PMDA Perspective: Regulatory Updates on Process Validation Standard

Transcription

1 CMC Strategy Forum Japan 2014 Tokyo, Japan, December 8-9, 2014 PMDA Perspective: Regulatory Updates on Validation Standard Kazunobu Oyama, PhD Office of Cellular and Tissue-based Products PMDA, Japan Disclaimer: The views and opinions expressed in this presentation are those of the presenter and does not necessarily represent the views and opinions of the PMDA. 1

2 Outline 1.CMC Development Understanding of quality Knowledge control Technical transfer Lifecycle Management 2.Revision of validation standard in Japan Point of the amendment 3.Summary 2

3 Overall picture of CMC development Typical Development Clinical Study Approval Non- Clinical Study Phase 1 Phase 2 Phase 3 Post- Approval Target product Profile Establishment of Design Quality and Product Quality by CMC study Validation Control strategy Control strategy Control strategy Quality Attributes CQA Parameters CPP Control Strategy Consistency Equivalency Knowledge Control/Quality Risk Management Investigational Product GMP GMP 3

4 Matters of description on application form S.2.6 Manufacturing Development Development Strategy CPP, CQA identification Control Strategy Analytical Method Comparability etc S.2.5 Validation and/or Evaluation Control Strategy Demonstration of Validated State/State of Control design is evaluated to demonstrate that the control strategy is capable of delivering the desired product quality for commercial launch etc 4

5 Matters of description on application form ICH Q11 7. Validation/Evaluation For biotechnological processes, or for aseptic processing and sterilisation process steps for drug substances, the data provided in support of process validation is included as part of the marketing application (3.2.S.2.5) 5

6 Understanding of Product Quality Design Quality Procedure Product Quality Material Equipment Quality Management Quality Risk Management / Knowledge Control Quality of the manufacturing is affected by various factors. Understanding the variables in the process, it is possible to be control it, leading to quality control. 6

7 QbD Approach QTPP CQAs Risk Management Option Control strategy Quality target product profile Identify the critical quality attributes based on the potential risks Linking material attributes and process parameters to CQAs, in this case, risk assessment is useful Mathematical analysis model, design space or realtime release testing (not required) Establishment of control strategy Continual improvement Knowledge and understanding could facilitate continual improvement

8 ICH Q10 Pharmaceutical Quality System Pharmaceutical Development Investigational Products Technology Transfer Commercial Manufacturing GMP Product Discontinuation PQS elements Management Responsibilities Performance and Product Quality Monitoring System Corrective Action / Preventive action system Change Management System Management Review Enabler Knowledge Management Quality Risk Management Quote or altered from ICH Q10 Annex2

9 Accumulation and transfer of knowledge R&D Development Stage Transfer Manufacturer Commercial Manufacturing Stage QTPP Define Quality target product profike QbD QbD information Monitoring Product quality review Change management (impact assessment) Deviation management (CAPA) CQA Identify critical quality attributes Scale-up Evaluation of impact Reevaluation Review of CPP, DoE and Design Space. CPP (Design Space) Risk assessment DoE Assay Master plan of transfer Tech.Transfer Reevaluation Revalidation Control Strategy understanding, Knowledge accumulation PV Justification of control strategy Monitoring Life cycle Management Knowledge control

10 Technical Transfer R&D Development Stage Transfer Manufacturer Commercial Manufacturing Stage A B C Tech.Transfer Tech. Transfer Report Knowledge of Development stage Knowledge of Commercial Manufacturing Stage Knowledge accumulated in the development department and manufacturing department, important to support consistently the robustness of the process C 10

11 Commercial Manufacturing Stage Feedback of knowledge Transfer of accumulated knowledge in the commercial manufacturing stage continual improvement R&D Development Stage Transfer Monitoring Product quality review Change management (impact assessment) Deviation management (CAPA) QTPP Define Quality target product profike QbD QbD information Reevaluation Review of CPP, DoE and Design Space. CQA Identify critical quality attributes Scale-up Evaluation of impact Reevaluation Revalidation CPP (Design Space) Risk assessment DoE Assay Master plan of transfer Tech.Transfer Monitoring Life cycle Management Knowledge control Control Strategy understanding, Knowledge accumulation PV Justification of control strategy

12 Knowledge management in the lifecycle New variation factors Knowledge is continuously accumulated Quality system of GMP to feedback the knowledge in process control is important CAPA improvement Control strategy improvement Revalidation Commercial Manufacturing Stage CAPA Development Stage CAPA Transfer CAPA Commercial Manufacturing Stage Monitoring Complaint development Product Quality Review Change Management

13 Scheme of Validation in FDA Non-Clinical Research Clinical Research After the Launch FDA s PV GL Stage1 Stage2 Stage3 Knowledge Control in Research &/or Development Div. PhaseIII~ Tech. Transfer Knowledge Control in Mfg. Plant Investigational Product Production in Pilot &/or Commercial Scale PPQ Commercial Lots Consistency of and Product Quality Guidance for Industry Validation: General Principles and Practices 13

14 In August 30, 2013, validation standard have been revised. 14

15 Risk-based Approach Required GMP Regulatory Framework in Japan Pharmaceutical Affairs Law (PAL) Enforcement Ordinance of PAL GMP Ministerial Ordinance GMP Enforcement Notification Notification (JP, Standard for BI) GCP Ministerial Ordinance Enforcement Notification for Investigational Product GMP Enforcement Notification and Administrative notice (ICH Q7, Q8, Q9, Q10, Q11) JP General Information Administrative notice (GMP Question and Answer) Administrative notice (MHLW Research Report) PIC/S GMP Guide

