Q8 and Q8 annex An industry Perspective

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Bethany Harvey
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an individual expert and not as an EFPIA representative.

1 Workshop on Implementation of ICH Q8/Q9/Q10 and Other Quality Guidelines Beijing December 2008 Q8 and Q8 annex An industry Perspective Brian Withers, Abbott Laboratories, United Kingdom I attend this conference as an individual expert and not as an EFPIA representative. The views expressed here are my personal views and may not be understood or quoted as being made on behalf of EFPIA or in any way reflecting the position of EFPIA

2 Content Q8 and Q8R QbD Design Space Control Strategy Benefits Of QbD Flexible Regulatory approaches Implementing QbD

3 July 2003: An ICH vision Our vision: The future Pharmaceutical Quality System Quality Risk Management The Regulatory Quality System Quality Risk Management (Q9) For companies with : 1. Good design and control strategies 2. Good Risk Management strategies 3. Good Quality Systems Quality Systems Quality by Design (Pharmaceutical Development) Existing GMP s Quality by Design (Q8) Quality Systems (Q10) Reduced regulatory burden: Reduction of submissions on changes/variations Inspection of quality systems We are responsible for ensuring the quality of product we manufacture

4 The Opportunity Pharmaceutical Quality Risk Development: + Management + Quality by Q9 Design Q8 Modern Effective Pharmaceutical Quality Systems Q10 Lower Risk Operations Innovation and Continual Improvement Optimized Change Management Process Flexible Regulatory Approaches

5 Structure of Q8 Q8 is a 2 part guideline Part 1 Core document Baseline expectations Optional information Regulatory Flexibility Part 2 Exemplifies Quality by Design References to use of risk management Focus on guiding towards Desired State Step 4: Nov 2005 Step 4 Nov 2008

6 Q8 What is it? The Pharmaceutical Development section provides an opportunity to present the knowledge gained through the application of scientific approaches and quality risk management to the development of a product and its manufacturing process.

7 Q8 an opportunity for change Traditional Empirical Data Driven Retrospective Test to document quality Acceptance criteria based on limited batch data Variability not understood and avoided Q8 Systematic Future Knowledge driven Prospective Science and Risk based Acceptance criteria based on patient needs Variability explored and understood (Design Space) Adapted from J Berridge

8 Q8: Pharmaceutical Development Parent guideline Introduced the general principles of pharmaceutical development Components of the drug product Formulation development Manufacturing development Introduced new concepts Minimal versus enhanced Design space Real time release (testing)

9 Q8 Parent Guideline Minimum Expectations At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. Optionality In addition, the applicant can choose to conduct pharmaceutical development studies that can lead to an enhanced knowledge of product performance over a wider range of material attributes, processing options and process parameters. Flexibility The guideline also indicates areas where the demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.

10 Q8 (R1) Annex At a minimum approach to Pharmaceutical Development Quality Target Product Profile Identification of potential critical quality attributes of the drug product Determining the critical quality attributes of the components of the drug product Selecting an appropriate manufacturing process Determining a control strategy

11 Q8 (R1) Annex Enhanced Approach (QbD) to Pharmaceutical Development Additionally:- Systematic evaluation, understanding Use of prior knowledge, risk assessment Functional relationship between material attributes and process parameters to product critical attributes Establishment of design space, real time release testing As a consequence facilitates continual improvement and innovation (ICH Q10)

12 Approaches to Pharmaceutical Development Aspect Minimal Approaches Enhanced, Quality by Design Approaches Overall Pharmaceutical Development Mainly empirical Developmental research often conducted one variable at a time Systematic, relating mechanistic understanding of material attributes and process parameters to drug product CQAs Multivariate experiments to understand product and process Establishment of design space PAT tools utilised illustrates some potential contrasts between what might be considered a minimal approach and an enhanced, quality by design approach We are responsible for ensuring the quality of product we manufacture

13 Quality by Design Quality by Design: A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. QbD DESIGN SPACE QbD ADJECTIVE

14 QbD: Key Scientific Elements and Flow Target Product Profile Definition of Product Intended Use and predefinition of Quality targets (wrt clinical relevance, efficacy and safety) Prior Knowledge Summary of Prior Scientific Knowledge Initial Risk Assessment Product/ Process Dev. Overview of key actions taken to develop New Scientific Knowledge, e.g. DoE, PAT, Risk Assessment and Risk Control Product/ Process Design Space Summary of Scientific Understanding of Product and Process. Justification and description of design space Control Strategy Definition of Control Strategy Regulatory Flexibility Proposal of Regulatory Flexibility based on Product and Process Scientific Knowledge and Quality Risk Mgmt. Adapted from EFPIA

15 Thoughts on QbD QbD approach: Builds more science and knowledge into regulatory submissions Facilitates regulatory review and approval process Is optional and should not become a regulatory requirement as agreed to in ICH Q8 Will not necessarily be included in all submissions Can provide knowledge and understanding of critical product and process parameters and quality attributes DoE, PAT, etc. are tools that can facilitate QbD, but may not always be necessary

