CDER Office of Compliance and the

          CGMP Revisions (cont.)                                      CGMP Revisions (cont.)
     First Phase...

                             ICH Quality Vision                                                              ...

            ICH Q10 Content (cont.)                                            ICH Q10 Content (cont.)
3.    ...

                       Q10 and Q9 Link                                                               Quality ...

  Where Do the Challenges Lie? (cont.)                       Where Do the Challenges Lie? (cont.)
Testing and...

        Lifecycle Approach
       to Process Validation                                               Commerc...

 FDA Progress in PAT Implementation                     FDA Progress in PAT Implementation

 Training        ...

What are the Challenges that
        Lie Ahead?
Global Market Place
Variable Regulation or Understanding
of P...
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GMPs for the 21st Century May 2008


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GMPs for the 21st Century May 2008

  1. 1. 5/9/2008 CDER Office of Compliance and the Critical Path Initiative “Since the initial report, we have broadened our Pharmaceutical Quality for thinking about the Critical Path Initiative to include veterinary medicines, generic drugs, and even foods. the 21st Century For all product areas, the basic idea is to reduce uncertainty about product performance throughout the product lif cycle through scientific research. W h d life l h h i ifi research. We have h set up a large number of collaborations with partners to Temple University get this research done, in areas as disparate as drug May 06, 2008 manufacturing and clinical trial design.” -Janet Woodcock 8/17/07 Joseph Famulare, Deputy Director Sustainability of product quality throughout the product FDA CDER Office of Compliance lifecycle is a major role of the Office of Compliance FDA Initiatives: A Quality Timeline Scope of Recent Guidances Process Product Monitoring/ Design Continuous Process Manufacturing Verification Design 2004 2005 2006 2007 2008 ICH Q8/Q8(R) - Pharmaceutical Development PAT Guidance ICH Q9 – Quality Risk Management FDA Guidance on Quality Systems (9/06)/ ICH Q10 – Pharmaceutical Quality Systems CGMP Revisions Modernizing and harmonizing CGMPs Phased approach …1-2-3 …1- Revisions to First Phase – ‘non-controversial’: ‘non- Withdraw proposed 1996 changes CGMP R Regulations l ti Change no asbestos filter to no particle shedding material Potable water can be as defined by, e.g., Japan and EU Equipment needing to be sterilized shall be sterilized 1
  2. 2. 5/9/2008 CGMP Revisions (cont.) CGMP Revisions (cont.) First Phase – ‘non-controversial’ (cont.): ‘non- Second Phase: ‘substantive’ issues Eliminate second person check on automated Proposed rule being drafted equipment Includes incorporation of essential quality system Require sterile container depyrogenation elements processes to be validated Require bioburden testing, as necessary, on in-in- process material Require that both aseptic fill as well as other sterilization processes be validated FDA’s Quality System Guidance Result of the CGMPs for the 21st Century Initiative – finalized August 2006 Encourages the use of modern quality management Pharmaceutical Quality y systems System Emphasizes self-management of change self- Consistent with overall efforts to reduce manufacturing supplements – 21 CFR 314.70 revisions Pharmaceutical Quality Systems ICH Quality Vision - 2003 ICH Q10 A new vision for ensuring product quality Three new letters to learn as we approach the Desired (Brussels, July 2003) 2003) State for pharmaceutical manufacturing in the 21st A harmonized pharmaceutical quality system applicable Century across the life cycle of the product emphasizing an integrated approach to quality risk management and science PQS New ICH guidelines (high level guidelines, more visionary, less prescriptive, flexible regulatory approaches) Pharmaceutical Development (Q8) Quality Risk Management (Q9) How did we get here? Are there challenges ahead? Pharmaceutical Quality Systems (PQS) (Q10) 2
