What to control? CQAs and CPPs Dr. Thomas Stangler On behalf of - PowerPoint PPT Presentation

What to control? CQAs and CPPs Dr. Thomas Stangler On behalf of the European Generic medicines Association Development Strategy & Technology Manager Sandoz Biopharmaceuticals BWP Workshop on Setting Specifications London, 9 September 2011 1 1 | Martin Schiestl | Singapore, 27 November 2010

Agenda  Critical Quality Attributes (CQAs) • Scoring Impact and Uncertainty • Uncertainty Dilemma • Continuous quality attribute critical scale  Critical Process Parameters (CPPs) • Process control point analysis – High level overview on process – product linkage • FMEA risk assessment as life cycle approach • Considering process parameter range  CQAs and CPPs as basis for the control strategy 2 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Elements in Biopharmaceutical Development  Establish Quality Target Product Profile – the QTPP forms the QTPP basis of design for development of the product  Determine Critical Quality Attributes – linking quality attributes CQAs to clinical safety and efficacy Process Risk  Linking process parameters and critical material attributes to Assessment CQAs – Definition of critical process parameters (CPPs)  Optional: Define the design space – (multivariate) acceptable Design Space process parameter ranges Process Knowledge  Design and implement control strategy using risk management Control Strategy e.g. by linking CQAs to process capability and detectability Continual  Manage product life cycle, including continuous process Improvement verification and continual improvement 3 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Regulatory landscape for CQAs ICH Q7 Validation: “Defining the API in terms of its critical product attributes“ “At a minimum, those aspects of drug substances [...] that are critical to ICH Q8(R2) product quality should be determined and control strategies justified“. Definition in ICH Q8(R2) ANNEX : 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. “Manufacturing process development should include, at a minimum, the ICH Q11 following elements: Step 3 Identifying potential CQAs associated with the drug substance [...]” “Applications should include the following minimal element [...]: FDA MaPP - Critical Quality Attributes (CQAs) of the drug product “Applying ICH Q8, Q9, Q10 - CQAs of the drug substance and excipients” Principles to CMC Review” CQAs are a key concept for a pharmaceutical product development 4 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Assessing quality attribute criticality  Using quality attribute Start with list of all possible quality attributes criticality for: – Consider mode of action and molecule type •Prioritization in QbD cell line &  Risk-based approach to identify CQAs process development – Links quality attributes to safety and efficacy •clone and process selection – Standardizes judgment and documents establishing and justifying analytical rationale program  •comparability exercises, justification Criticality reflects impact on safety and of acceptance ranges and quality efficacy differences  Keep process considerations separate from •process characterization (linking CQA assessment process parameters to quality – CQA impact on safety & efficacy is attributes) independent of process capability, process • control strategy (process, IPCs, changes shouldn’t impact QA criticality specifications) – makes CQA assessment more modular •dossier (CQA as regulatory expectation) •Knowledge management (beyond licensing) 5 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Quality Attribute Criticality Assessment  Risk assessment for ranking and prioritizing quality attributes  General concept described in A-MAb case study (Tool #1) Criticality Score = f(Impact,Uncertainty) e.g.: Criticality Score = Impact x Uncertainty (A-MAb) Criticality Score Impact Uncertainty Quantitative measure for Known or potential Relevance of information e.g. an attribute‘s impact on consequences on safety safety and efficacy. and efficacy, considering: literature •Biological activity prior knowledge Using best possible •PK/PD in vitro surrogates for clinical •Immunogenicity preclinical safety and efficacy •Safety (Toxicity) clinical or combination of information Manufacturer‘s accumulated experience, relevant information, data e.g. literature, prior & platform knowledge, preclinical and clinical batches, in vitro studies, structure-function relationships 6 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Scoring Impact – examples scales from A-Mab  Scoring Impact on biological activity, PK/PD, immunogenicity and safety individually for all quality attributes 7 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Scoring Uncertainty – example from A-Mab  Scoring Uncertainty for every scored Impact  Criticality Scores for A-Mab calculated by Impact x Uncertainty – Criticality Score between 2 and 140 8 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Benefits of a continuum of criticality  FDA guidance on process validation – The degree of control over those attributes or parameters should be commensurate with their risk to the process and process output. In other words, a higher degree of control is appropriate for attributes or parameters that pose a higher risk. – Perception of criticality as a continuum rather than a binary state is more useful. Source: FDA Guidance on process validation 9 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Criticality Score: Dilemma of high uncertainties  Highest scores for high impact – combined with high uncertainty  Lower scores for high impact – combined with low uncertainty high 140 14 28 High uncertainty – high impact e.g. mistranslations, hybrid What is more glycans 20 critical? Uncertainty “I know it has an Appropriate ranking for impact“ Criticality = Impact x Uncertainty development & control? or Low uncertainty – high impact “It might have an e.g. Modification in CDR region impact“ 2 20 low low high Impact 10 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Approaches to solve the Uncertainty dilemma Impact-only Criticality Threshold High Uncertainty Criticality = Impact x Uncertainty with CQA threshold Impact only Low low high low high Impact Impact  May only be applicable very late-  Low threshold necessary to avoid any phase with very good product false non-criticals understanding  Loosing continuous criticality score  Loosing the uncertainty information 11 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Alternative approach for the criticality score  Putting highest criticality on high impact & low uncertainty – And ensure sufficient criticality for high uncertainty attributes  Criticality as a continuum rather than a binary state High Low certainty “It might have an impact” – high impact Uncertainty Increasing Criticality High certainty “I know it has an impact” – high impact Low low high Impact 12 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Example for a continuous criticality scoring  Scoring of Impact & Criticality Score Uncertainty conceptually 45 50 70 80 90 7 similar to A-Mab Uncertainty 6  Determination of criticality 31 39 73 90 107 5 score using either 24 34 74 95 115 4 • Scoring matrix as shown 16 28 76 100 123 3 (5 criticality categories or 9 23 77 104 132 2 continuous score) 1 2 17 79 109 140 • Calculation using a formula 2 4 6 8 10 12 14 16 18 20 Impact 13 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011

Elements in Biopharmaceutical Development  Establish Quality Target Product Profile – the QTPP forms the QTPP basis of design for development of the product  Determine Critical Quality Attributes – linking quality attributes CQAs to clinical safety and efficacy Process Risk  Linking process parameters and critical material attributes to Assessment CQAs – Definition of critical process parameters (CPPs)  Optional: Define the design space – (multivariate) acceptable Design Space process parameter ranges Process Knowledge  Design and implement control strategy using risk management Control Strategy e.g. by linking CQAs to process capability and detectability Continual  Manage product life cycle, including continuous process Improvement verification and continual improvement 14 |What to control?, BWP Workshop on Setting Specifications | Thomas Stangler, September 9th, 2011