16 Definitions for CQA & CPP Critical Quality Attribute 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. Critical Process Parameter A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure to process produces the desired quality. No Definition of Critical Flexibility on how a company determines criticality We are responsible for ensuring the quality of product we manufacture

17 Design Space Three Key Concepts: Design Space: the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval.

18 More about Design space What to include Select input variables that impact quality Where to apply a design space Guideline gives freedom to apply to one or more unit operations Importance of scale Design space will generally be established at small or pilot scale Need to establish the relationship on scale BUT Does not mean need to replicate work at scale Design Space vs Proven acceptable Ranges Design Space vs Edge of failure

19 CONTROL STRATEGY A control strategy is designed to consistently ensure product quality. Elements of a control strategy can include: Control of input material attributes Product Specifications Controls for unit operations that have an impact on downstream processing or end-product quality In-process or real-time release testing in lieu of end-product testing A monitoring program for verifying multivariate prediction models Enhanced understanding of product performance can justify the use of surrogate tests or support real-time release testing in lieu of end-product testing. A control strategy can include alternative elements We are responsible for ensuring the quality of product we manufacture

20 Real Time Release Testing Approach Traditional Release Approach LOD endpoint Granulation Milling Drying Granulation endpoint model to control dissolution NIR granule drying endpoint model Weight, thickness, hardness, disintegration, friability AQL DP release tests Description ID Content (HPLC) Impurity (HPLC) Uniformity (Mass) Dissolution Milling Blending Lubrication Compression Film Coating Laboratory NIR blend uniformity NIR composite assay On-line dosage uniformity by tablet press weight control Main compression height to control dissolution Description by AQL NIR for ID DP release tests Impurity (HPLC) GlaxoSmithKline

21 Benefits

22 QbD Everyone Benefits Reduce Post-approval regulatory submissions Recalls & manufacturing failures Uncertainty & Risk Cost Regulatory burden Non value regulatory &/or compliance exercises Need for process validation NDA documentation Improve Operational flexibility Process understanding Application of technology, e.g., PAT, modeling, scale Quality Regulatory review criteria Scientific/technical literacy among regulators Capitalization on experience Development efficiency Global harmonization

23 Benefits to industry better products risk-based regulatory decisions (reviews and inspections); manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review; reduction of post-approval submissions; real-time release testing, leading to a reduction of end product release testing. We are responsible for ensuring the quality of product we manufacture

24 Regulatory Flexibility

25 Flexible Regulatory Approaches Objective: greater empowerment to self-manage innovation and improvement Enhanced product and process understanding (multi-variate) leading to Design Space Pharm Quality Systems (Q10) plus Quality Risk Management (Q9) Flexible Approaches This should not be considered to be about de-regulation Adapted from Dr J Berridge

26 Flexible Regulatory Processes Investment by Industry in enhanced process and product understanding should lead to more flexible regulatory approaches More meaningful and realistic specifications Parametric/real-time release Skip-lot testing Flexible, adaptive and learning (manufacturing and analytical) processes Reduction in routine commitments (e.g., stability) Reduction in categorisation of post-approval changes (pre-approval -> notification) We are responsible for ensuring the quality of product we manufacture

27 Implementing QbD What are the next steps? How do we transition to the new quality paradigm? What are the hurdles and opportunities?

28 If only applying QbD was simple from R.Baum

29 Cost and Benefit of QbD Development & Manufacturing Costs Increased Resources (e.g., development costs, organizational planning) Current State Empirical development approach Quality by testing & inspection Frozen process with reactive changes Initiate QbD Efforts Decreased Expenses (e.g. manufacturing costs, compliance costs) Desired State Quality by design development Flexible process & continual improvement QbD Fully Realized QbD Implementation Progress From M.Nasr

30 Alternative QbD Investment QbD Way #1 QbD Way #2 $ Investment More Limited Knowledge at Launch Launch Launch IND Commercial IND Commercial Products launched at same time, at same quality Same overall investment in development

Summary Q8 and Q8(R1) provides an opportunity to share knowledge with regulator Application of QbD Approach to development benefits everyone BUT Is optional Companies

31 Summary Q8 and Q8(R1) provides an opportunity to share knowledge with regulator Application of QbD Approach to development benefits everyone BUT Is optional Companies are implementing enhanced approaches but takes time and will not always be applied to all products We are responsible for ensuring the quality of product we manufacture

32 THANK YOU

STRATEGIES FOR SUCCESSFUL SCALE-UP USING QUALITY BY DESIGN

STRATEGIES FOR SUCCESSFUL SCALE-UP USING QUALITY BY DESIGN CHRISTOPHER J POTTER ISPE ADVISOR AND CMC CONSULTANT 1 AGENDA Background ICH Guidelines Terms and Definitions Supporting Information ISPE publications