Guidance on Drug Master File System

in Japan

Master File Management Group

Division of Pharmacopoeia and Standards for Drugs
Office of Review Management

Pharmaceuticals and Medical Devices Agency (PMDA) 1

 Notes

In Japan, the Drug Master File (DMF)

is called “Master File” or “MF”.

Pharmaceuticals and Medical Devices Agency (PMDA) 2

 Topics

Part 1. How to register to MF in Japan

Part 2. Generic Drug Review System, MF System

Pharmaceuticals and Medical Devices Agency (PMDA) 3

 Topics

Part 1. How to register to MF in Japan

Part 2. Generic Drug Review System, MF System

Pharmaceuticals and Medical Devices Agency (PMDA) 4

 Contents

Part 1. How to register to MF in Japan

1.What is the Drug Master File(MF) System?

2.Registration, and Changes in MF “

Pharmaceuticals and Medical Devices

5
Agency (PMDA)
 Contents

Part 1. How to register to MF in Japan

1.What is the Drug Master File(MF) System?

2.Registration, and Changes in MF “

Pharmaceuticals and Medical Devices

6
Agency (PMDA)
What is the Drug Master File(MF) System?

Pharmaceuticals and Medical Devices Agency (PMDA) 7

 “know-how” of API manufacturing methods

 To protect the “know-how” of API manufacturing methods

from the marketing authorization applicant (MAA) / holder
(MAH) of pharmaceutical products.(* MF is not a patent.)
 Registration in the MF is optional, not required by law. An MF
registration certificate is not a marketing certificate.
 In a regulatory review, items registered in the MF are quoted
as information necessary for the review. Some of these items
will be approval items.
 Foreign manufacturers applying for MF registration must
appoint an in-country caretaker for drug substances (APIs), etc.

Pharmaceuticals and Medical Devices Agency (PMDA) 8

 Outline of Application Flow for Pharmaceutical Products

Without MF

Approval application
for pharmaceutical products
+

marketing authorization applicant

CTD-3
Disclosed(Open) Part
Restricted(Closed) Part

No need for protection

APIs manufacturer
PMDA

Pharmaceuticals and Medical Devices Agency (PMDA) 9

 Outline of Application Flow for Pharmaceutical Products
With MF

Approval application
for pharmaceutical products

+ MF number
+ MF registered number
marketing authorization applicant

Disclosed(Open)
Part ONLY
protect “know-how”
(Restricted Part) for MAA

MF registered number

APIs manufacturer CTD3 In-country

Disclosed(Open) Part
(as MF Holder) Restricted(Closed) Part caretaker
PMDA
Pharmaceuticals and Medical Devices Agency (PMDA) 10
 Foreign manufacturers applying for MF
registration the Act on Securing Quality, Efficacy
and Safety of Pharmaceuticals,
Medical Devices, Regenerative and
Cellular Therapy Products, Gene
Therapy Products, and Cosmetics

[the Enforcement Regulations for PMD Act]

1. Select an in-country caretaker for drug substances (APIs) etc., who lives in
Japan and will undertake clerical work for the relevant registration, etc.
Foreign manufacturer(MF Holder) cannot submit “CTD-3” of API
manufacturing methods to PMDA directly.

Foreign manufacturer
(MF Holder) In-country caretaker PMDA

Pharmaceuticals and Medical Devices Agency (PMDA) 11

 Items for MF registration

PFSB / ELD Notification No.11173 December 11, 2014

 Drug substances, intermediates (for medical use)

 New excipients and pre-mix excipients with
different composition ratios from the existing
ones
 Materials used for manufacturing Cellular and
Tissue-based Products
（Cell, Medium, Medium Excipient, etc.）
 Others

Pharmaceuticals and Medical Devices Agency (PMDA) 12

 Qualification of MF Holder

manufacturer

Synthetic route development Synthetic route development

companies(manufacturer) companies(not manufacturer)

Pharmaceuticals and Medical Devices Agency (PMDA) 13

 Qualification of MF Holder
The requirement for MF Holder:
A company manufactures actually the APIs for MF registrations.

