Concept Paper Consideration for setting Specification

Transcription

1 CASSS CMC Strategy Forum EBE Satellite Session Concept Paper Consideration for setting Specification 23 rd April 2012, Berlin, Germany Christoph Lindenthal on behalf of the concept paper focus group

2 Development of the Concept Paper The EBE BioManufacturing Group endorsed the writing of a concept paper with the topic of Setting of Specification. In Dec a drafting group was formed consisting of members of Abbott, Amgen, Baxter, BMS, Janssen Biologics, Leo Pharmaceuticals, Merck Serono, MedImmune, Novartis, Novo Nordisk, Pfizer, Roche A first working draft was generated beginning of By Dec the first draft was circulated within the EBE Manufacturing Group and to the participating companies. Comments were received and incorporated in a second draft by March Second round of review within EBE and participating companies in March 2012 Comments and Suggestions from a joined EBE/BWP Workshop in September 2011 were considered and included in the latest draft version 2

3 Further Steps Open-up discussion to broader group, to resolve open points May 2012: Incorporate outcome of discussion and considerations from this meeting into third draft and perform additional review cycle within EBE June 2012: Publish Concept Paper Further discussion and 3rd review seen beneficial in order to generate a concept paper, which is broadly accepted. 3

4 Objective/Scope of the paper The purpose of the concept paper is to discuss considerations for setting of specifications for commercial biotech drug substances and drug products as part of an overall control strategy. t The document identifies three relevant steps: Criticality assessment for product attributes Establishing the specifications as part of an overall control strategy Setting of acceptance criteria The paper is applicable in a traditional development setting as well as in cases where an enhanced process understanding has been achieved for a particular product (e.g. QbD). 4

5 Objective/Scope cont. This concept paper will promote a consistent application of the existing guidance on specification setting based on a common understanding of the requirements amongst EBE member companies. Not intended to replace the available regulatory guidelines Intended to augment the guidance available by providing expanded discussions on certain topics with the intent of ensuring that applicants meet the current expectations of regulators. The concept paper reflects the ongoing dialogue between health authorities and biotech industry on the topic of specification setting, and presents the current thinking. 5

6 Criticality assessment for product attributes (1) Overall Process Definition of Target Product Profile (TPP), Defines key aspects related to the supply and use of the product and desired efficacy and safety Establishment of quality target product profile (QTPP), Defines the quality characteristics that should be met in order for the TPP to be achieved Based on QTPP, a detailed process of establishing the critical quality attributes of the product is performed 6

7 Criticality assessment for product attributes (2) 1. Initial criticality assessment Based on the QTTP and prior knowledge of the product type, a list of potential ti critical quality attributes (pcqas) is identified 2. Definition of CQAs Based on the results of the product characterization studies and further assessment against the QTTP, the list of CQAs is established. The list of CQAs is typically established during development and finalized prior to marketing application. 3. Criticality score/ Impact score of quality attributes A rating is typically assigned to each attribute, which will subsequently be used together with other knowledge, such as information on how the process impacts the identified QAs, in order to determine the control strategy. 7

8 Criticality assessment for product attributes (3) In general, criticality can be considered as a continuum. A different level of criticality can be assigned to each QA depending on its criticality assessment with respect to impact on: 1. Biological Activity or Efficacy 2. Pharmacokinetics/ Pharmacodynamics 3. Immunogenicity/ 4. Safety Attributes of sufficiently low criticality may be excluded from further consideration within the design of the control strategy non-cqa Attributes of moderate to high criticality are taken forward to next stages of the development of the control strategy depending on the results of criticality assessment. 8

9 Criticality assessment for product attributes (5) The criticality of each attribute has to be assessed individually Glycosylation is not by definition a CQA, but has to be considered as any other QA. Only if there is a potential impact on Efficacy, PK/PD, Immunogenicity or Safety, a moderate to high criticality score is assigned and it would have to be controlled as part of the overall control strategy. Content and Potency always have to be tested, however potency is considered a non-cqa since they reflect the combined effects of numerous discrete molecular l attributes t 9

10 Criticality assessment for product attributes, points for discussion. Is there a clear borderline between CQA and non-cqa or is it rather a continuum, where the criticality score defines if and how a QA has to be controlled? What knowledge has to be available/considered in order to define an attribute as non-critical during critically assessment? How much data is required in order to control an attribute by other means rather than testing in the overall control strategy? 10

