regulatory system on generic drugs in japan · •the following tests are also considered generally...

Mr. TANAKA Katsuya（田中克哉）

Section Chief, Pharmaceutical Evaluation Division,

Pharmaceutical Safety and Environmental Health Bureau,

Ministry of Health, Labour and Welfare (MHLW)

Feb 5th, 2020

4th India -Japan Medical Products Regulatory Symposium

Regulatory system on Generic drugs in Japan

4th India - Japan Medical Products Regulation Symposium 2019 1

Contents

• Introduction of Review Points and BE Guidelines

• Overview of Japan’s Strategy for promoting the use of Generic Drugs

24th India - Japan Medical Products Regulation Symposium 2019

Contents




・Expiration of re-examination period of the original product

・No valid patent (substance/utility patent for the active ingredient) at the time of

approval

・Warranty of equivalent quality and bioequivalence to the original product

Requirements for application/approval of generic drugs

Comparing with the original, brand drug, generic drug have the same:

・API (active pharmaceutical ingredients)

・Strengths

・Route of administration

・Dosage form

・Dose and administration and Indications

What are generic drugs?

About generic drugs


Documents Originator Generic

a. Origin or background of discovery, condition of use in foreign countries

1 Origin or background of discovery ○ ×

2 Conditions of use overseas ○ ×

3 Special characteristics, comparisons with other drugs etc. ○ ×

b. Manufacturing methods, specification and test methods

1 Chemical/physical characteristics and structure property ○ ×

2 Manufacturing methods ○ △

3 Specification and test methods ○ ○

c. Stability1 Long-term storage tests ○ ×

2 Tests under severe conditions ○ ×

3 Accelerated tests ○ ○

d. Pharmacological action1 Tests to support efficacy ○ ×

2 Secondary pharmacology, safety pharmacology ○ ×

3 Other pharmacology △ ×

e. Absorption, distribution, metabolism, and excretion

1 Absorption ○ ×

2 Distribution ○ ×

3 Metabolism ○ ×

4 Excretion ○ ×

5 Bioequivalency × ○

6 Other pharmacokinetics △ ×

f. Acute/sub acute/chronic toxicity, teratogenicity, and other type of toxicity

1 Single dose toxicity ○ ×

2 Repeated dose toxicity ○ ×

3 Genotoxicity ○ ×

4 Carcinogenecity △ ×

5 Reproductive toxicity ○ ×

6 Local irritation △ ×

7 Other toxicity △ ×

g. Clinical trials 1 Results of clinical trials ○ ×

h. Package inserts 1 Points to consider of package inserts ○ ○

Note) ○ means necessary, × means not necessary, and △ means to depend on each product

Requirements of data in application in Japan


1. Specifications and analytical procedures

• Specifications are one part of a total control strategy for the drug substance and drug product designed to ensure product quality and consistency (ICH Q6A guideline).

• The following tests are also considered generally applicable to generic drugs.

- Limits of the content of the ingredient(s) and/or the unit of potency, Description, Identification tests, Specific physical and/or chemical values, Purity tests, Water or loss on drying, Residue on ignition, Assay, and so on.

Points of quality review

4th India - Japan Medical Products Regulation Symposium 2019 6

1. Specifications and analytical procedures （continued）

• Assay

• Set acceptance criteria assuring the equal efficacy and safety based on the batch data and stability data, etc.

• Impurities

• Equal or tighter acceptance criteria than that of

the original drug in principle.

• Review based on ICH guidelines (Q3A, Q3B, Q3C) about impurities which are not detected in the original drug.



2. Manufacturing processes

The Marketing Approval Document includes all processes from starting material(s) to packaging process.

• Starting materials

• Intermediates

• Critical steps

• In-process control

• Container closure system, and so on

• An applicant should demonstrate that the manufacturing process is capable of consistently producing drug substance and drug product of the intended quality.



3. Stability

• An applicant should submit 6 months of accelerated stability data.

- at 40 ℃, RH 75%, 3 lots, for 6 months

• In some cases, the applicant should also submit the following stability data at the time of submission.

Long-term storage tests

- at 25 ℃, RH 60%, 3 lots, for 12 months at least

Tests under severe conditions

- photostability, etc.



4.Bioequivalence

• Assure therapeutic equivalence of a generic drug to the original drug.

• Compare the bioavailability between a generic drug and the original drug.

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• Guideline for Bioequivalence Studies of Generic Products + Q&A (February 29, 2012)

– Q&A has not been denied the possibility of acceptance of foreign subjects BE data.

– Japanese research group has summarized the consideration from the scientific view point to cope with BE study (including acceptance of foreign subjects data).

Summary:

− The target of BE studies is to detect differences between formulations, and the influence that the racial difference bring to the result could be considered to be small.

− Foreign BE studies are acceptable as a rule in light of the current guideline concept.

− However, if there is a significant difference between the dissolution rates of the standard formulation and the investigational formulation, it is necessary to conduct BE studies for Japanese who are subject to administration.

− The standard formulation should be the brand name product that is approved and distributed in the Japanese domestic market.

