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Copyright 2005, All Rights Reserved The Quantic Group, Ltd

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0 FDA Compliance and Regulatory Symposium Understanding the FDA’s Latest cGMP Guidances: Opportunities and Pitfalls Claudio Pincus, President, The Quantic Group R. Owen Richards, President, Quantic Regulatory Services Daniel Pincus, Consultant, The Quantic Group 9AM Thursday August 25 Harvard University Copyright 2005, The Quantic Group, All Rights Reserved The Quantic Group sm 5N Regent Street Suite 502 Livingston, NJ (973)

1 Copyright 2005, All Rights Reserved The Quantic Group, Ltd
Copyright 2005, All Rights Reserved The Quantic Group, Ltd., Livingston, NJ This document contains and refers to methodologies that are a Trade Secret of The Quantic Group, Ltd. and are presented with the purpose of describing Quantic’s capabilities or experiences. These Methodologies remain the exclusive property of The Quantic Group, Ltd. Contact Claudio Pincus, President The Quantic Group, Ltd. 5N Regent Street Suite 502 Livingston, NJ 07039

2 There are emerging efforts to improve the industry
Introduction There are emerging efforts to improve the industry “The ICH vision is to move beyond the limitations of the current GMPs to create an integrated quality system that encourages rather than stymies improvement” 1 “The present state is focused on documentation, following SOPs validating the process, meeting specifications, and not changing the process”2 “The desired state, by contrast, would focus on data analysis, understanding critical to quality attributes, measuring process capability, performing continuous quality verification, and undertaking Continuous improvement” 2 2. G. Migliaccio, Pfizer Global Operations VP, Gold Sheet June 2004 3. Adapted from D. Ellsworth, Gold Sheet, April 2005 1. J. Ramsbotham, Solvay, Gold Sheet, June 2004 FDA oversight and pre-approval of manufacturing change will be replaced by the company making the change, subject to routine inspection3

3 FDA is Defining Expectations for Industry
Introduction FDA is Defining Expectations for Industry FDA has initiated a new approach toward cGMPs that creates opportunities and pitfalls for industry The new approach has been defined as “cGMPs for the 21st Century” and includes multiple components intended to provide consistency and efficiency Industry has actively participated in the development and hopes that consistency will provide for a more competitive pharmaceutical manufacturing environment

4 Introduction “The desired state … is for there to be a process control strategy that prevents or mitigates the risk of producing a poor quality product”1 The desired state of manufacturing2 Product quality and performance achieved and assured by design of effective and efficient manufacturing processes Continuous improvement approaches, with innovative use of new technology as desired The desired state of regulation2 [Transparent regulations] and up-to-date guidance Managed within a quality system Uses a risk management framework Regulatory policies and procedures tailored to recognize the level of scientific knowledge supporting product applications and cGMP coverage of products Risk based regulatory scrutiny that weighs factors such as the capability of process control strategies to prevent or mitigate risk of producing a poor quality product J. Famulare, CDER, 2004 Presentation to CHPA D. Horowitz, FDA, 8/24/04

5 cGMPs for the 21st Century
Current Situation FDA Industry Public Faces resource cuts Industry’s technical challenges are increasingly complex Difficult to enforce manufacturing standards globally, with more sites Perceived as a barrier to innovation, not an enabler Since 1990 more than a dozen cGMP-related Consent Decrees have incurred over $20bn in costs to industry Because of regulatory constraints, Industry has been slow to adopt innovative technologies to improve products and operations Pressure to reduce costs Global manufacturing subject to not harmonized regulatory requirements Outsourcing has become a viable alternative with regulatory implications Lower trust in both FDA and Industry Seeks lower cost medications without compromising quality