  3. 3. 5/9/2008 ICH Quality Vision ICH Q10 PQS Pre- Pre-2003: quantitative guidance Pharmaceutical Technology Manufacturing Discontinuation Development Transfer Post- Post-2003: strategic guidance Q8/Q9/Q10 For companies with : Management Responsibilities Quality Risk 1. Good design and The Regulatory Management Quality System control strategies (Q9) 2. Good Risk Process Performance & Product Quality monitoring Quality Risk Management strategies CAPA Management 3. 3 Good Quality Systems PQS elements Change Management Management review Quality by Design (Pharmaceutical Quality Development) by Design Reduced regulatory Quality Knowledge Management Systems (Q8) burden: Enablers • Reduction of Quality risk Management submissions on changes/variations Existing GMP ’s GMP’ Quality • Inspection of quality Systems systems GMP (Q10) ICH Q10 Key Points ICH Q10 Content Common terminology 1. Pharmaceutical Quality System Definition and maintenance of the Quality System 2. Management Responsibility The role of management, including senior g g management 3. Continual Improvement of Process Identification of performance indicators and Performance and Product Quality management of trends to achieve highly capable processes 4. Continual Improvement of the Pharmaceutical Effective change control procedures Quality System ICH Q10 Content (cont.) ICH Q10 Content (cont.) 1. PHARMACEUTICAL QUALITY SYSTEM 2. MANAGEMENT RESPONSIBILITY Scope / Objectives Management Commitment / Quality Policy / Relationship of ICH Q10 to Quality Planning Regional GMP Requirements ISO Standards and ICH Q7 Resource Management / I R M Internall Regulatory Approaches Communication Enablers Knowledge management Management Review Quality Risk management Oversight of Outsourced Activities Design & Content Considerations / Quality Manual 3
  4. 4. 5/9/2008 ICH Q10 Content (cont.) ICH Q10 Content (cont.) 3. CONTINUAL IMPROVEMENT OF 4. CONTINUAL IMPROVEMENT OF PROCESS PERFORMANCE AND THE PHARMACEUTICAL QUALITY PRODUCT QUALITY SYSTEM Lifecycle Stage Goals PQS Elements Management Review of the PQS Pharma. Development Monitoring Monitoring of Internal and External Factors Tech. Transfer Corrective/Preventive Manufacturing Actions Impacting the PQS Product Discontinuation Change Management Outcomes of Management Review and Management Review Monitoring Potential Opportunities to Enhance ICH Q10 Comments Regulatory Approaches Docket in E.U., Japan, & U.S. Scenario Potential Opportunity 1. Comply with GMPs Compliance - status quo Over 300 unique comments 2. Demonstrate effective Opportunity to Some themes: PQS, including effective • increase use of risk-based approaches Integration with Other ICH Q Guidelines use of quality risk mgt f li i k for f regulatory inspections l i i principles (ICH Q9 & Q10) Lifecycle: Pharmaceutical Development 3. Demonstrate product and Opportunity to: Definition of “Control Strategy” process understanding, facilitate science-based pharma. Regulatory Impact including effective use of quality assessment quality risk mgt enable innovative approaches to principles (ICH Q8 & Q9) process validation establish real-time release mechanisms Potential Opportunities to Enhance Q10 and Q8 Link Regulatory Approaches Scenario Potential Opportunity Processes for pharmaceutical development (Q8 or 4. Demonstrate Opportunity to: equivalent) are key linkages to product realization effective PQS and increase use of risk-based approaches within the Pharmaceutical Quality System. product and for regulatory inspections process facilitate science based pharmaceutical science-based understanding, quality assessment Q8 provides for robust development and including the use optimize science and risk-based post- understanding that serves as the basis for continual of quality risk approval change processes to maximize improvement. mgt. principles benefits from innovation and continual (ICH Q8, Q9, & improvement Q10) enable innovative approaches to process validation establish real-time release mechanisms 4