With Following conditions; no MF application is accepted.

the processes of manufacturers are only following conditions;
repackaging, packing, labeling, storage, examination
(these processes are not fit the purpose of MF system)

Customer and Contract Manufacturer combination status

(A customer actually does not manufacture APIs)
An important matter

Pharmaceuticals and Medical Devices Agency (PMDA) 14

 the Drug Master File System Summary

• It is important for the MAA/MAH, the MF Holder and the in-

country caretaker to understand the Japanese regulation (PFSB /
ELD Notification No. 0210001 February 10, 2005) and the
guidance.
• [Disclosed(Open) part] The MAA/MAH, the MF Holder and the
in-country caretaker must communicate with each other.
• [Restricted(Closed) part] The MF Holder and the in-country
caretaker must communicate with each other.

Pharmaceuticals and Medical Devices Agency (PMDA) 15

 Disclosed(Open) part／Restricted(Closed) part(2)
CTD module3 Disclosed(Open) part Restricted(Closed) part
3.2.S.1 General Information (name, manufacturer) ○

3.2.S.2 Manufacture (name, manufacturer)

3.2.S.2.1 Manufacturer(s) (name, manufacturer) ○

3.2.S.2.2 Description of Manufacturing Process and Process Controls (name, manufacturer) ○ ○

3.2.S.2.3 Control of Materials (name, manufacturer) ○

3.2.S.2.4 Controls of Critical Steps and Intermediates (name, manufacturer) ○

3.2.S.2.5 Process Validation and/or Evaluation (name, manufacturer) ○

3.2.S.2.6 Manufacturing Process Development (name, manufacturer) ○

3.2.S.3 Characterisation (name, manufacturer)

3.2.S.3.1 Elucidation of Structure and other Characteristics (name, manufacturer) ○

3.2.S.3.2 Impurities (name, manufacturer) ○

3.2.S.4 Control of Drug Substance (name, manufacturer)

3.2.S.4.1 Specification (name, manufacturer) ○

3.2.S.4.2 Analytical Procedures (name, manufacturer) ○

3.2.S.4.3 Validation of Analytical Procedures (name, manufacturer) ○

3.2.S.4.4 Batch Analyses (name, manufacturer) ○ ○

3.2.S.4.5 Justification of Specification (name, manufacturer) ○ ○

3.2.S.5 Reference Standards or Materials (name, manufacturer) ○

3.2.S.6 Container Closure System (name, manufacturer) ○

3.2.S.7 Stability (name, manufacturer) ○

Note)
* shown in both of the restricted and disclosed part are basically disclosed. But, information related to intellectual properties of
MF holder may not be disclosed.
✢ Enter data related to the safety / pharmacological effects of related substances into the body of approval application as necessary.

Pharmaceuticals and Medical Devices Agency (PMDA) 16

 Restricted(Closed) part

Disclosed Restricted
CTD module3
(Open) part (Closed) part
3.2.S.2.3 Control of Materials (name,
*○
manufacturer)
3.2.S.2.4 Controls of Critical Steps and
*○
Intermediates (name, manufacturer)
3.2.S.2.5 Process Validation and/or
*○
Evaluation (name, manufacturer)
3.2.S.2.6 Manufacturing Process
*○
Development (name, manufacturer)

Note)
* Enter data related to the safety / pharmacological effects of related
substances into the body of approval application dossier as necessary.

Pharmaceuticals and Medical Devices Agency (PMDA) 17

 Disclosed(Open) part

Disclosed Restricted
CTD module3
(Open) part (Closed) part
3.2.S.1 General Information (name, manufacturer) ○
3.2.S.2.1 Manufacturer(s) (name, manufacturer) ○
3.2.S.3.1 Elucidation of Structure and other
○
Characteristics (name, manufacturer)
3.2.S.3.2 Impurities (name, manufacturer) ○
3.2.S.4.1 Specification (name, manufacturer) ○
3.2.S.4.2 Analytical Procedures (name, manufacturer) ○
3.2.S.4.3 Validation of Analytical Procedures (name,
○
manufacturer)
3.2.S.5 Reference Standards or Materials (name,
○
manufacturer)
3.2.S.6 Container Closure System (name, manufacturer) ○
3.2.S.7 Stability (name, manufacturer) ○

Pharmaceuticals and Medical Devices Agency (PMDA) 18

 The sections below are basically present
in both the restricted and disclosed parts.

