April 26, 2017, WHO – MFDS in Korea

Post‐Approval Changes of Biologicals inJapan: CMC
Teruhide Yamaguchi
Kanazawa Institute of Technology (KIT)Phamaceutical Medical Device Agency (PMDA)

The views and opinions expressed in this presentation are those of the presenter

Outline Regulatory Framework of Common
Technical Document
 Regulatory Pathway for Post Approval
Changes ...and Future

Regulatory Framework in Japan‐Focus on biologics CMC‐Law
Government
Ordinance
MHLW Ministerial
Ordinance
MHLW
Notification

 Pharmaceuticals and Medical Devices (PMD) Act.
 Enforcement Ordinance of the PMD. Act Enforcement Regulations of the PMD. Act
 GMP, GQP
 Japanese Pharmacopoeia
 Standard for Biological Ingredients (vaccine, BloodProducts)
 Minimum Requirements for Biological Products

PSEHB Notification
PSEHB/ELD Notification
PSEHB/ELD Administrative Notice ICH guidelines
 Guideline for Descriptions on Application Forms forMarketing Approval of Drugs, etc. under the Revised
Pharmaceutical Affairs Law
 Etc.
• MHLW: Minister of Health Labour and Welfare• PSEHB: Pharmaceutical Safety and Environmental Health Bureau• ELD: Evaluation and Licensing Division

Structure of Common Technical DocumentApplication
Form

Module 1
Out of scope for CTD

2.1-2.2 Contents,
Preface
２．３
Summaryof Quality
２．３．S
２．３．P
２．３．A
２．３．R
Quality

Module 2
２．４
Summaryof NonclinicalNonclinical

２．５
Summaryof Clinical

ClinicalModule3-5

Relationship between Application Form and ICH CTD
Approved Matters

Main review document

Application Form……….

2.1-2.2 Contents,
Preface
２．３
Summaryof Quality
２．３．S
２．３．P
２．３．A
２．３．R

………

Application
Form

Module 1
Out of scope for CTD

Module 2

２．５
２．４
Module 2Summary(QOS) Summaryof……….

Qualityof NonclinicalNonclinical

ClinicalModule 3Clinical

Module3-5Section of Application Form


General name (JAN)
Brand nameComposition
Manufacturing process, incl. control of materials
Specifications
Dosage and administration
Indications
Storage condition and shelf‐life
Manufacturing sites information

PMD. Act(Marketing approval to drug etc.)
Article 14 Persons intending to market a drug …… must obtain approvalof the Minister for marketing of each item.

Partial Change Application (PCA)

9 When persons who have received an approval as specified inParagraph 1 wish to make a partial change of approval items (excludingcases where such changes are minor changes as specified by MHLW
Ordinance), approval of the Minister must be obtained for such cases. In
such cases, the provisions of the preceding paragraphs shall apply
mutatis mutandis.Minor Change Notification (MCN)
10 A person who has obtained approved specified in Paragraph 1 shallsubmit a notification of minor changes specified by MHLW Ordinance inthe preceding paragraph to the Minister as specified by MHLW
Ordinance.

Enforcement Regulations of the PMD. Act(Range of minor change in the approval items)
Article 47 The minor changes specified by MHLW Ordinance pursuant to theprovisions of Article 14, Paragraph 10 of the Act shall be changes other thanthose specified below.
(1) Changes in the manufacturing methods, etc. that will affect the nature,properties, performance, or safety of a product(2) Deletion of items from the specifications and changes in the specifications(3) Changes concerning methods for the inactivation or elimination ofpathogenic factors(4) Addition, changes or deletions concerning the dosage and administration,or the indications(5) In addition to those specified in the preceding items, any changes thatcould potentially affect the quality, efficacy, or safety of a productOutline Regulatory Framework of Common
Technical Document
 Regulatory Pathway for Post Approval
Changes ...and Future