  5. 5. 5/9/2008 Q10 and Q9 Link Quality by Design (QbD) The Quality System should encourage and facilitate the use of Quality Risk Management (Q9) A systematic approach to development approaches throughout the system. that begins with predefined objectives The design and application of processes within the and emphasizes product and process d h i d d Quality System should be based on appropriate understanding and process control, risk management principles and methods based on sound science and quality risk management (ICH Q8(R), step 2) Quality by Design (QbD) – A Systematic Approach (QbD) Implementation Effects of Science and to Pharmaceutical Development and Manufacturing Quality Aspects Traditional QbD Closer collaboration between R & D and Commercial Manufacturing – Commercialization Initiative Pharmaceutical Empirical; typically univariate Systematic; multivariate experiments Restructuring of plants worldwide bringing in closer proximity development ,tech Development experiments transfer and initial commercial manufacturing Manufacturing Fixed Adjustable within design Opportunity Costs Tangible business and quality benefits in deviation Process space; opportunities for reduction, health and safety, quality plan conformance, and reduction in innovation (PAT) manufacturing losses and recalls. f i l d ll Process Control In- In-process testing for go/no-go; go/no- PAT tools utilized for offline analysis System of Integrated Quality Standards in place for Development, Manufacturing, feedback and feed forward and Product Surveillance controls Product Primary means of control; based Part of the overall quality control Integrated Pharmaceutical Quality System Drives Sustainability and Specification on batch data at time of strategy; based on desired product Improvement Manufacturing was approximately $200 million under plan for submission performance (safety and efficacy) one year, and approximately $70 million under plan the next year due to quality system improvements Control Strategy Mainly by intermediate and end Risk- Risk-based; controls shifted product testing upstream; reducing product Deviations reduced 70%. variability; real-time release real- Lifecycle Reactive to problems & OOS; Continual improvement facilitated Management post- post-approval changes needed CGMP Quality Program Accomplishments Where Do the Challenges Lie? CDER,CBER,CVM,ORA Aseptic Processing Guidance, Part 11 Guidance, Update of the Validation Compliance Policy Guide, Phase 1 IND CGMP Draft Comments heard: Guidance and Proposed Rule, Study of CGMP regulations, Application to PIC/s, Guidance on Out of Specification Test How do I release the batch with real time Results, Development of the PI Curriculum, Guidance on release? Can I default to “traditional end product Glycerin Testing, PAT, CGMP Q&A. ICH Strategy, ICH Q10 Coming Soon: testing testing” Guidance on the Prevention of Cross Contamination of What is considered Out of Trend Out of Spec Potent Compounds Technology Transfer Initiative and Warrants an Investigation ICH Implementation Working Group What does process validation look like. Lifecycle Approach to Process Validation Guidance 5
  6. 6. 5/9/2008 Where Do the Challenges Lie? (cont.) Where Do the Challenges Lie? (cont.) Testing and Release for Distribution: For each Data, Trends and Investigations: requirement batch of drug product there shall be appropriate under US CGMP to review annually laboratory determination.... Modern manufacturing methods and controls make this possible in real time Doesn t Doesn't have to be end product Not all trends require investigations, however Real time release is sufficient and does not have to “unexplained discrepancies” do be backed up with “traditional end product testing” Manufacturers should be better able to understand nor is it appropriate to substitute at will those with real time monitoring and controls The “need” to do “traditional testing” is covered by stability Process Validation Process Validation Old Approach ? Process Validation for Active Two decades old Pharmaceutical Ingredients is enforceable Design/development foundation weak under the Statute Emphasizes replication at commercial scale p p does not promote a fuller process understanding Statutory cGMP provision at 501(a)(2)(b) of making deviation/problem analysis dubious the Federal Food, Drug, and Cosmetic Act biased batches feasible and valuable Does not sufficiently enable appropriate CGMP guidance available - ICH Q7A regulatory oversight Process Validation Lifecycle Approach to Process Validation The ‘process’ of process validation Lifecycle Overall validation is not “complete” but ongoing Requires comprehensive process design to identify and Series of activities taking place over mitigate significant sources of variability achieve process understanding the ‘life’ of the product/process life’ May incorporate risk management Recognizes that more knowledge will be gained during commercial distribution 6