Disclosed Restricted
CTD module3
(Open) part (Closed) part
3.2.S.2.2 Description of Manufacturing Process
○ *○
and Process Controls (name, manufacturer)
3.2.S.4.4 Batch Analyses (name, manufacturer) ○ *○
3.2.S.4.5 Justification of Specification (name,
○ *○
manufacturer)

Note)
*Items marked with in both the restricted and disclosed parts are basically
disclosed. But, information related to intellectual properties of MF holder may not
be disclosed.

Pharmaceuticals and Medical Devices Agency (PMDA) 19

 Disclosed(Open) Attentions
part

• It is necessary for the MAH/MAA to understand the

outline (summary) of the API's manufacturing
methods part if the API is MF-registered.

protect “know-how” “Guidelines on Utilization of Master

(Restricted Part) for MAA/MAH File for Drug Substances, etc 4(1).”

• The MF Holder must communicate with or notify the

relevant MAH/MAA about the proposed data changes
for items in the registered Disclosed(Open) part
information (including the MF registration application
form) in advance.

Pharmaceuticals and Medical Devices Agency (PMDA) 20

 Requirements for MF Registration
protect “know-how”
(Restricted Part) from
 Must? MAA/MAH
No, it is not required Need for MF Registration
by law(voluntary). No need for
protection

No need for MF Registration

 How much is MF registration fee?

No fee is charged for MF registration.

Pharmaceuticals and Medical Devices Agency (PMDA) 21

Registration, and Changes in MF

Pharmaceuticals and Medical Devices Agency (PMDA) 22

 the application form, notification, and other
related documents
Japanese
English • In Japan, the application form,
notification, and other related
documents for pharmaceutical products
application form, which are submitted to the PMDA,
notification written in Japanese.
CTD
module3
and other related
• The MF registration application form,
documents
notification, and other related
documents shall be written in Japanese.

an in-country caretaker for

drug substances (APIs) etc.,
who lives in Japan and will
undertake clerical work for the
relevant registration.

MF In-country
caretaker
Pharmaceuticals and Medical Devices Agency (PMDA) 23
 Relationship between the approval application of pharmaceutical
products and the MF registration application
The approval application of pharmaceutical
MF registration application
products using MF
If the pharmaceutical product's applicant The MF Holder shall describe the detailed
quotes MF for their application, the applicant manufacturing process for API on the MF
shall attach a copy of the registration certificate registration application. If the MF Holder is a
and a copy of the contract with the MF Holder foreign manufacturer, the appointed in-
regarding utilization of the MF. countrycaretaker shall prepare the MF
registration application based on CTD M3, etc.
[Manufacturing Methods column on the approval application [Manufacturing Methods column on the MF registration
form (pharmaceutical products)] application]
(Examples) (Examples)
・・・・using the drug substance A (MF Registration Step 1 (Critical process)
Number: XXXXXXXXXX (YYYY/MM/DD, Version Number X Mix 2-(1-triphenylmethyl-1H-tetrazole-5-yl)-4’-
of MF Registration), Method B) bromomethylbiphenyl [1]『(21.6 kg)』, 2-formyl-5-[(1E,3E)-
1,3-pentadienyl]-1H-imidazole [2]『(6.9 kg)』, potassium
carbonate『(11.8 kg)』, and dimethylformaldehyde『(60 L)』
at『25℃ for 24 hours』. Add sodium borohydride 『(3.2
The information
kg)』, andismix further at『25℃ for 24 hours』. Filter the
equivalent.
reaction mixture, and remove the insoluble matter.
Concentrate the filtrate under vacuum. Add water『(50
L)』to the residue, and extract it with ethyl acetate『(50
L)』. Wash the organic layer with water 『(50 L)』and“10%”
saline solution『(30 L)』.
Pharmaceuticals and Medical Devices Agency (PMDA) 24
 “New MF Registration Application”

 Application for Registration of Drug Substances, etc.

Application (Original 1, Duplicate 1; Duplicate must not be a Xerox

copy of Original)
Data of Application for MF Registration(including CTD Module3*)

*The CTD M3 submits only electronic data.

Pharmaceuticals and Medical Devices Agency (PMDA) 25

 After New MF Registration
For the MF Holder (or In-country caretaker)

After MF registration, an MF registration certificate and a duplicate of

the registration application will be issued.
An MF registration
certificate is not a
marketing certificate.
At PMDA

At a later date, MF registration number, registration date, date of the

change in registered item, name and address of the MF Holder, the
name of registered items, and the registration category will be
published in the PMDA Japanese homepage. These published contents
are Japanese only.