Regulatory change in Application Form (1) Chemicals
Specifications

Mandatory for all products

Specifications

Mfg. process
Mfg. process Biologics
Specifications
Mfg. process

Specifications

 Discussions in research groups Guideline incl. mock for chemicals

Mfg. process

Guideline for Descriptions on Application Forms for Marketing Approvalof Drugs, etc. under the Revised Pharmaceutical Affairs Law in 2005
http://www.pmda.go.jp/files/000153677.pdf (in English)

Regulatory change in Application Form (2) Minor Change Notification in manufacturing
process section was introduced.
 Harmonization among ICH regions was considered.
 CBE30/Type1B, Annual Report/Type1A, Comparability
Protocol were NOT introduced.
 Information/elements classified as Annual Report/
Type1A were considered as non‐Approved Matters.

Post‐Approval Change Reporting Categories
Impact onqualityHighModerateLowJapan
Partial changeApplication(prior approval forchange)
Minor changeNotification(within 30 days after
implementation orshipping)(Non‐approvedmatters)

USEU

Major change(Prior approvalsupplement)

Type II variation(Application for approval ofvariation)

Moderate change
1)Supplement‐changes being
effected (CBE) in 30 days

Type IB variation(Notification before
implementation and MAHs
must wait a period of 30 days)2)Supplement‐changes being
effected (CBE)Minor change(Annual report)

Type IAIN variation(Immediate notification)
Type IA variation(Notification within 12 months
after implementation)

In Japan, according to the impact of MFG changes on quality, safety and efficacy, sponsor
should submit the partial change application or minor change notification.

Concept of the Revised PAL for Biologicals


Because biological drugs are produced by utilizing biosynthesis
processes in biological bodies, it may be possible that materials thatare inhomogeneous in molecular structure are produced.
Furthermore, as some changes in the higher structure of the moleculethat are difficult to be determined by physicochemical analyses canaffect biological activity, evaluation of the impact by changes in themanufacturing method on the quality, safety, and efficacy of theproduct is considered as being different from that of ordinary chemicaldrugs. Since biological drugs consist of various kinds of materials
such as proteins, glycoproteins, polypeptides, and their derivatives,and their controls also vary, it is difficult to uniformly specify thematters to be addressed in a minor change notification forbiological drugs.
Accordingly, in the case of biological drugs, changes in the mattersdescribed on an approval application form shall, in principle, beaddressed in a partial change approval application.

A partial change approval application and a minorchange notification for the manufacturing method
As changes in the matters entered in the Manufacturing
Method should be adequately controlled, they shalltherefore be addressed in a partial change approval
application, in principle.
 When there is an extremely low possibility of the change
having an adverse impact on the quality/safety of the final
product, and in the following confirmed cases, a minorchange notification may be applicable;For the applicable cases, the applicant may make such a proposal
when submitting an approval application; the proposal will be judged
during the review as to whether it can be accepted.
In cases where in-house in-process control tests and similar target
values are described.
Etc.

Manufacturing Method (Process parameter)

Expression of minor notification and partial change
approval application

Among the standard batch sizes or the process parameters that serve
as target values/set values, the matters to be addressed in a minorchange notification shall be expressed as enclosed in 『 ○ ○ 』.
The standard batch sizes or the process parameters to be addresses
in partial change approval application shall be expressed as
enclosed in 《 ○ ○ 》.
The matters to be addressed in a minor change notification otherthan target values/set values shall be enclosed in “ ○ ○ ”.

Update Remaining Challenges
 Our 2005 GL has provided the basic principle of approved matters in
the manufacturing process and helped both regulators and theindustry.
 However, there still remain some challenges, including; Adverse effects of mock• Some just followed the mock described in the guideline to meet deadline.
• Both regulators and the industry tend to follow the mock (?), although thedescription in the AF is on a product‐by‐product basis.

 Document management• The discrepancy between the actual situation (e.g. MBR) and AF is caused bymultiple factors.

 Others• Some tend to lose sight of the original purpose of the AF.
• Some tend to think MAHs manufacture and control their products onlyaccording to the AF.
• There had been no detailed discussion on Specification.