  7. 7. 5/9/2008 Lifecycle Approach to Process Validation Commercial Production Revised Process Validation Guidance (in progress) Validation in production Process Design: Lab, pilot, small-scale, and commercial scale studies to small- establish process Activities to continually assure that the process remains in a state of control Process Qualification: Facility, utilities, and equipment Confirm commercial process design Commercialization: Monitor, collect information, assess Maintenance, continuous verification, process improvement Monitoring Periodic Evaluation Timely monitoring of critical Re- Re-validation – not using this term in the revised operating and performance Process Validation Guidance parameters Monitoring of product Production h P d i phase monitoring i i characteristics (e.g., stability, product specifications) evaluate quality indicator data, changes, and adverse trends Monitoring adequacy of personnel periodically decide if new studies, e.g., conformances training and material, batches or other verification experiments, need to be done facility/equipment Investigate problems for root cause Retrospective and implement corrective action FDA’s View of PAT Tools Process Analytical Technologies Process Analytical Technology (PAT) a system for designing, analyzing, and controlling PAT tools can be categorized as: manufacturing Process analyzers through timely measurements of critical quality and performance attributes of raw and in-process materials and f ib f d in- i i l d Process control tools processes Multivariate tools for design, data acquisition with the goal of ensuring final product quality and analysis PAT Fundamental Tenets Quality cannot be tested into the product; it should be Continuous improvement and knowledge management built-in or should be by design built- tools PAT Goals Enhance understanding and control of processes PAT is more than just an analyzer! 7
  8. 8. 5/9/2008 FDA Progress in PAT Implementation FDA Progress in PAT Implementation Training CMC Review experience 1st PAT Cadre – 15 investigators and reviewers ONDQA CMC pilot program trained PAT Tools in all CMC pilots PAT tools used in development 2nd PAT Cadre – 45 investigators and reviewers In- In-process controls of manufacturing being trained Process analyzers used for end-product release, including real time end- release Pharmaceutical Inspectorate – training incorporates fundamentals of PAT CMC applications outside the pilot Model based feed-forward control feed- Reviewer training – multiple sessions on many PAT for product/batch release aspects of PAT Additional implementation for generic and veterinary drugs Industry Progress: Examples of Industry Progress: Examples of PAT Tools in Development Process Analyzers in Manufacturing In- In-line laser light scattering analyzer to monitor Monitoring only: nucleation during crystallization Assay by on-line measurement on- FTIR and FBRM (Focus Beam Reflectance Identity by on-line measurement on- Measurement) to understand crystal growth and M t) t d t d t l th d On- On-line particle size monitoring nucleation Monitoring and control: At- At-line DSC to monitor crystalline form Table compression weight check and adjustment Endpoint determination of blending At- At-line pressure test to force drug substance degradation Weight check and adjustment of powder filling operation Adjustment of process parameters based on starting material At- At-line particle size distribution monitoring attributes NIR to understand & design blending process Implementation of PAT Implementation of PAT Regulators/FDA Challenges Industry Challenges Training reviewers and investigators Lack of experience in developing and implementing Developing new approaches for review and inspection Integration of review and inspection y PAT systems Communicating expectations to industry Training of scientific, operational and regulatory International harmonization personnel Industry’s apprehension in adopting new Fear of change approaches and investing in new technologies Perceived regulatory risks Industry’s apprehension in sharing information Investment - more resources needed initially with FDA Management support crucial 8
  9. 9. 5/9/2008 What are the Challenges that Lie Ahead? Global Market Place Variable Regulation or Understanding of Product Quality Economic Pressures and Incentives The Need for Industry to Control Sources and Outsourcing of Activities 9