[excel,pdf] https://www.pmda.go.jp/review-services/drug-
reviews/master-files/0008.html
Pharmaceuticals and Medical Devices Agency (PMDA) 26
 “MF partial change approval application”

 partial change approval application in PFSB / ELD Notification

No. 0210001 February 10, 2005

Application (Original 1, Duplicate 1; Duplicate must not be a

copy of Original)
Data of Application for MF Registration(including CTD
Module3*)
Original Registration Certificate
Other (Old/New Comparison table, etc)

*The CTD M3 submits only electronic data.

Pharmaceuticals and Medical Devices Agency (PMDA) 27

 Scope of “MF partial change”
The MF Holder must communicate with or notify relevant MAH/MAA about the
changes in the registered information (including the MF registration application
form) .
[Scope of partial change approval application in PFSB / ELD Notification
No. 0210001 February 10, 2005];
(i) Changes in the manufacturing methods, etc. affecting the nature,
characteristics, performance, and safety of the APIs.
(ii) Deletion of items listed in the specifications and test methods or
changes in the specification.
(iii) Changes in the inactivation or removal methods for pathogenic factors.
(iv) The changes, other than those described in (i) to (iii), which may affect
the quality, efficacy, or safety.

[Note] If the changes in the items in MF will substantially alter the API, please
note that a new MF registration form, not a change of registration must be
submitted.

Pharmaceuticals and Medical Devices Agency (PMDA) 28

 “MF minor change notification”

 minor change notification : PFSB / ELD Notification No.

0210001 February 10, 2005

Minor Change Notification (Original 1)

Data of Application for MF Registration
(including CTD Module3*); as necessary
Statement (appropriate validation, change control, etc.)
Other (Old/New Comparison table, etc)

*The CTD M3 submits only electronic data.

** Basicaly, the MF Holder must submit the notification to PMDA within 30
days after the change made.

Pharmaceuticals and Medical Devices Agency (PMDA) 29

 Scope of “MF minor change”
The MF Holder must communicate with or notify relevant MAH/MAA about the
changes in the registered information (including the MF registration application
form) .
[Scope of minor change notification : PFSB / ELD Notification No. 0210001
February 10, 2005]; other than those described below.
(i) Changes in the manufacturing methods, etc. affecting the nature,
characteristics, performance, and safety of the APIs
(ii) Deletion of items listed in the specifications and test methods or changes in
the specification
(iii) Changes in the inactivation or removal methods for pathogenic factors
(iv) The changes, other than those described in (i) to (iii), which may affect the
quality, efficacy, or safety

[Note] “Minor change notification : PFSB / ELD Notification No. 0210001

February 10, 2005.” does not constitute any part of so called "annual report"
which does not exist in Japan..

Pharmaceuticals and Medical Devices Agency (PMDA) 30

 “Cancellation of MF”
 Notification for MF Registration Cancellation

Notification (Original 1)
Statement (confirming that there is no product using the
MF number to be cancelled)
Original MF Registered Certificate

Pharmaceuticals and Medical Devices Agency (PMDA) 31

Points to Consider

Pharmaceuticals and Medical Devices Agency (PMDA) 32

What is the Drug Master File System?

The Drug Master File (MF) system allows

Japanese or foreign manufacturers of drug
substances to register at the discretion of the
holder the data on quality and manufacturing
methods of their drug substances at the PMDA.

Pharmaceuticals and Medical Devices

33
Agency (PMDA)
What is the Drug Master File System?
Q. What is the great merit of MF? (for manufacturers)

A. Protection of an intellectual properties and know-

how(Restricted-part) etc,. including the registered-
data from marketing authorization holders who are
often competitors at the same time.

Pharmaceuticals and Medical Devices

34
Agency (PMDA)
What is the Drug Master File System?
Ｑ．Who should register the MF?
Ａ．The registration of an MF is not required by law.
An MF is registered solely at the discretion of the
MF holder (Actual manufacturers). That is to say,
anybody (Actual manufacturers) can register.