6 The Objectives of the 21st Century Approach
cGMPs for the 21st Century The Objectives of the 21st Century Approach The primary objectives of that initiative were to encourage innovation and new manufacturing technologies, to focus the agency’s resources on the areas of manufacturing considered to pose the most risk, and to improve the consistency and predictability of the agency’s work in ensuring drug quality and safety1 The FDA wants to take a new role as an enabler of the innovation and change itself and industry to meet this new additional role 1. From CGMPs to Critical Path, L. Bush, Pharm Tech, July 2004

7 FDA desires for industry to have more knowledge and more control
cGMPs for the 21st Century FDA desires for industry to have more knowledge and more control FDA is restructuring its oversight of pharmaceutical quality regulation by developing a product quality regulatory system which provides a framework for implementing quality by design, continuous improvement, and risk management. The guiding principles are Risk-based orientation Integrated quality systems orientation Science-based policies and standards International cooperation Strong public health protection 1. Pharmaceutical CGMPs for the 21st Century-Risk-Based Approach Final Report, Sept 2004 2. D. Ellsworth, FDA, Gold Sheet, May 2005

8 FDA’s “cGMPs for 21st Century” Initiative
cGMPs for the 21st Century FDA’s “cGMPs for 21st Century” Initiative In response to today’s challenges facing pharmaceutical manufacturing and quality, FDA launched its “Pharmaceutical cGMPs for the 21st Century” to:* Focus FDA’s resources on areas of greatest manufacturing risk Encourage innovation and early adoption of advanced manufacturing technologies Facilitate industry application of modern quality management techniques, including implementation of quality systems approaches Encourage the use of risk-based approaches to focus on critical areas Ensure regulatory review, compliance and inspection policies are based on state-of-the-art science Enhance the consistency and coordination of FDA’s drug quality regulatory programs by integrating enhanced quality systems approaches into the agency’s business processes and regulatory policies 1. Pharmaceutical CGMPs for the 21st Century-Risk-Based Approach Final Report, Sept 2004 2. From cGMPs to the Critical Path: FDA Focuses on Innovation, Quality and Continuous Improvement – Inside and Out, Laura Bush. Pharmaceutical Technology, July 2004

9 Risk-Based Model for GMP Inspection and Product Quality Review
cGMPs for the 21st Century Risk-Based Model for GMP Inspection and Product Quality Review To more efficiently and effectively use FDA resources to protect public health, FDA now uses a risk-based model to prioritize manufacturing sites for GMP inspection and product quality review. The risk model considers the intensity and frequency of FDA inspections, including: The manufacturer’s understanding of its product and process Robustness of quality system Public health impact Manufacturer’s compliance status and history FDA applies the risk model to the product quality review process to: Focus on critical pharmaceutical quality attributes and their relevance to safety and efficacy Evaluate a manufacturer’s understanding of process control and quality 1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004

10 Quality System Approaches
cGMPs for the 21st Century Quality System Approaches FDA wants its regulatory practices to encourage implementation of modern quality systems and risk management systems to satisfy cGMPs. By Modern quality systems that correlate closely with regulatory requirements Achieving product quality characteristics Processes to achieve quality by design Risk management and assessment CAPA Change control Quality Unit Quality Systems Model Management responsibilities Resources Manufacturing operations Evaluation activities 1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004

11 Science-Based Policies
cGMPs for the 21st Century Science-Based Policies FDA encourages the application of enhanced science and engineering knowledge in regulatory decision-making, establishment of specifications, and evaluation of manufacturing processes to improve the efficiency and effectiveness of both manufacturing and regulatory decision-making. PAT PAT brings a systems perspective to the design and control of manufacturing processes Regulatory framework to encourage voluntary development and implementation of innovative approaches in pharmaceutical development, manufacturing and quality assurance New technologies are available that provide information on physical, chemical, and microbiological characteristics of materials to improve process understanding and to measure, control, and/or predict quality performance Facilitates introduction of new technologies to improve efficiency and effectiveness of manufacturing process design and control and quality assurance Comparability Protocols Allows manufacturing changes without the submission of a prior approval supplement Establish to facilitate continuous improvement and innovation Systemic, risk-based approach to review and approval process for post-approval manufacturing changes 1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004

