FDA_ICH Training（2012）

_____ Guidance for Industry Q8, Q9, & Q10 Questions and Answers Appendix Q&As from Training Sessions U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2012 ICH 蒲公英转载——www.ouryao.com __________   Guidance for Industry Q8, Q9, & Q10 Questions and Answers Appendix Q&As from Training Sessions Additional copies are available from: Office of Communications Division of Drug Information, WO51, Room 2201 Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Silver Spring, MD 20993-0002 Phone: 301-796-3400; Fax: 301-847-8714 druginfo@fda.hhs.gov http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or Office of Communication, Outreach and Development, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm (Tel) 800-835-4709 or 301-827-1800 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2012 ICH 蒲公英转载——www.ouryao.com TABLE OF CONTENTS I. INTRODUCTION (1)....................................................................................................... 1 II. WHAT ARE THE POINTS TO CONSIDER FOR CRITICALITY OF QUALITY ATTRIBUTES AND PROCESS PARAMETERS (2) ................................................... 2 A. Considerations for Establishing CQAs and CPPs (2.1).............................................................. 2 B. Relationship of Criticality to Control Strategy (2.2) .................................................................. 3 III. WHAT ARE THE POINTS TO CONSIDER FOR CONTROL STRATEGY (3)..... 3 A. Lifecycle of the Control Strategy (3.1) ......................................................................................... 3 B. Suitability of Control Strategy at Different Scales (3.2)............................................................. 4 C. Specifications and Certificate of Analysis (CoA) for Real-Time Release Testing (RTRT) (3.3).................................................................................................................................................. 5 D. Process for a Batch Release Decision (3.4)................................................................................... 6 IV. WHAT ARE THE POINTS TO CONSIDER FOR LEVEL OF DOCUMENTATION IN ENHANCED (QBD) REGULATORY SUBMISSIONS (4) ............................................................................................................................................. 7 A. Risk Management Methodologies (4.1)........................................................................................ 8 B. Design of Experiments (4.2) .......................................................................................................... 8 C. Manufacturing Process Description (4.3) .................................................................................... 9 V. WHAT ARE THE POINTS TO CONSIDER FOR ROLE OF MODELS IN QUALITY BY DESIGN (QBD) (5) ................................................................................. 9 A. Categorization of Models (5.1)...................................................................................................... 9 B. Developing and Implementing Models (5.2) .............................................................................. 11 C. Model Validation and Model Verification During the Lifecycle (5.3)..................................... 11 D. Documentation of Model-related Information (5.4) ................................................................. 12 VI. WHAT ARE THE POINTS TO CONSIDER FOR DESIGN SPACE (6)................. 13 A. Development of Design Space (6.1)............................................................................................. 13 B. Verification and Scale-up of Design Space (6.2)........................................................................ 14 C. Documentation of Design Space (6.3)......................................................................................... 14 D. Lifecycle Management of a Design Space (6.4) ......................................................................... 15 VII. WHAT ARE THE POINTS TO CONSIDER FOR PROCESS VALIDATION/CONTINUOUS PROCESS VERIFICATION (7) ............................ 15 A. General Considerations (7.1) ...................................................................................................... 16 B. Continuous Process Verification (CPV) (7.2) ............................................................................ 16 C. Pharmaceutical Quality System (7.3) ......................................................................................... 17 蒲公英转载——www.ouryao.com Contains Nonbinding Recommendations Guidance for Industry1 Points to Consider for Q8, Q9, and Q10 This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. INTRODUCTION (1)2 The ICH Quality Implementation Working Group (Q-IWG) has prepared this Points to Consider document covering topics relevant to the implementation of ICH Q8(R2), Q9, and Q10, which supplement the existing guidance Q8, Q9, and Q10 Questions & Answers3 and workshop training materials4 already produced by this group. They should be considered all together. The points to consider are based on questions raised during the ICH Q-IWG training workshop sessions in the three regions. The points to consider are not intended to be new guidance. They are intended to provide clarity to both industry and regulators and to facilitate the preparation, assessment, and inspection related to applications filed for marketing authorizations. The development approach should be adapted based on the complexity and specificity of product and process; therefore, applicants are encouraged to contact regulatory authorities regarding questions related to specific information to be included in their application. Using the Quality by Design (QbD) approach does not change regional regulatory requirements but can provide opportunities for more flexible approaches to meet them. In all cases, good manufacturing practice (GMP) compliance is expected. 