Post-Approval Change Regulations in Japan

Pharmaceuticals and Medical Devices Agency Office of Cellular and Tissue-based Products

Futaba Honda, Ph.D.

Agenda

• Application Forms and attached documents for market approval of drugs in Japan

• Standard periods and procedures for a partial change approval application and a minor change notification

• A Partial change approved application and a minor change notification Manufacturing sites, Specifications and test methods,

Period of validity, manufacturing methods

• Data requirement for a partial change approval application

• Abbreviation

– a partial change approval application ＝ PCA

– a minor change notification ＝MCN

M3:

Information

on Quality

M4:

Nonclinical

Study Reports

M5: :

Clinical

Study Reports

M2:

Summaries

2.3 quality Overall Summary

:

:

M1:

Administrative Information

and Prescribing Information

Brand Name Ingredients and Quantity Annex Specifications Manufacturing procedures Dosage and administration Indications Storage Conditions and Period of Validity Specifications and test methods Manufacturing Sites

Application Form for marketing approval

Any changes in the matters entered in the Application Form, shall be addressed in a PCA or a MCN.

3.2.S.2.1 Manufacture 3.2.S.2.2 Manufacturing process and process controls 3.2.S.2.3 Control of materials 3.2.S.2.4 Controls of Critical Steps and Intermediates 3.2.S.4Control of DS 3.2.S.5 Reference Standards 3.2.S.6 Container Closure System 3.2.S.7 Stability

3.2.P.3.1 Manufacture 3.2.P.3.2 Batch Formula 3.2.P.3.3 Manufacturing process and process controls 3.2.P.3.4 Controls of Critical Steps and Intermediates 3.2.P.4 Control of Excipients 3.2.P.5 Control of DP 3.2.P.6 Reference Standards 3.2.P.2.4 Container Closure System 3.2.P.8 Stability

M3

2.3.S.2 Manufacture 2.3.S.4 Control of DS 2.3.S.5 Reference Standards 2.3.S.6 Container Closure System 2.3.S.7 Stability

2.3.P.1Description and Composition of DP 2.3.P.3 Manufacture 2.3.P.4 Control of Excipients 2.3.P.5 Control of DP 2.3.P.6 Reference Standards 2.3.P.7 Container Closure System 2.3.P.8 Stability

M2

【Ingredient and Quantity】

【Annex Specifications】

【Manufacturing Procedures】

【Period of Validity and Storage condition】

【Specifications and Test methods】

【 Annex Specifications】

Application Forms for Marketing Approval of Drugs

【Manufacturing sites】

Standard Period and procedures for PCA and MCN

Minor change notification

Partial change approval application

One year

Approval application Application for GMP inspection Approval

Shipping Six months

Notification

Next PCA, GMP periodic

inspection

Shipping

Within 30 days

Approval and Notification in EU, US and Japan

Approval Application EU Type II

US Major change

Japan Partial change approval

Notification Before change EU Type IB Type IA

US Moderate change

After Change Japan Minor change notification

Report US Annual Report

• A MCN is not reviewed at the time.

• In the event that it is discovered in the GMP inspection that a MCN had been submitted concerning changes in manufacturing process that should not have originally been addressed in the MCN, the MCN becomes invalid, and there may be the possibility that the manufacturer may be accused of violating the Pharmaceutical Affairs Law.

Standard Periods and procedures for a PCA and a MCN

The matter is confirmed at the next PCA, but････

What change is addressed in a PCA and a MCN?

• A general rule for Drugs • A change other than listed below is addressed in a MCN

（H16.7.9 yakushokuhatsu No.0709004）

– Change of manufacturing procedures that affect quality, characteristics, efficacy and safety of the final products

– Deletions or changes of the item of specifications and test methods

– Change of the manufacturing processes concerns inactivation or elimination of pathogens

– Additions , changes or deletion of Dosage and administration, and Indications

– Any other change fear of being affected quality, efficacy or safety of the final products

What change is addressed in a PCA and a MCN?