12 Integration of Pre-Approval and cGMP Inspection Programs
cGMPs for the 21st Century Integration of Pre-Approval and cGMP Inspection Programs Pharmaceutical inspectorate seeks to improve the integration of the pre-approval and cGMP inspection programs by using highly trained individuals within Office of Regulatory Affairs (ORA) to: Conduct inspections of pharmaceutical operations Participate in other investigations that require their technical expertise Revised PAI inspection program Eliminates mandatory categories for conducting inspections 1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004

13 International Collaboration for Compliance
cGMPs for the 21st Century International Collaboration for Compliance Harmonization of international quality standards in the face of a global economy to achieve public health goals and leverage resources. International Conference on Harmonization (ICH) quality standards: Q8: Quality by Design and pharmaceutical development Q9: Risk Management principles and tools Q10: Quality systems enhancements emphasizing change controls 1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004

14 Rule and Guidance Interpretations
cGMPs for the 21st Century Rule and Guidance Interpretations FDA has implemented the guiding principles through various rule and guidance interpretations. Part 11 Addresses uncertainties of regulatory specifications, particularly by narrowly defining electronic records subject to the rule Validation Deletes the reference to “three validation batches” at commercial scale Recognizes emerging technologies (PAT). Aseptic processing Incorporates a more risk-based approach Modernization and automation Dispute Resolution Mechanism to surface scientific and technical disagreements related to GMPs for resolution and dissemination Warning Letter Review by Office of General Counsel All proposals to issue warning letters to manufacturers are reviewed by the centers and the Office of the Chief Counsel 1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004 2. FDA Conference Report, Drug Quality System: CGMPs for a New Era – 2004 3. J. Fuse, Journal of Validation Technology, Nov 2004

15 cGMPs for the 21st Century
FDA’s Next Steps The next phase of the “cGMPs for the 21st Century” initiative include:1 Develop additional guidance on quality systems to enhance and modernize the regulation of pharmaceutical manufacturing and product quality Continue development of the risk-based pharmaceutical quality assessment system that will replace the current CMC review to remove hurdles to continuous improvement following drug approval Revise the 1987 guideline on Process Validation to include 21st century concepts, including risk management and a lifecycle approach Continue to explore and formalize risk-based tools to enhance FDA’s regulatory oversight Refine cGMPs and meet our harmonization (internal and international) goals Continue timely communication of our current thinking on various quality issues to the public to facilitate compliance with FDA requirements Further enhance FDA’s own quality systems (including more mechanisms to facilitate communication within the FDA) Continue and expand on opportunities to integrate science-based policy standards into our product quality regulatory approach 1. Pharmaceutical CGMPs for the 21st Century, Risk-Based Approach, Final Report, Sept. 2004

16 The Quality System Let’s define systems
GMPs are best viewed from a systems perspective – The whole exceeds the sum of the parts1 A system is a design of integrated components that can measure the performance of the whole and can predictably and consistently detect and correct deficiencies2 Systems thinking is a framework for seeing interrelationships rather than things, for seeing patterns of change rather than static snapshots3 3. P. Senge, The Fifth Discipline, 1994 1. D. Horowitz, FDA, 8/24/04 2. The Quantic Group

17 Product Quality Systems – Definition1
The Quality System Product Quality Systems – Definition1 A series of interrelated processes or activities representing an integrated approach to the philosophy and practices contributing to drug substance and drug product safety, identity, strength, purity and quality The Product Quality Systems definition groups the processes and activities into three main categories: Process Reliability and Product Consistency Batch Release, Stability, APR, Validation Manufacturing & Lab Decision Process Change Control, Deviations, Notification to Management Facility Reliability and Product Purity Facility Design, Facility Qualification, Contamination Control 1 As defined by The Quantic Group

