April 26, 2017, WHO – MFDS Joint Meeting in Korea

Post-Approval Changes of Biologicals inJapan: CMCTeruhide 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 Future1Regulatory Framework in Japan-Focus on biologics CMC-Law

 Pharmaceuticals and Medical Devices (PMD) Act.

GovernmentOrdinance Enforcement Ordinance of the PMD. Act
 Enforcement Regulations of the PMD. Act
 GMP, GQP

MHLW MinisterialOrdinance Japanese Pharmacopoeia
 Standard for Biological Ingredients (vaccine, BloodProducts)

MHLWNotification

 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 Document

Application
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

ClinicalModule3-52Relationship between Application Form and ICH CTD
Approved Matters

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

………

Module 1
Out of scope for CTD

Main review document

Application Form……….

Application
Form

Module 2

２．４
２．５
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

3

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. Insuch 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 that
could potentially affect the quality, efficacy, or safety of a product4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)5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 onqualityHigh

ModerateLowJapanPartial changeApplication(prior approval forchange)Minor change
Notification(within 30 days afterimplementation orshipping)(Non-approvedmatters)

USEU

Major change(Prior approvalsupplement)

Type II variation(Application for approval ofvariation)

Moderate change
1)Supplementchanges being
effected (CBE) in 30 days

Type IB variation(Notification before
implementation and MAHs
must wait a period of 30 days)2)Supplementchanges 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.

6

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.

7

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 asenclosed 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 only
according to the AF.
• There had been no detailed discussion on Specification.

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

Thank you for your attention

Pharmaceuticals and Medical Devices Agency

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