Pharmaceuticals and Medical Devices

35
Agency (PMDA)
What is the Drug Master File System?
Q. How much is the MF registration fee?

A. No fee is charged for MF registration.

Pharmaceuticals and Medical Devices

36
Agency (PMDA)
What is the Drug Master File System?
Q. Is the MF registration the same thing as MF Approval?.

A. MF registration itself is Neither approved Nor disapproved.

It is NOT a substitute for an marketing approval. The
registered data are used as reference for an approval
review of the drug (pharmaceutical products) in which the
drug substance are applied.

Pharmaceuticals and Medical Devices

37
Agency (PMDA)
 Topics

Part 1. How to register to MF in Japan

Part 2. Generic Drug Review System, MF System

Pharmaceuticals and Medical Devices Agency (PMDA) 38

Generic Drug Review System, MF System

Pharmaceuticals and Medical Devices

39
Agency (PMDA)
 Contents
Part 2. Generic Drug Review System, MF System
1. Approval review for drug products quoting MF
2. Considerations at MF reviews
3. Considerations at change of information
registered in MF

Pharmaceuticals and Medical Devices

40
Agency (PMDA)
 Contents
Part 2. Generic Drug Review System, MF System
1. Approval review for drug products quoting MF
2. Considerations at MF reviews
3. Considerations at change of information
registered in MF

Pharmaceuticals and Medical Devices

41
Agency (PMDA)
 Approval reviews for drug products
quoting MF (Simplified outline)
A system in which companies other than applicants submit information
on quality and manufacturing method of drug substances used for Non-disclosed
information (which
drug products separately (optional submission)
excludes information
on public health safety,
required specifically)
For avoiding troubles over disclosure of drug substance data
among drug product/drug substance manufacturers in reviews.

Pharmaceutical manufacturer Application Regulatory

(Applicant for marketing approval) data authority

Materials to be attached to Review as

Efficacy, safety, application complete data
(part of) quality
MF registration
number
Drug substance
manufacturers Register quality and
(approval not required) manufacturing method data MF
registration
Quality and manufacturing
method data

Pharmaceuticals and Medical Devices

42
Agency (PMDA)
 Issues in MF reviews
Warranty of consistency between use and non-use of MF
MF registration is optional system.
Ensure that the presence or absence of MF use makes no difference in
information provided for reviews. PFSB/ELD Notification No. 0210001
dated February 10, 2005

Does a change fall into "minor change" or "partial change

application"?
In registration application, a change is classified into minor change notification
or application for partial change based on the expected effect on product
quality.
If a registrant is an overseas manufacturer, the MF
registrant shall appoint an in-country caretaker who
<< >> ""
has an address in Japan and delegate MF
registration application to the representative. ‘'
Sufficient cooperation between MF registrant (in-country
caretaker) and marketing authorization holder is required for
ensuring quality of drug product and smooth MF reviews.
Pharmaceuticals and Medical Devices
43
Agency (PMDA)
 Status of information registered in MF
Information registered in MF Application form is filled
in Japanese

 Partial substitution for marketing approval application for a drug

products
 Partial substitution for attached documents for marketing
approval application for a drug products
Original documents of Module 3 of
CTD can be submitted only where it is
written in English.
The summary written in Japanese or
Module 2 of CTD is to be submitted
where required by reviewers.
 The registered information is reviewed in the approval application for
the drug product using the relevant MF.
 In the review of the product, submission of data equivalent to
Module 2 (Summary of Attached Data) is recommended as well as
Module 3 of CTD.
Pharmaceuticals and Medical Devices
44
Agency (PMDA)
 Overview of approval review for drug
products quoting MF
If a registrant is an overseas
manufacturer, inquiries are made
by way of in-country caretaker. MF registration
by way of in-country caretaker

MF Registrants Doubt inquiries on MF

PMDA
Applicant of
Notification on doubt inquiries concerning MF
drug products
(Drug products using
Doubt inquiries on drug products
drug substances with
registered MF)
Marketing approval application for drug
products
Data specified in the Enforcement Ordinance of the Scope of the left column (PFSB Notification No. 0331015 dated
Pharmaceutical Affairs Law, Article 40-1-1. on March 31, 2005)
Management of A. Origin or history of discovery and usage conditions in foreign 1 Origin or history of discovery
countries etc. 2 Usage conditions in foreign countries
impurities and
3 Characteristics and Comparison with other drugs
residual solvent is
reviewed based on B. Manufacturing methods and specifications 1 Identification and physicochemical properties
required measured 2 Manufacturing process
3 Specifications
data and, in some
cases, results of C. Stability 1 Long-term testing 2 Stress testing
3 Accelerated testing
validation of
analytical procedure.
Pharmaceuticals and Medical Devices
45
Agency (PMDA)
 Contents

Part 2. Generic Drug Review System, MF System

1. Application reviews of drug products quoting MF
2. Considerations at MF reviews
3. Considerations at change information registered
in MF

Pharmaceuticals and Medical Devices

46
Agency (PMDA)
CONSIDERATIONS FOR PROCEDURE
OF MF REGISTRATION APPLICATION

 "Guidance on handling of applications submitted on flexible disk etc."