18 FDA Quality System Definition
The Quality System FDA Quality System Definition This system assures overall compliance with cGMPs and internal procedures and specifications The system includes the quality control unit and all of its review and approval duties (e.g. change control, reprocessing, batch release, annual product review, validation protocols, and reports, etc.). It includes all product defect evaluations and evaluation of returned and salvaged drug products See the CGMP regulation, 21 CFR 211 Subparts B, E, F, G, I, J, and K

19 Plan/Prevent Correct Do in Control Check/Detect/ Audit
The Quality System Deming’s Plan-Do-Check-Act was a keystone in design of cGMP in the 1960’s Plan/Prevent Correct Do in Control Check/Detect/ Audit

20 FDA Definition of Quality System Elements
The Quality System FDA Definition of Quality System Elements The FDA definition For each of the following items, the firm should have written and approved procedures Verified through observation wherever possible . . . Product reviews at least annually Complaint reviews, quality and medical Discrepancy and failure investigations related to manufacturing and testing – includes corrective action where appropriate Change control Product Improvement Projects Reprocess/Rework Returns/Salvages Rejects Stability Failures Quarantine products Validation Training/qualification of employees in quality control unit functions

21 Management Controls Quality System
The Quality System Management Controls Quality System Organizational effectiveness for compliance is where . . . Plan/Prevent Correct Do In Control Check/Detect/ Audit . . . Everyone predictably responds

22 Design Space Right now I think the agency has a view that it is actually involved too extensively in the management of change to pharmaceutical processes1 The current regulatory review process before launch sets specifications, followed by the pre-approval inspection Most changes are managed through an FDA prior-approval process1 Issues with current regulatory approach:1 Product and process development may not be ideal Validation may not be adequate to assure the process capability Continuous improvement is not optimal, lack of adopting innovation 1 Adapted from D. Ellsworth Interview, Gold Sheets, April 2005

23 Design Space It is really a multi-dimensional space that defines how different variables interact with each other and shows all the different things that can happen and how the process and product will react1 Part of the solution is the new focus on Design Space, a concept for filing additional development data at approval to justify broader manufacturing parameters based on the science of the product1 The data can be developed and shared with FDA Design Space requires a multivariate analysis of related critical to quality parameters Design space allows FDA to base their agreement on specifications on data 1 Adapted from D. Ellsworth Interview, Gold Sheets, April 2005

24 Design Space FDA oversight and pre-approval of manufacturing change will be replaced by the company making the change, subject to routine inspection1 The benefit to industry is the later flexibility in the development process. It allows for continuous improvement and the management of change The benefits come in the post approval process, when changes within the design space parameters are allowed and will simply be reviewed on the next cGMP inspection as a matter of course 1 Adapted from D. Ellsworth Interview, Gold Sheets, April 2005

25 Plan/Prevent Correct Do in Control Check/Detect/ Audit/Measure
Design Space The New Quality System Incorporates Science, Change Process, Risk & Management Control Design Space Plan/Prevent Redesign Design Space In-house change process In-process parameters Correct Do in Control PAT Revisit procedures, validation and organizations Risk Check/Detect/ Audit/Measure Real time test and trending Processes and products

26 Risk Risks are seen differently by agency and industry, with different actions needed at different stages FDA FDA Risk decisions used to prioritize inspection resources Uses risk-based framework to prioritize sites for cGMP inspection Determines risk at the Plan stage, primarily through the Approval process for new drugs and the pre-approval of changes Based on product history, process characteristics, and facility history Uses the site risk potential to evaluate which sites to audit in the Detect stage Primarily focused on product risk to patients, but also risks of non-supply and risk to consumer confidence Site Risk Potential Product Process Facility Risk = Frequency x Severity -> SRP = %P x %P x %F