Outline Regulatory Framework of Common
Technical Document
 Regulatory Pathway for Post Approval
Changes ...and FutureJapan’s Effective/Efficient/Flexible Quality Regulation
Module 1(Application Form)

Legally binding

Module 2 (QOS)

Module 3

Not‐Changeable without
regulatory procedures (PCA/MCN)

Changeable without regulatory
procedures (PCA/MCN)

Thank you for your attention

Pharmaceuticals and Medical Devices Agency

19

Japan’s Effective/Efficient/Flexible Quality Regulation
Module 1(Application Form)

Legally binding

Module 2 (QOS)

Module 3

Not‐Changeable without
regulatory procedures (PCA/MCN)

Changeable without regulatory
procedures (PCA/MCN)

Outline
 Past, Present
 ...and Future
Reminder!
Some of the content are currently under discussion.
The views and opinions expressed in this presentation arethose of the presenter and should not necessarily represent
the views and opinions of the PMDA.

Issues to be addressed in ICH Q12
 Regulatory Dossier Explore the development of a harmonised approach to “regulatory commitments” for inclusion in theguideline. Such approaches could enable post approval changes that facilitate continual improvement
and encourage the adoption of innovative technologies.
 Delineate the appropriate level of detail and information necessary for regulatory assessment andinspection in the dossier, in order to create a more enabling post approval change management
system.

 Pharmaceutical Quality System (PQS) aspect
 Establish criteria for a harmonised risk‐based change management system based on product, process
and/or clinical knowledge that effectively evaluates the impact of change on quality, and, as applicableto safety and efficacy.
 Clarify expectations and reinforce the need to maintain a knowledge management system that ensurescontinuity of product and process information over the product lifecycle.

 Post‐Approval Change Management Plans and Protocols
 Introduce the concept of a post‐approval management plan that can be used to proactively identify
post‐approval changes and the mechanism to submit and assess these changes by regulatory
authorities (Assessors and Inspectors)
 Establish criteria for post‐approval change management protocols that can be adopted by the ICH
regions (enabling a harmonised proactive approach for lifecycle management) Encourage enhanced product development and control strategy approaches (Quality by Design (QbD))
providing opportunities for scientific and risk based foundations for post‐approval change management
plans.
From ICH Q12 Concept Paper

Approved Matters ≈ Established Conditions
ICHJapan

Summarized
Module 3

Module 3
Extracted

Module 2 (QOS)?

Approved Matters
Module 1(AF)Established Conditions

Review Process of MAA with document flow
Applicant‐Focus on CMC‐

AF,M2,M3

PMDA

Application

External
experts

F2F meeting
AF,M2,M3

Expert discussion

Inquiry/
Response
Manufacturing
site

GMP
audit

AF(M2,M3, if needed)

AF

Review report
AF,M2,M3

AF,M2

Review report

Review report（Approval Letter）

Ministry of Health
Labour and Welfare

Approval

Consultation

Opinion(Positive/Negative）

PharmaceuticalAffairs and Food
Sanitation Council

Japanese Application FormMHLWMAHs

Japanese Application Form/Approved Matters AF, found in Module 1.2, is a legally binding document inJapan.
 Essential elements to ensure pharmaceutical quality
should be described in AF.
 A post‐approval regulatory action is required if a MAH
changes the content in the AF (Approved Matters; AMs).
 AMs (incl. PCA/MCN) are determined on a product‐by‐product basis.

 AF provides the transparency and flexibility interms of post‐approval changes.

AF and Review/Inspection
inspection‐Focus on post‐approval change‐AFreview

Modified from draft Q12 document

Japanese Application Form/Approved Matters AF, found in Module 1.2, is a legally binding document inJapan.
 Essential elements to ensure pharmaceutical quality
should be described in AF.
 A post‐approval regulatory action is required if a MAH
changes the content in the AF (Approved Matters; AMs).
 AMs (incl. PCA/MCN) are determined on a product‐by‐product basis.

 AF provides the transparency and flexibility interms of post‐approval changes.