1 This guidance was developed within the Quality Implementation Working Group of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, June 2011 and November 2011. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. 2 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Steering Committee at Step 4 of the ICH process, June 2011 and November 2011. 3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 4 Materials for ICH quality training on Q8, Q9, and Q10 are available at www.ich.org under “ICH Training.” 1 蒲公英转载——www.ouryao.com Contains Nonbinding Recommendations II. WHAT ARE THE POINTS TO CONSIDER FOR CRITICALITY OF QUALITY ATTRIBUTES AND PROCESS PARAMETERS (2) Scientific rationale and quality risk management (QRM) processes are used to reach a conclusion on what are critical quality attributes (CQAs) and critical process parameters (CPPs) for a given product and process The quality target product profile (QTPP) describes the design criteria for the product, and should therefore form the basis for development of the CQAs, CPPs, and control strategy. The information developed to determine CQAs and CPPs will help to:  Develop control strategy  Ensure quality of the product throughout the product lifecycle  Increase product and process knowledge  Increase transparency and understanding for regulators and industry  Evaluate changes A. Considerations for Establishing CQAs and CPPs (2.1) The introduction of ICH Q9 states that “…the protection of the patient by managing the risk to quality should be considered of prime importance.” The QTPP provides an understanding of what will ensure the quality, safety, and efficacy of a specific product for the patient and is a starting point for identifying the CQAs. As part of risk assessment, risk analysis, as defined by ICH Q9 is “the qualitative or quantitative process of linking the likelihood of occurrence and severity of harm. In some risk management tools, the ability to detect the harm (detectability) also factors in the estimation of risk.” Relationship between risk and criticality:  Risk includes severity of harm, probability of occurrence, and detectability, and therefore the level of risk can change as a result of risk management.  Quality attribute criticality is primarily based upon severity of harm and does not change as a result of risk management.  Process parameter criticality is linked to the parameter’s effect on any critical quality attribute. It is based on the probability of occurrence and detectability and therefore can change as a result of risk management. Considerations for identifying and documenting CQAs can include the:  Severity of harm (safety and efficacy) before taking into account risk control and the rationale for distinguishing CQAs from other quality attributes;  Link to the patient as described in the QTPP;  Basis on which the CQAs have been developed (e.g., prior knowledge, scientific first principles, and experimentation); and 2 蒲公英转载——www.ouryao.com Contains Nonbinding Recommendations  Inter-dependencies of the different CQAs. Considerations for identifying and documenting CPPs can include the:  Risk assessment and experimentation to establish the linkage between potential CPPs and CQAs;  Basis on which the CPPs have been identified (e.g., prior knowledge, scientific first principles, QRM, design of experiment (DoE), and other appropriate experimentation);  Interdependencies of the different CPPs; and  Selected control strategy and the residual risk. CQAs and CPPs can evolve throughout the product lifecycle, for example:  Change of manufacturing process (e.g., change of synthetic route) and  Subsequent knowledge gained throughout the lifecycle (e.g., raw material variability, pharmacovigilance, clinical trial experience, and product complaints). B. Relationship of Criticality to Control Strategy (2.2) The identification and linkage of the CQAs and CPPs should be considered when designing the control strategy. A well-developed control strategy will reduce risk but does not change the criticality of attributes. The control strategy plays a key role in ensuring that the CQAs are met and, hence, that the QTPP is realized. III. WHAT ARE THE POINTS TO CONSIDER FOR CONTROL STRATEGY (3) A. Lifecycle of the Control Strategy (3.1) The lifecycle of the control strategy is supported by pharmaceutical development, quality risk management (QRM), and the pharmaceutical quality system (PQS), as described in ICH Q8(R2), Q9, and Q10. The following points can be considered:  Development of control strategy:  The control strategy is generally developed and initially implemented for production of clinical trial materials. It can be refined for use in commercial manufacture as new knowledge is gained. Changes could include acceptance criteria, analytical methodology, or the points of control (e.g., introduction of real-time release testing).  Additional emphasis on process controls should be considered in cases where products cannot be well-characterized and/or quality attributes might not be readily measurable due to limitations of testing or detectability (e.g., microbial load/sterility).  Continual improvement of the control strategy: 3 蒲公英转载——www.ouryao.com Contains Nonbinding Recommendations  Consideration should be given to improving the control strategy over the lifecycle (e.g., in response to assessment of data trends over time and other knowledge gained).  