• Biological Products･･･････ （H17.02.10 yakushokushinsahatu No. 0210001 Attachment 3）

• As changes in the matters entered in the Manufacturing Method column require adequate change control, they shall therefore be addressed in a PCA, in principle.

What change is addressed in a PCA and a MCN?

• It is difficult to uniformly specify the matters to be addressed in a MCN for biological drugs.

• Biological drugs are produced by utilizing biosynthesis processes in biological bodies, it may be possible that materials that are inhomogeneous in molecular structure are produced.

• Some changes in the higher structure of the molecule are difficult to be determined by physicochemical analyses can affect biological activity, evaluation of the impact by changes in the manufacturing method on the quality safety.

• Biological drugs consist of various kinds of materials such as proteins, glycoproteins, polypeptides, and their derivatives, and their controls also vary.

What change is addressed in a PCA and a MCN?

• Change of manufacturing sites • Since change in manufacturing sites require adequate

change control, they shall be, in principle, addressed in a PCA for matters that have been approved. However, for changes that are related to facilities for inspection and testing, it shall be addressed in a MCN.

What change is addressed in a PCA and a MCN?

• Specifications and test methods

– They shall be, in principle, addressed in a PCA

– Changing strictly an acceptance criteria without changing the substance of the item of specifications, it can be addressed in a MCN

• Period of validity

– They shall be, in principle, addressed in a PCA

Description of the manufacturing method column in the application form

• The processes required to ensure the quality of the drug shall be described

• For clarifying the operation of the whole process, the manufacturing method shall be described follow the manufacturing process.

appropriate implementation of process management by GMP

Description of the manufacturing method column in the application form

Raw materials

reagents

Critical processes

Major equipment

Critical process parameters

In-process control tests

Key intermediates Testing items, analytical methods, acceptance criteria

Storing conditions and duration, in-process control test

The applicant personally distinguish and establish in advance the matters to be addressed in a PCA , and the matters to be addressed in the MCN.

Process parameters

Description

<<PCA>> 『MCN』

or

none

M2 M3

Validation Data

Design of Experiments

Risk Management

Prior Knowledge

Target value/ Set value

• Target values/set values may be included in operating conditions, etc. If a target value/set value is set, the reference value shall be enclosed in 『 』 or ≪ ≫, and at the same time, an allowable range for the target value/set value must be established in the product master formula or SOPs.

• However, if these parameters are set for parametric release, or if the parameters can affect the quality significantly, it is necessary to specify an allowable range on the approval application form, and they must not be made a target value/set value

PCA MCN

The matter addressed in a MCN on Biological Products

– In the event that it is evident that 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 MCN may be applicable.

• Based on the type of drug and the type of change in the manufacturing method, a MCN 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. As an example of applicable case, the allowable range for process parameters, etc. that is proposed at the time of application may be changed during the review for approval or on the occasion of the actual production results.

Changes in manufacturing method

– For changes in the manufacturing method of drugs, etc., adequate validation and change control, etc. shall be conducted as a prerequisite for changes in either a PCA or a MCN, regardless of the magnitude of the impact on quality. That is, a change shall be made based on the judgment that the change imposes no obvious impact on the quality though change control as performed under GMP.

• Manufacturing Sites – Process validation data and lot analysis data at a new

manufacturing site, comparability data, etc. • Specifications and test methods

– Validation data, comparability data, etc. • Period of Validity

– a real-time/real-temperature stability data • Manufacturing procedures

– Process validation data, comparability data (characteristics, specifications, stability etc.), etc.

Necessary data for a PCA

The Necessity of data may be depend upon degree or substance of the change

Change of the matter addressed in a PCA to a MCN

• a MCN to a PCA

– Minor change notification

• a PCA to a MCN

– Partial change approval application

Thank you for your attention!

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