(PFSB/ELD Notification No. 0320005 dated March 20, 2006) should be
referred to for considerations in preparing an application form.
 Before application procedure, check carefully that application data and
attached documents are complete.
 Reflect the contents of past instruction related to inquiries to a new
registration application.
 If anything is unclear in registration application procedure, use simple
consultation for correct application and smooth reviews.
 Incorrect contact information causes wrong transmission of inquiries, etc.
Pharmaceuticals and Medical Devices
47
Agency (PMDA)
 Information on attached files
[Information on attached file] on an FD application form has [Appendix file name] and
[File name of attached documents] . The difference is as follows:

[Appendix file name]

 Approved product information such as charts is required to be converted to PDF files and
attached as well.
e.g., structural formula, picture of a container
 List of drug products quoting the MF (not required to be attached where it is described in the
remarks)
 Comparison table of before and after change (only for application for change registration and
minor change notification)
 Statement (only for minor change notification)

[File name of attached documents]

 Reference data is required to be converted to PDF files and attached as well.
Examples: "Flow diagram of manufacturing process," "Rationale for partial and minor changes,"
"Written reason for diverting foods and industrial products," and "particular account," etc.

Pharmaceuticals and Medical Devices

48
Agency (PMDA)
 Manufacturing method [1]
Administrative Notice from
ELD, PMSB, MHLW, dated
 Concept for description of manufacturing method May 20, 2008

Refer to "Question-and -Answer (Q&A) on Description of Manufacturing Method

in Application Forms for Drugs"
 Concept for eligibility for minor change notification/application for partial
changes
 Each company should evaluate eligibility based on the following notifications.
Simple consultation is available for a case in a gray zone.
PFSB/ELD Notification No.
0210001 dated February 10, 2005

 "Guideline for Descriptions on Application Forms for Marketing Approval of Drugs, etc. under
the Revised Pharmaceutical Affairs Law"
 Other relevant notification and administrative notice (Q&A)
 Administrative Notice from ELD, PFSB, MHLW, dated Nov 16, 2006
 Administrative Notice from ELD, PFSB, MHLW, dated Dec 14, 2006
 PFSB/ELD Notification No. 0112001 dated Jan 12, 2007
 Administrative Notice from ELD, PFSB, MHLW, dated Jun 28, 2010
 Administrative Notice from ELD, PFSB, MHLW, dated Jul 26, 2010
 PFSB/ELD Notification No. 0530-8 dated May 30, 2014
 PFSB/ELD Notification No. 0710-9 dated Jul 10, 2014
Pharmaceuticals and Medical Devices
49
Agency (PMDA)
 Manufacturing method [2] PFSB/ELD
Notification No.
0210001 dated
February 10, 2005

– Manufacturing method of chemical drug substance

• According to Appendix 1 of the notification, describe more than one
reaction process in principle, starting with an appropriate starting
material.
Reaction process: process including formation or cutting of a covalent bond,
excluding base exchange or purification process.
• Note that only sufficiency of number of reaction processes is
evaluated, not appropriateness of manufacturing method.
Justification for selection of a starting material
Evaluation on control strategy
• Control standards for starting materials, raw materials, critical
intermediates, and final intermediates are appropriately established.
• Control standards for raw materials after final intermediates are
developed in principle.

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50
Agency (PMDA)
 Manufacturing method [3]
PFSB/ELD
Notification No.
0210001 dated
February 10, 2005

• Critical processes are established based on data collected appropriately.

Critical process:A process impacting the quality and including process conditions, tests, and other relevant
parameters in which operation within predetermined action limits to ensure conformity of drug
substances to specifications is required.Where inquiry on rationale for critical process is made during
review, the applicants should provide scientific explanation based on data, etc.