Continuous process verification is one approach that enables a company to monitor the process and make adjustments to the process and/or the control strategy, as appropriate.  When multivariate prediction models are used, systems that maintain and update the models help to assure the continued suitability of the model within the control strategy.  Change management of the control strategy:  Attention should be given to outsourced activities to ensure all changes are communicated and managed.  The regulatory action appropriate for different types of changes should be handled in accordance with the regional regulatory requirements.  Different control strategies for the same product:  Different control strategies could be applied at different sites or when using different technologies for the same product at the same site.  Differences might be due to equipment, facilities, systems, business requirements (e.g., confidentiality issues, vendor capabilities at outsourced manufacturers) or as a result of regulatory assessment/inspection outcomes.  The applicant should consider the impact of the control strategy implemented on the residual risk and the batch release process.  Knowledge management:  Knowledge management is an important factor in assuring the ongoing effectiveness of the control strategy.  For contract manufacturing, knowledge transfer in both directions between the parties should be considered, particularly for model maintenance and/or updates, application of design space, and control strategies incorporating real-time release testing. B. Suitability of Control Strategy at Different Scales (3.2)  Management of risk on scale-up:  Risk associated with scale-up should be considered in control strategy development to maximize the probability of effectiveness at scale. The design and need for scale-up studies can depend on the development approach used and knowledge available.  A risk-based approach can be applied to the assessment of suitability of a control strategy across different scales. QRM tools can be used to guide these activities. This assessment might include risks from processing equipment, facility environmental controls, personnel capability, experiences with technologies, and historical experience (prior knowledge). See the ICH Q-IWG case study for examples. 4 蒲公英转载——www.ouryao.com Contains Nonbinding Recommendations  Scale-up considerations for elements of Control Strategy:  Complexity of product and process  Differences in manufacturing equipment, facilities and/or sites  Raw materials: - Differences in raw material quality due to source or batch-to-batch variability - Impact of such differences on process controls and quality attributes  Process parameters: - Confirmation or optimization - Confirmation of the design space(s), if used  In-process controls: - Point of control - Optimization of control methods - Optimization and/or updating of models, if used  Product specification: - Verification of the link to QTPP - Confirmation of specifications (i.e., methods and acceptance criteria) - Confirmation of real-time release testing (RTRT), if used C. Specifications and Certificate of Analysis (CoA) for Real-Time Release Testing (RTRT) (3.3) The purpose of specifications and CoAs remains the same in the case of RTRT, but the way to develop them is different. Real-time release tests(RTRT) are considered to be specification testing methods and follow the established regional regulatory requirements for release specifications (as interpreted in e.g., ICH Q6A and ICH Q6B) together with other regional regulatory requirements (e.g., formats, GMP, batch acceptance decisions). The use of RTRT has been addressed (see ICH Q8(R2), section II.E (2.5); ICH Q8, Q9, and Q10 Q&As, section II.B (2.2)). The following points should be considered when developing a specification and CoA for RTRT:  Quality attributes:  Not all CQAs need to be included in the specification.  The attribute to be measured (e.g., surrogate for a CQA) can depend on the point of testing and/or control (e.g., materials, process steps, process parameters).  Linking of the measured attribute to CQA and QTPP  Methods of control:  The type of control used (e.g., models, process analytical technology (PAT), test of isolated material, end product test, stability and regulatory test)  Reference to the testing method used, if relevant 5 蒲公英转载——www.ouryao.com Contains Nonbinding Recommendations  Validation of control method  Acceptance criteria:  Acceptance criteria at control point  Criteria for stability and regulatory testing  CoA elements:  Reported results (e.g., values calculated from models, established calibrations, and actual test results)  Acceptance criteria related to the method used  Method references D. Process for a Batch Release Decision (3.4) Different development approaches lead to different control strategies. Regardless of the control strategy, the batch release process should be followed. For a batch release decision, several elements should be considered. See in the figure below an illustration of the elements of the batch release process leading to the batch release decision. Elements of a Batch Release Process 1. Regulatory compliance data Batch not released 2. System related data for the current batch manufactured Distribution Batch rejection M an uf ac tu rin g Batch Release decision according to regional procedures by manufacturer for the marke t Elements defined regarding outsourced activities, if applicable 3. Product-related data based on the manufacturing process 4. Product-related data from quality control B atch record C oA C on tr ol S ta rt eg y &