16 Risk-based Approach Required GMP Regulatory Framework in Japan Pharmaceutical Affairs Law (PAL) Enforcement Ordinance of PAL Validation standard (Basic requirements of Validation) GMP Ministerial Ordinance GMP Enforcement Notification Notification (JP, Standard for BI) GCP Ministerial Ordinance Enforcement Notification for Investigational Product GMP Enforcement Notification and Administrative notice (ICH Q7, Q8, Q9, Q10, Q11) JP General Information Administrative notice (GMP Question and Answer) Administrative notice (MHLW Research Report) PIC/S GMP Guide

17 Contents of Validation Standard (1) Objectives of validation (2) Implementation subjects (3) Procedure for validation (4) Responsibilities of responsible person in validation (5) Implementation of validation a) Qualification (DQ, IQ, OQ, PQ) b) validation (PV) c) Cleaning validation d) Revalidation e) validation on change control

18 Important Concept on Validation 1. Quality risk management 2. Technical transfer 3. Knowledge control through the product quality review 4. Validation master plan 5. Continuous/Continued Verification 18

19 Key Points of the amendment Activities of validation: Implementation based the quality risk : ICH Q9 Clarification of qualification (DQ / IQ / OQ / PQ) Master plan that summarizes the overall validation Product lifecycle: ICH Q10 Technical transfer Feedback from product quality review Continuous process verification: ICH Q8, Q11 7

20 Quality Risk Management (QRM) GMP is a quality management system, QRM on the GMP, is essential elements that constitutes the manufacturing and quality management. QRM can be useful for identifying potential risks to quality, establishing a scientific evaluation and control systems for the manufacturing process. QRM can be effective approaches for promoting continuous improvement of performance of the manufacturing process and product quality, thereby, manufacturers are intended to encourage the use of science and risk based approaches on GMP. Implementation of QRM(ICH Q9) Risk Assessment Risk Control Risk Communication Risk Review

21 Implementation of validation Objectives of Validation The purpose of validation is to verify that the manner of manufacturing control and quality control on the facilities, systems and equipment, procedures and processes achieve the intended results, and documented the evidence that the process, operated within established parameters, can perform reproducibly to produce a product meeting its predetermined specifications and quality attributes. To achieve its purpose, all validation activities should be considered using knowledge and information accumulated throughout the product lifecycle, including medicinal product development, process monitoring/process verification and product quality review. 21

22 Implementation of validation validation is to confirm that processes operating under permissible parameters defined based on consideration for variable factors (material attribute, operating conditions, etc.), which have been predetermined as affecting product quality based on knowledge of industrialization research and past manufacturing similar products, are valid for consistently manufacturing products meeting its predetermined specifications and quality attributes, and these are documented. (1) Before starting process validation, confirm that qualification of the facilities, system or equipment used for validation has been appropriately completed, and evaluate the validity of the test method used to evaluate validation. (2) Batches made for process validation should be the same size as the intended industrial scale batches. It is generally considered acceptable that three consecutive batches within the finally agreed parameters or equivalent approaches would constitute a validation of the process.

23 Application of Continuous/Continued Verification It might be acceptable for an equivalent approach as an alternative to process validation of three consecutive batches with same size as the intended industrial scale, if the manufacturing process has been developed based on the "enhanced approach" of ICH Q11 can be verified according to continuous process verification (ICH Q8). Continuous process verification can be acceptable to utilize, where development is conducted on the basis of the "enhanced approach" and control strategy have been established. If going to adapt the CPV for existing products, it is necessary to develop a manufacturing process and control strategy based on the ICH Q11.

24 Application of Continuous/Continued Verification Points to consider on implementation of process validation in the application of the continuous process verification is as follows, It needs to be appropriately evaluated at each stage of process validation throughout the product lifecycle, process design, process performance qualification, continued process verification. It is necessary to describe the validation plan applying continuous process verification. It is necessary to verify consistency of process through the product life cycle, according to review the products quality on the basis of data obtained from continuous monitoring. Justification of the control strategy which subsequently yields reproducibly a product meeting its predefined quality criteria should be evaluated by the product quality review, as a result, revalidation will be performed.

25 Overall picture of activities through the product life cycle Product Quality Review Technical Transfer Knowledge Cycle that connects development and commercial production Research Commercial Production Quality Improvement Development Validation Technical Transfer Report of Research and Development

26 Summary Stage Research and Development Transfer Commercial Manufacturing Knowledge Control and Tech. Transfer Knowledge Control in Research &/or Development Div. Technical Transfer Knowledge Control in Mfg. Plant Activity Investigational products Production (Pilot &/or Commercial Scale) Manufacturing Design Development Manufacturing Improvement Control Strategy PV (PPQ) Control Strategy Knowledge Control Manufacturing Verification Commercial Batches Manufacturing Manufacturing Monitoring Approach of Evaluation Verification, Cleaning method of Investigational product Validation Analytical method, Computer Systems, Sterility assurance, etc. Validation Qualification of Equipment Validation/Verification Change Control Revalidation Consistency of and Product Quality 26

27 Thank you for your attention! 27