockdorff Novo Nordisk A/S, Copenhagen, Denmark Estimation of potency (bioactivity) for peptide and protein based pharmaceuticals is essential to ensure a constant physiological effect of drug compound from batch to batch. Therefore, potency is one of the most important specification analyses for biopharmaceuticals. We will describe how potency results may be interpreted, and how results from in vitro bioassays differ from in vivo bioassays. Finally, different types of in vitro bioassays will be presented, in order to address the question: What Characterizes a Biologically Relevant in vitro Bioassay? This issue will be discussed in the light of the recommendations stated in the ICH Q6B Guideline.

26

27 STABILITY REQUIREMENTS FOR PRODUCTS IN CLINICAL DEVELOPMENT SESSION ABSTRACT Ensuring the stability of clinical trial material is critical both with respect to patients safety and also with respect to the interpretation of the trials result. Recognizing the limited stability database available early on in drug development, the discussion should focus on essential stability information that should be submitted in regulatory dossiers in order to initiate clinical trials throughout the different development phases. Ideally best practice recommendations on how to set retest dates for drug substance and drug product should be elaborated during the discussion too. What stability data sets (e.g. conditions, duration) for drug substance, drug product as well as placebo formulations are required in order to initiate clinical trials? How to set limits for shelf life specifications? What are acceptable procedures for setting retest-dates (e.g. real time data versus predictions)? What drives the need for substantial IMPD-amendments if retest dates are changing?

28 STABILITY REQUIREMENTS FOR PRODUCTS IN CLINICAL DEVELOPMENT PRESENTER ABSTRACTS Considerations and Expectations on Stability Data During Clinical Development Ivana Haunerova State Institute for Drug Control, Prague, Czech Republic Stability of the drug substance/ product is one of the most critical parameters that predict the quality of the medicinal product which is applied to patients. It has to be ensured that the investigational medicinal products that are applied to different patients at different time points during the clinical trial have a comparable quality and safety. Stability data are assessed on a case-by-case basis. There are a few aspects that have to be taken into consideration during the assessment of the stability studies, e.g. stability protocol, amount of batches placed into studies, available supportive data, studies at accelerated or stressed conditions, validation of analytical methods. The requirements are changing depending on a phase of development as well. Results from at least three time points for one representative batch are required as minimal data in the Czech Republic. However, the extrapolation based only on results from a long-term stability study for one batch is very problematic. Therefore, results of a long-term stability study for at least two batches are expected at a later stage of development. In addition, results of accelerated stability study should demonstrate that used control methods are stability indicating. The case-by-case way of assessment causes that regulatory requirements vary among individual assessors from different member states. However, the Guideline on the Requirements to Quality Documentation Concerning Biological Investigational Medicinal Products in Clinical Trials is in preparation and this document should help harmonize regulatory requirements within the EU. A few concrete examples of a stability data assessment will be presented and discussed during the presentation.

29 How to Ensure the Stability of Products in Clinical Trials An Industry Perspective Volker Schnaible F. Hoffmann-La Roche Ltd., Basel, Switzerland Stability is an important aspect for all stages of pharmaceutical development. A stable product has to be administered in (pre-) clinical trials to ensure patients safety and to achieve clear cut (pre-) clinical trial results. When stability is considered right from the start, eliminating hot spots for degradation can improve stability of the molecule. Besides the chemical nature of the molecule manufacturing processes for API and DP have an impact on quality/stability of (clinical) trial material. Therefore, suitable processes for manufacturing of API and DP have to be developed. A stable formulation of the DP depends also on the choice of excipients and suitable primary packaging materials. When formulation development is performed before initiation of GLP- Tox studies, these studies can be carried out with stable material representative for clinical trial material. To ensure that the right quality is delivered to the patients, adequate measures for all steps of the supply chain have to be taken to ensure stability of the product during shipment and administration. Stability during storage of API and DP is evaluated by collecting stability data at the intended storage temperature and accelerated conditions. For setting of retest periods, extrapolation of stability data by linear regression is justified, as stability data follow a linear relationship. Setting of shelf life specification limits requires consideration of several sources of information. For some parameters pharmacopeial limits are defined, whereas other parameters (e.g. ph) are specified based on the results of formulation studies. Specification limits for parameters that are related to efficacy and purity are difficult to set in early stages of clinical development and require product specific knowledge including input from (pre-) clinical experts. By considering all the above mentioned aspects a set of different measures are in place to ensure the stability of clinical trial material.

30

31 EU GUIDANCE ON MONOCLONAL ANTIBODY: PRACTICAL IMPLEMENTATION ASPECTS SESSION ABSTRACT This session will focus on the practical implementation aspects of the New EU guidance on Production and Quality Control of Monoclonal Antibody, and will aim at providing additional details on how and when to gather the required information and justifications throughout the product clinical development phases. In particular, the following key topics within the guidance will be addressed in detail: 1) Requirements for Particulates Testing: a) Monograph requirements and the need for harmonisation b) Analytical methods sub-visible and visible - suitability and limitations c) Relative significance of intrinsic versus extraneous particulates d) Impact of particle formation on stability e) Control and mitigation of particulate formation 2) Platform Manufacturing Processes: a) How will platform knowledge be documented internally and changes managed as the platform evolves? b) How is the applicability of prior or platform knowledge justified for a new product? c) How is prior or platform knowledge documented and the applicability justified in Regulatory submissions? 3) MAB Fc Effector Function: Role and Control: a) How to assess potential impact of glycosylation on effector function? b) How to assess unwanted effector function? What is the control strategy for unwanted effector function? c) Does the presence of engineered glycoforms augment effector function? d) What is the impact of manufacture changes on glycoforms profiling? How to ensure manufacturing consistency? The session will include brief plenary presentations on the above topics followed by an open discussion on key questions facilitated by a panel of international regulatory and industry experts.

32 EU GUIDANCE ON MONOCLONAL ANTIBODY: PRACTICAL IMPLEMENTATION ASPECTS PRESENTER ABSTRACTS The CHMP Guideline on Monoclonal Antibodies for in vivo Use in Humans Robin Thorpe National Institute for Biological Standards & Control (NIBSC), Potters Bar, United Kingdom The CHMP (EMEA) guidance on monoclonal antibodies has undergone significant revision over the past few years, with a new guideline coming into effect on 1 st July This guideline covers principles and general requirements for development, production, characterisation and specifications for monoclonal antibodies to be used as, or in the production of, human medicinal products. An overview of the new guideline will be given, with new additions being highlighted. Cross reference to other European guidance documents will be made where this is relevant.

33 Monoclonal Antibodies for Human Use 2031 Guy Rautmann European Directorate for the Quality of Medicines Council of Europe (EDQM), Strasbourg, France Abstract is not available at time of printing.

34 Requirements and Challenges for Particulates Testing Paul Varley MedImmune Limited, Cambridge, United Kingdom The presence of particulates in monoclonal antibody drug products remains a significant challenge. This challenge is reflected in many areas of manufacturing and development including: Formulation and the drivers to minimise particulate formation Characterisation and analysis of particulates: including differentiating between intrinsic vs. extraneous particles Regulatory requirements and expectations: including the harmonisation of monograph requirements The aim of this presentation is to review the current issues in order to facilitate discussion and understanding around what information is required for antibody development.

35 TITLE TBD Ron Taticek Genentech, Inc., South San Francisco, CA USA Abstract is not available at time of printing.

36 A Risk-based Strategy for Characterization of Effector Functions of Therapeutic Antibodies Xu-Rong Jiang MedImmune, Gaithersburg, MD USA Abstract is not available at time of printing.

37