11 Establishing the specifications as part of an overall control strategy (1) A complete discussion of all of the factors required to define the control strategy is beyond the scope of the paper. The Scope is to define a testing strategy: which tests should be routinely conducted to control defined process parameters and materials attributes, What is included on the registered specifications for drug substance and drug product, including the test methods and associated acceptance criteria Defining a testing strategy is independent of the extent to which the principles described in an enhanced approach have been followed in the development of the product 11

12 Establishing the specifications as part of an overall control strategy (2) RISK ASSESSMENT Severity (Define CQA) Impact on Safety and Efficacy Detectability Capability of Analytical Methods Probability Relationship of product knowledge to process capability CONTROL STRATEGY Develop Control Strategy Periodical Re-assessment Control of Material Attributes Procedural Controls Process Parameters Controls End Product Testing Intermediate Testing In Process Testing Life Cycle Management Stability Testing 12

13 Establishing the specifications as part of an overall control strategy (3) Testing Strategy Develop and define a composite set of analytical tests and acceptance criteria to confirm consistency of the process to produce drug substance and drug product with the required product quality attribute profile. Defines whether a CQA is controlled by testing or by other means. If testing ti is required, defines where testing ti is performed, e.g. on inprocess samples, on drug substance and/or drug product and/or during stability studies. Defines which parameters and acceptance criteria are registered within the marketing application and which apply within the context of the Quality Management System. 13

14 Establishing the specifications as part of an overall control strategy (4) Attribute classification Medium to High criticality/impact t (CQA) Action Control of attribute is required by any of the following actions dependingdi on the impact of the CQA: Analytical testing: Routine testing (in process or end product testing) No routine testing required. Monitoring during life cycle management or comparability testing may apply Process control as demonstrated by process validation Monitoring selected process parameters including KPIs Control of Critical Process Parameter s (running the process within its design space) No testing because the attribute is not abundant/does not form under stress conditions and worst case process conditions Low Criticality/ Impact (Non- CQA) No Control required and no routine testing performed. Reassessment during life cycle management 14

15 Establishing the specifications as part of an overall control strategy (5) Principles for Method Selection Selection may be different for traditional or enhanced approach Method capability to detect t and control individual id CQA Method Suitability for extended Characterization and CQA identification Method validation Compendial Methods 15

16 Definition of acceptance criteria (1) The control strategy should ensure that the level of each critical quality attribute is maintained within a range that yields a product of acceptable quality from the perspective p of clinical safety and efficacy. Acceptance ranges are primarily defined by a knowledge- and riskbased approach Acceptance limits may be wider than clinically qualified ranges Process capability is not the main driver to define acceptance ranges Available dataset at time of filing is typically limited and the observed variability does not necessarily reflect the variability expected during routine production. 16

17 Definition of acceptance criteria (2) Sources of data in general, any data from clinical, preclinical, development and commercial batches can be used to define acceptance ranges. Under careful consideration, data from other, similar molecules and published data (e.g. platform). prediction of immunogenicity and safety in humans cannot be made from preclinical data in animal models. Statistical approaches DS and DP limits may differ, if the storage of drug product and/or the handling during fill and finish could cause a change in the quality attribute Whenever a pharmacopoeia-defined acceptance criterion is available this should be adhered to. 17

18 Acknowledgements Concept paper focus group: Brian Fitzpatrick, Pfizer Brian Withers, Abbott Casper Leuenhagen, Novo Nordisk Christoph Lindenthal, Roche David Peck, BMS Donato Curci, Merck Serono Karin Sewerin, consultant for MedImmune Ken Sejling, Novo Nordisk Louise Ploug, Novo Nordisk Wilemijn Neher van Minnen, Janssen Biologics Margit Jeschke, Novartis Mark Rosolowsky, BMS Michaela Klaudia Bittner, Baxter Niels Vaever-Hartvig, Novo Nordisk Sandra August Bowler, Leo Pharmaceuticals Simon Hotchin, Amgen All reviewers and contributors from the EBE BioManufacturing Working Group member companies experts in setting specifications. 18