PMDA Perspective:

Regulatory Updates on Process

Validation Standard

1

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.

Kazunobu Oyama, PhD Office of Cellular and Tissue-based Products

PMDA, Japan

CMC Strategy Forum Japan 2014

Tokyo, Japan, December 8-9, 2014

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

Non-

Clinical

Study

【Typical Development】

Establishment of Design Quality and

Product Quality by CMC study

Clinical Study

Phase 1 Phase 2 Phase 3

Investigational Product GMP GMP

Post-

Approvaｌ

Control strategy Control strategy Control strategy

Process Parameters CPP

CQA Quality Attributes

Knowledge Control／Quality Risk Management

Control Strategy

Equivalency Consistency

Target product Profile

Process

Validation

Approval

4

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

Matters of description on application form

5

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)

Matters of description on application form

Design

Quality

Product

Quality

Quality

Management

Procedure

Equipment

Process

Material

Quality Risk Management / Knowledge Control

6

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.

Understanding of Product Quality

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 real-time release testing (not required)

Establishment of control strategy

Knowledge and understanding could facilitate continual improvement

QTPP

CQAs

Risk Management

Option

Continual improvement

QbD Approach

Control strategy

Pharmaceutical

Development

Technology

Transfer

Commercial

Manufacturing

Product

Discontinuation

GMP

Quote or altered from ICH Q10 Annex2

Management Responsibilities

Process Performance and Product Quality Monitoring System

Corrective Action / Preventive action system

Change Management System

Management Review

Knowledge Management

Quality Risk Management

PQS elements

Enabler

Investigational

Products

ICH Q10 Pharmaceutical Quality System

Review of CPP, DoE and Design Space.

Revalidation

Life cycle Management

Knowledge control

R&D Manufacturer

QTPP

Define Quality target product profike

CQA

Identify critical quality attributes

Risk assessment

DoE

Control Strategy

Process understanding, Knowledge accumulation

QbD information

Evaluation of impact

Process

Assay

Master plan of transfer

Justification of control strategy

Tech.Transfer (Design

Space)

CPP

QbD

Scale-up

PV

Re-

evaluation

Process

Monitoring

Development Stage Transfer Commercial

Manufacturing Stage

Accumulation and transfer of knowledge

Product quality review

Change management (impact

assessment)

Deviation management (CAPA)

Process

Monitoring

Re-

evaluation

Tech.Transfer

Process

A

Process

B

10

Knowledge accumulated in the development department

and manufacturing department, important to support

consistently the robustness of the process C

Tech. Transfer

Report

Technical Transfer

R&D Manufacturer

Development Stage Transfer Commercial

Manufacturing Stage

Process

C

Knowledge of

Development stage

Knowledge of Commercial

Manufacturing Stage

Development Stage Transfer Commercial

Manufacturing Stage continual improvement

Transfer of accumulated knowledge in the

commercial manufacturing stage

Feedback of knowledge

Review of CPP, DoE and Design Space.

Revalidation

Life cycle Management

Knowledge control

Re-

evaluation

Process

Monitoring

Product quality review

Change management (impact

assessment)

Deviation management (CAPA)

Process

Monitoring

Re-

evaluation

R&D

QTPP

Define Quality target product profike

CQA

Identify critical quality attributes

Risk assessment

DoE

Control Strategy

Process understanding, Knowledge accumulation

QbD information

Evaluation of impact

Process

Assay

Master plan of transfer

Justification of control strategy

Tech.Transfer (Design

Space)

CPP

QbD

Scale-up

PV

Development Stage Transfer Commercial

Manufacturing

Stage

Commercial

Manufacturing

Stage

Complaint

CAPA

Process

development

Change

Management

CAPA CAPA CAPA

Process Monitoring

・Process improvement ・Control strategy improvement ・Revalidation

• Knowledge is continuously accumulated

• Quality system of GMP to feedback the

knowledge in process control is important New variation factors

Product Quality Review

Knowledge management in the lifecycle

Non-Clinical Research

Clinical Research After the Launch

Stage2 Stage3

Investigational Product Production in Pilot

&/or Commercial Scale

PPQ

Commercial Lots

PhaseIII～

FDA’s PV GL

Knowledge Control in Research &/or Development Div.

Stage1

13

Scheme of Process Validation in FDA

Guidance for Industry

Process Validation: General Principles and Practices

Consistency of Process and Product Quality

Knowledge Control in Mfg. Plant

Tech. Transfer

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

14

Administrative notice

(GMP Question and Answer)

Administrative notice

(MHLW Research Report)

GMP Ministerial

Ordinance

GMP Enforcement

Notification

Enforcement

Ordinance of PAL

Enforcement

Notification

and

Administrative

notice (ICH

Q7, Q8, Q9,

Q10, Q11)

JP General

Information

PIC/S GMP Guide

GMP Regulatory Framework in Japan

Pharmaceutical

Affairs Law (PAL)

GCP Ministerial

Ordinance

Notification

(JP, Standard for BI)

Enforcement Notification for

Investigational Product GMP Required

Ris

k-b

ased

Appro

ach

GMP Regulatory Framework in Japan

Administrative notice

(GMP Question and Answer)

Administrative notice

(MHLW Research Report)

GMP Ministerial

Ordinance

GMP Enforcement

Notification

Enforcement

Ordinance of PAL

Enforcement

Notification

and

Administrative

notice (ICH

Q7, Q8, Q9,

Q10, Q11)

JP General

Information

PIC/S GMP Guide

Pharmaceutical

Affairs Law (PAL)

GCP Ministerial

Ordinance

Notification

(JP, Standard for BI)

Enforcement Notification for

Investigational Product GMP Required

Ris

k-b

ased

Appro

ach

Validation standard （Basic requirements of Validation）

(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) Process validation (PV)

c) Cleaning validation

d) Revalidation

e) validation on change control

Contents of Validation Standard

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 Process Verification

• 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

Key Points of the amendment

Implementation of QRM（ICH Q9） Risk Assessment

Risk Control

Risk Communication

Risk Review

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.

21

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.

Implementation of validation

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.

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.

Application of Continuous/Continued Process Verification

Product Quality Review

Report of Research and Development

Process Research

Process Validation

Overall picture of activities through the product life cycle

Cycle that connects

development and

commercial production

Commercial Production Development

Technical Transfer

Technical Transfer

Technical Transfer

Knowledge

Quality Improvement

Research and Development Transfer

Commercial Manufacturing

Investigational products’ Production

(Pilot &/or Commercial Scale)

PV

(PPQ)

Commercial Batches Manufacturing

Consistency of Process and Product Quality

Validation ・Qualification of Equipment ・Process Validation/Verification ・Change Control ・Revalidation

Manufacturing Process Design 【Development】

Manufacturing Process

【Improvement】

Manufacturing Process

【Verification】

Stage

Knowledge Control and Tech. Transfer

Activity

Approach of Evaluation

Verification Process, Cleaning method of

Investigational product

Validation Analytical method, Computer Systems,

Sterility assurance, etc.

Knowledge Control in Research &/or

Development Div.

Knowledge Control in

Mfg. Plant

Technical

Transfer

26

Summary

Manufacturing Process

【Process Monitoring】

Control Strategy

Control Strategy

Knowledge Control

27

Thank you for

your attention!