• Abbreviated description of Manufacturing method of specific drug substances

listed in Appendix 1 of PFSB/ELD Notification No. 0304018 dated March 4, 2009
can be acceptable.
• Manufacturing site information, range of manufacturing process and flow
diagram of manufacturing method (flow diagram is attached as appendix [PDF
file] ) are to be described to indicate summary of manufacturing process.

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51
Agency (PMDA)
 Specifications [1]
• Residual solvent in drug substance
In view of manufacturing process and classification of solvents (Guideline for Residual
Solvents) , it should be considered whether including in the manufacturing method or
establishing the specifications is necessary.
If not necessary, explanation based on scientific evidence such as actual data is given.
 Actual data and the results of validation of analytical procedure are to be submitted at
registration to explain the necessity of listing as specifications or process controls and the
justification for acceptance criteria.

• Impurities in drug substances

List all expected impurities and related substances, which are included as applicable in
controls of starting materials or intermediates and specifications of final drug substances.
List of structures of expected impurities, actual data, and the results of validation of analytical
procedure are to be submitted at registration to explain the necessity of the final
specifications or establishing the control values of starting materials or intermediates, and
justification for acceptance criteria.
* It should be kept in mind that insufficient confirmation on expected impurities may lead
to delay of reviews.
Pharmaceuticals and Medical Devices
52
Agency (PMDA)
 Specifications [2]

• In cases where manufacturer's specifications are established,

 Full description of the specifications is required by reference to
the Guideline for the Preparation of the Japanese
Pharmacopoeia.
 Where non-pharmacopoeial reagents/test solutions are used,
provide a section for reagents/test solutions in which the quality
and preparation procedure are described.
 Check carefully that the description is correct and complete.

Pharmaceuticals and Medical Devices

53
Agency (PMDA)
 Manufacturing site of drug
substances
• Before application/notification, check carefully that
information on manufacturing site is correct.
• Where the following dummy number is used for a
manufacturing site of a drug substance, confirm the
justification carefully and describe appropriate information.
<Reference>
 For manufacturing sites of intermediates of drug substances (excluding case of diversion)
License (accreditation) No.: 99AZ666666
License (accreditation) date: April 1, 2005
 In cases where foods or industrial products are necessarily diverted (only when the
appropriateness is established)
License/accreditation No.: 99AZ777777/AG99977777
License (accreditation) date: April 1, 2005
Pharmaceuticals and Medical Devices
54
Agency (PMDA)
 CONSIDERATIONS FOR REPLACEMENT
For MF replacement, for all inquiries and response, the following
materials should be submitted:
Both of
 A paper file of hard copies
 Electronic media (CD or DVD) with text
<Precaution for submitting electronic media>
• Convert it to a PDF file with text recognition available.
• Confirm electronic media is in accord with the paper media.
(Attention should be paid to loss or overlap of pages, integrity of order)
• Electronic media of FD application, attached documents, and inquiry responses
should be made separately.
• Generate a file name appropriately.
(Too long names or symbol should not be used)
• Check for virus with the latest definition file before submission.

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 Other considerations
• For an in-country caretaker, prepare "in-country caretaker"
column and describe it appropriately in the column, not in the
remarks column.
• For MF registration application, data with logical explanation
based on the results from sufficient evaluation and evidence
should be prepared.
• Check carefully before application as incorrect or incomplete
description may damage the confidence in the registrants.

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 Contents

Part 2. Considerations for Description of

Manufacturing Method in MF and Drug
Application Form for Marketing Approval
1. Application reviews of drug products quoting MF
2. Considerations at MF reviews
3. Considerations at change for information
registered in MF
4. Case introduction
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 Procedure for changes in registered items
[1] Potential changes in the nature of drug substances
due to changes in registered items New application for
registration

Major
[2] Normal Changes (Changes not classified to Application for change
[1] or [3] ) registration
Degree of changes

[3] Minor Change

Changes other than the following:
• Changes in the manufacturing method, etc.
affecting the nature, characteristics,
performance, and safety of drug substances. Minor change
• Deletion of the items listed in the notification
specifications or changes in the
specifications
• Changes in the inactivation or removal

Minor method for pathogenic factors

• Other changes which may affect the quality,
efficacy, and safety.

