Characterization of Biotechnology Products: A Regulatory Perspective Laurie Graham Acting Team Leader FDA/CDER/OPS/OBP Division of Monoclonal Antibodies WCBP 2013 1
Disclaimer The views and opinions expressed should not be used in place of regulations, published FDA guidance, or discussions with the Agency 2
Characterization: Product and Process Understanding CQAs In vitro, animal, and clinical data, prior knowledge, and published information used to assess impact on PK/PD, potency, immunogenicity, and safety Enhanced approaches Increased product and process understanding Control Strategy Process Development and Characterization Process characterization studies to determine how CQAs are influenced by the manufacturing process and material attributes 3
Presentation Outline 1. CQA identification 2. Control Strategy 3. Assay Lifecycle Management Changing Analytics 4
Critical Quality Attributes Enhanced approaches Enhanced understanding of product and process CQAs In vitro, animal, and clinical data, prior knowledge, and published information used to assess impact on PK/PD, potency, immunogenicity, and safety Process Development and Characterization Studies to determine how CQAs are influenced by the manufacturing process and material attributes Control Strategy 5
Critical Quality Attributes A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH Q8) 1. Define product heterogeneity 2. Preliminary CQA assessments and further studies 3. Identifying CQAs 6
Defining Heterogeneity ICH Q6B Characterization efforts should include assessments of - physiochemical properties - biological activity - immunochemical properties - purity - impurities 7
Heterogeneity of Biotechnology Products: ICH Q6B Product related variants Process related impurities - Host Cell Proteins, DNA, raw materials, leachables/extractables Process Contaminants - Adventitious agents 8
Examples of Mab Product Related Variants In addition - Aggregation/particulates - Fragmentation - Glycation, etc Arthur J Chirino & Anthony Mire-Sluis Nature Biotechnology 22, 1383-1391 (2004) 9
Regulatory Expectations: CQAs The structural and functional complexity of biotechnology proteins makes identification of a product s critical quality attributes challenging as a large number of attributes need to be assessed Expect some information at phase 1 with continued refinement during development For enhanced approaches, CQA identification generally more systematic, detailed, and involves the use of formal risk assessment tools and CQA score 10
CQA assessments and Further Studies: Product Variants Non-clinical and clinical data, prior knowledge, published information are used to assess impact on PK/PD, activity, immunogenicity, safety, etc. Additional Studies: - in vitro: variants assessed for bioactivity, antigen and Fc binding including FcRn binding (PK). Involves isolation/enrichment/generation of variants - in vivo: variants assessed during animal or clinical studies 11
Examples of CQA Risk Assessment Tools Sponsor 1 and 2: Severity x Uncertainty - Activity, safety, immunogenicity, PK/PD Sponsor 3: Impact x Probability x Uncertainty - Includes process capability and detectability - Consider safety and efficacy and strength of data Sponsor 4: Severity x Uncertainty - Activity, safety (including immunogenicity), PK Sponsor 5: Impact x Uncertainty - Effect on safety and efficacy Sponsor 6: Impact x Probability attribute impacted by process - Rationale for scoring not provided 12
CQA Identification Risk Assessment Tool Deficiencies Not all CQAs identified (impacts process characterization, design space, control strategy) Incorrect assessment of quality attributes in the risk assessment (e.g., exclusion of potential mechanism of action from evaluation) Underestimation of criticality of attribute because process capability and/or detectability were included in the CQA risk assessment 13
CQA Risk Assessment Tool Deficiencies Underestimation of the impact of an attribute because the risk assessment relied heavily on the lack of a clinical impact, but the product lots used clinically contained very low levels of the attribute Lack of assessment of attributes interactions Communicating information used in the CQA risk assessment Platform helpful throughout CQA identification process 14
Examples of General Characterization/CQA Issues Communicated by DMA for Original INDs Incomplete assessment of adventitious agent CQAs Raw material CQAs Not considering all potential product activities Clonality issues Additional attributes need to be considered (e.g. sub-visible particles < 10 µm) Specific product characteristic comments (e.g. IgG2, IgG4, IgM) Product specific immunogenicity comments CQAs based on formulation or presentation 15
Process Characterization Enhanced approaches Enhanced understanding of product and process CQAs In vitro, animal, and clinical data, prior knowledge, and published information used to assess impact on PK/PD, potency, immunogenicity, and safety Process Characterization Characterization studies to determine how CQAs are influenced by the manufacturing process and material attributes Control Strategy 16
Process Characterization In more traditional approaches, per ICH Q11, material specifications and process parameter ranges can be based primarily on batch process history and univariate experiments. Generally have some information on CQA impact by the manufacturing process and material attributes Enhanced approaches: Use preliminary risk assessment to identify material attributes and process parameters that will be studied further for their impact on CQAs. Systematically assess impact on CQAs in small scale univariate and multivariate studies. Establish process metric for CQA Platform helpful 17
Control Strategy Enhanced approaches Enhanced understanding of product and process CQAs In vitro, animal, and clinical data, prior knowledge, and published information used to assess impact on PK/PD, potency, immunogenicity, and safety Control Strategy Manufacturing Process Development Characterization studies to determine how CQAs are influenced by the manufacturing process and material attributes 18
Control Strategy Per ICHQ11, in a traditional approach, set-points and operating ranges are set narrowly to ensure process consistency. More emphasis is placed on the assessments of CQAs as end-product testing 19
Control Strategy: Benefits from Enhanced Approaches Testing strategy defined by CQA and process scoring along with strength of analytics Control strategy evolves throughout lifecycle with CQAs, process understanding, and changing analytics Flexibility in operating ranges and broader CQA acceptance criteria Testing strategy is more meaningful and efficient - Relevant assays with CQA testing to include IPC, lot release, stability, comparability, monitoring, etc Elements of an enhanced approach provide for control strategy benefits without a design space 20
CQA Acceptance Criteria Increased quality attribute knowledge can be used to broaden the acceptable range for some attributes so that they extend well outside manufacturing, clinical, (and potentially process characterization experience) While the range requested for the attribute itself may be acceptable, process/product knowledge would be needed to support the conditions that would result in an unexpected attribute result 21
General Considerations for Replacing an Existing Analytical Method Performance parameters of the new assay should be the same or better than the existing assay The stability indicating properties of the new assay should be the same or better than the existing assay If new product related variants or process related impurities are seen with the new assay, information from retain samples should be provided demonstrating that the variants/impurities are not new If making a major change in how a quality attribute is measured: - Assess consistency and comparability across multiple lots 22
Analytical Updates with Enhanced Approaches Analytical updates to assays that detect and monitor specific attributes (i.e. specific post-translational modification vs. charge assay) Assessment of analytical changes depends upon confidence that old assay does not provide meaningful CQA data not captured by new assay - Confidence that assessments to date have identified CQAs - Strength of the process/material and product understanding - Confidence in the proposed control strategy 23
Summary A thorough characterization- start early QbD experiences in DMA have revealed some common issues, but the inclusion of enhanced elements into DS development and manufacturing has significantly increased product and process understanding and resulted in control strategy benefits, even in the absence of a design space While the use of new analytics can provide benefits over existing assays or measure an emerging quality attribute, their implementation is often challenging. Appropriately store retain samples! 24
Acknowledgements Patrick Swann, Deputy Director, DMA Barbara Rellahan, Team Leader, DMA Jeffrey Baker, Deputy Director, OBP Regulatory Science Policy Branch, DMA 25