27 Plan Operate Detect Correct
Risk Risks are seen differently by agency and industry, with different actions needed at different stages INDUSTRY Industry Risk decisions are driven by company objectives Evaluates business, technical and compliance risks in the process of developing and manufacturing drugs Determines the risk-tolerance through decisions made at the Planning stage. Evaluates and reacts to risks that are identified in the Detect stage, including FDA inputs Technology/Design Risk Plan Operate Detect Correct Business Risk Implementation Risk Regulatory Risk

28 US v. Park (1975) US v. Dotterweich (1943)
FDA Enforcement US v. Park (1975) US v. Dotterweich (1943) Industry has the responsibility to put in place systems for assurance and prevention The assurance provisions of the Act are deemed demanding, but industry has chosen this work, and retains the responsibility to protect the public (Park) There is no one else who is in a position to act preventively to avoid problems with public health (Dotterweich)

29 Culture & Compliance FDA Enforcement’s View
To avoid Consent Decrees, injunctions and related enforcement actions:1 Create and foster a corporate spirit (“Culture”) of compliance Establish internal systems and controls to define, measure, monitor and assure compliance Obtain qualified, experienced, independent evaluations of your company’s compliance Take prompt and comprehensive action to correct the violative situation Monitor the corrective action to assure the fix works in both the short term and long term Communicate promptly and constructively with FDA Any attempt to excuse a violation on FDA’s failure to discover the problem during previous inspections will not be heard sympathetically. It is your responsibility to assure the continuous compliance of your processes and products1 FDA does not bear the burden to prove that a GMP violation would cause an unsafe or ineffective product to be marketed2 Prevent Detect Detect Correct Correct 1 E. Blumberg, Deputy Associate, Office of Chief Counsel, Office of the Commisioner, FDA 2 G David Horowitz, FDA 8/24/04 Correct

30 Consent Decrees are Court enforced “contracts” . . .
. . . created to ensure the prompt correction of certain deficiencies while safeguarding the public. Related to: Products Facilities Systems Organizational Structures to achieve compliance with Laws & Regulations.

31 Management Controls and Quality Unit Warning Letter Issues
The QUALITY ASSURANCE UNIT failed to follow written procedures, which require OVERSIGHT and REVIEW responsibilities Company failed to have a QUALITY CONTROL UNIT adequate to perform its functions and responsibilities Company failed to establish procedures for MANAGEMENT with executive responsibility to review the suitability and effectiveness of the quality system to ensure that the system satisfies the requirements

32 Consent Decree Requirement for Evaluation of Management Controls
Evaluate the ADEQUACY of: Prevent Organizational structure and responsibilities of ALL involved in manufacture PREVENT Qualification of personnel and appropriate numbers DETECT and CORRECT Roles, responsibilities and resources of Quality Units to detect and correct deficiencies President MFG Q R&D QA/QC Eng Prod Q Dev Clin

33 Consent Decree Requirement for the Evaluation of Quality Units
The Quality Unit Consent Decree Requirement for the Evaluation of Quality Units Consultant to evaluate whether the Quality Unit Program is: Comprehensive Adequate to ensure compliance (In Place) and followed (In Use) Inclusive of policies, compliance monitoring, internal audits, training, investigations, records management President MFG Q R&D Eng Prod Q Dev Clin

34 Implications of Management Controls on the Quality Unit
“Adequate” is open to interpretation Challenges past behavior and decisions Process is Intrusive

35 There are emerging efforts to improve the industry
Introduction There are emerging efforts to improve the industry “The present state is focused on documentation, following SOPs validating the process, meeting specifications, and not changing the process”1 “The desired state, by contrast, would focus on data analysis, understanding critical to quality attributes, measuring process capability, performing continuous quality verification, and undertaking Continuous improvement” 1 1 G. Migliaccio, Pfizer Global Operations VP, Gold Sheet June 2004 US Pharmaceutical industry now has an opportunity and a duty to effect changes, So that The public health is ensured, and More value is returned to shareholders Is industry up to the challenge?


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