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Changes in registered items in MF and
partial changes of drug products
Minor changes in Changes in items requiring
registered items application for partial change

Marketing
MF registrants
Advance authorization holder
distribution and
share of
Minor change Application for information Application for
notification change partial change
registration

PMDA MHLW

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 Changes in registered items [1]
MF registrants should notify the applicants of changes in
registered items in advance.

 Where a product has been already approved using the MF, the
MF registrant also should notify the marketing authorization
holder of the product of the change.
 In notification of minor changes in registered items, involving
applicants and marketing authorization holders should be
notified of the change.
 As this involves not only MF registrants but also the MA
applicants or marketing authorization holders of drug
products made with the substances, poor cooperation
between them could led to troubles.
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 Changes in registered items [2]

In the case of changing the items registered in MF

MF registrants evaluate whether the change is classified as
"minor change" or "not minor change" and is required to follow
appropriate procedures for the change in registered items.

If the evaluation is difficult, they

should sufficiently confer with MA
applicant or marketing authorization
holder of the drug product and
confirm it.

Change registration Not minor change (changes affecting the quality of drug
substance)
Minor change notification Minor change (changes unlikely to affect the quality of
drug substance)

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Changes in registered items as partial changes [1]

Where registered items are changed partially, application

for change registration of MF is basically required.

However,
 Even changes regarded as minor change may be required to be applied
as MF change registration as well when the effect of the change on the
drug product is assessed not minor.

 In these cases, marketing authorization holders of drug products evaluate

whether the effect of the change is acceptable in view of contents of the
marketing authorizations and should submit the applications for partial
change of their drug products.

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Changes in registered items as partial changes [2]
In the cases that effect of a change is considered to be acceptable, in view of
the contents of the relevant marketing authorizations.
 MF registrants submit an application form for change registration
of registered items to the regulatory authority.
* Attached documents on changes in registered items
Actual data
Appropriate validation
A statement for the fact that change control has been performed, etc.

 Where contents of a change are considered to have an

unacceptable effect, the marketing authorization holder may not
accept the change.

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 Changes in registered items as minor changes [1]

A minor change notification in MF registered

items is submitted basically after confirming that
the effect of the change is minor.
 In the cases that the change is confirmed to be minor
MF registrants submit notification of the minor change in the registered
items to the regulatory authority.
* Attached documents
Appropriate validation
A statement for the fact that change control has been performed, etc.
* In this case, a marketing authorization holder of a drug product made
with MF registered drug substance is not required to notify minor
change in approved items.

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Changes in registered items as minor changes [2]

Justification for a change in MF registered items notified as a

minor change is not reviewed at the time of the notification
in principle.
 An MF registrant (and an applicant of a drug product) takes self-
responsibility for the notification.
 Justification for minor change notification is assessed on review after
an application for a partial change of a drug product or on GMP
inspection after the notification.

Perform routinely the change

control specified in revised GMP
regulation.
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Changes in registered items as minor changes [3]

A minor change notification in MF registered items is submitted

basically after confirming that effect of the change is minor.
However,
 In a case where effect of a change in MF registered items expected
to be minor at registration has been assessed as not minor
* where results that can not deny effect on the quality have been indicated
at change control procedure of a MF registrant, or
* where a change has been assessed as not minor as a result of discussion
with the marketing authorization holder of the product.

The change is canceled, re-examined, notified as an application for a partial

change or registered again as a new drug substance, etc.

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 Changes in registered items as minor changes [4]
 Where GMP inspection has revealed that a change in
manufacturing process, etc. which should not be treated
as a minor change has been notified as a minor change
 The minor change notification becomes nullified.
 It is likely to constitute a violation of the Pharmaceuticals and
Medical Devices Law.
 For products manufactured in the changed process,
cancellation of shipments, recall, or other regulatory actions
are to be taken according to risks due to the change.

Perform routinely the change control specified in

revised GMP regulation.
Due communication should be made with marketing
authorization holder.
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 Request

Where a MF registered item is changed, the procedure

related to approval of the drug product is generated along
with the procedure on MF registration. Sufficient information
sharing and adequate regulatory measures between MF
registrants and marketing authorization holder is critical.

Access on the PMDA website in Japanese

ホーム > 審査関連業務 > 承認審査業務（申請、審査等） > 原薬等登録原簿（MF）

https://www.pmda.go.jp/review-services/drug-reviews/master-files/0007.html

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