PMDA Perspective: Regulatory Updates On Process Validation Standard

CMC Strategy Forum Japan 2014 Tokyo, Japan, December 8-9, 2014 PMDA Perspective: Regulatory Updates on Process 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

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

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

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

Matters of description on application form ICH Q11 7. Process 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

Understanding of Product Quality Design Quality Product Quality Procedure Process 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 6 to be control it, leading to quality control.

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

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

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

Technical Transfer R&D Development Stage Process A Process B Manufacturer Commercial Manufacturing Stage Transfer Process C Tech. Transfer Report Tech.Transfer 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

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

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

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

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

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

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

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

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 Process Verification 18

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

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

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

Implementation of validation Process 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.

Application of Continuous/Continued Process 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.

Application of Continuous/Continued Process 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.