Foreign subjects BE study data


1. Pre-Consultation (free)

2. Face to Face Consultation (charge):

• On Bioequivalence

• On Quality

(URL) PMDA Websites (Japanese only)

1: https://www.pmda.go.jp/review-services/f2f-pre/consultations/0001.html

2: https://www.pmda.go.jp/review-services/f2f-pre/consultations/0018.html

PMDA’s Consultation


https://www.pmda.go.jp/review-services/f2f-pre/consultations/0001.html

https://www.pmda.go.jp/review-services/f2f-pre/consultations/0018.html

New Application

First inquires (major discussion points)

Notification of the application result

Marketing Approval

1 - 5 Months

4 Months

12 Months

-2 Months

1 Months

Review of equivalence

Replies

Additional inquiries

1-2 Weeks

Conformity to

reliable criterial, GLP

and GCP

Compliance of

manufacturers with GMP

(GMP Inspection)

Twice a year

In February/August

Timeline of Newly Applied Generic Products


Contents




Transition of Generic Drugs Market Share in Volume and its Goal

Goal of share in volume(Gov’s Policy in 2017)

By September 2020, the ratio of generic drugs use in volume should be 80% and

further promoting measures are studied to enable the goal as early as possible

32.5%34.9% 35.8%

39.9%

46.9%

56.2%

65.8%

72.6%

20%

40%

60%

80%Target 80%

(Source: MHLW survey) Volume share means ratio of quantity of “generics” against quantities of “branded drugs with generics” and “generics”15

Stable supplyEnsure the reliability of

quality

Information provision/Environmental Improvement

Matters on medical insurance system

Stable supply• Marketing authorization holder is

instructed to investigate cause and prevent recurrence in case of hindrance to stable supply.

• industry groups/companies are instructed to establish manuals for stable supply.

Provide information to medical personnel

• MHLW publishes information brochure on the quality of generic drugs.

• In each prefecture, medical institutions are encouraged to promote the use of generic drugs.

• The list of commonly used generic drugs is made and shared among local medical institutions.

Evaluation on medical treatment fee etc.

【medical institutions】• The requirement for incentives for use of

generic drugs has been enhanced.• Incentive of common name prescription has

been enhanced.【Pharmacy】• The requirement for incentives for dispensing

generic drugs has been enhanced. etc.

Ensure the reliability of quality

• National Institute of Health Science implements quality inspections and discloses information.

• companies hold seminars for medical personnel, factory tours etc.

Environmental Improvement• Government promotes dissemination and awareness

through government public relations, posters, leaflets, etc.• Medical insurance insurers inform insured about

differences in burden amount when using generic drugs• Designate priority areas from prefectures where

incomplete use of generic drugs is not sufficient, conduct research and analysis of problem points, implement model projects

• Promotion of use promotion in each prefecture based on the Third Medical Cost Optimization Plan (FY 2018 to 2023)

etc.

Drug price revision / calculation

• As a general rule, one price range is set for generic drugs that have been 12 years since launch

Main measures for promoting generic drugs


○Quality revaluation（1997～）

■For solid pharmaceutical products for internal use applied before April 1995, standards for

dissolution of pharmaceuticals have been set.

→Conducted on 4,590 items (638 active ingredient). Results have been published in Orange Book.

○Action program for promoting the use of generic drugs without anxiety（2007～）

■Expansion of collection inspection items, implementation of on-site inspection, active publication of

inspection results

■Implementation of impurity test etc. in injections of generic drugs.

■Collect research papers on the quality of generic drugs and conduct tests as necessary.

○Roadmap for further promotion of use of generic drugs（2013 ～）

*Continuation of the above measures

○Comprehensive strategy to strengthen the pharmaceutical industry（2015～）

■Promoting centralized quality assurance by linking accelerated academic evaluation and

examination inspection for quality assurance

■Disseminating information that organizes data on quality. (Blue Book)

Recent efforts on securing the quality of generic drugs


MHLW implements two main projects:

• Promoting information provision in collaboration with academia

• Certifying quality in the market as a part of inspection

Joint Projects of Strengthening Quality Certification in Collaboration with Academia/Inspection

Project of Promoting Information Provision Project of Certifying Quality

Concerns from nationals/academia/medical

workers

PMDA

MHLW

Local Health

Centers

NIHSQuality Information

Committee

Local Prefectures

Products

under test

ResultsLocal Health

Centers

NIHSMHLW

Results

Marketing Authorization Holders

Consultation service


Test items Number of active ingredients

Number of products

Dissolution test ９２１２６１

Purity test １５１２７

Quantitative test ２２７

Content uniformity test ３６４

Component content ratio test １１３

Mass deviation test １８

Test results(Expert committee on quality of generic drug products) ；http://www.nihs.go.jp/drug/ecqaged/kentou-list.html

"Expert committee on quality of generic drug products" conducts inspections and evaluates products

in order to confirm that the quality of generic drugs is equal to or higher than that of original drugs.

Product evaluated by Expert committee on quality of generic drug products


http://www.nihs.go.jp/drug/ecqaged/kentou-list.html

• NIH starts publication of the Blue Book in March

2017.(URL) http://www.nihs.go.jp/drug/ecqaged/bluebook/list.html

• The blue book site publishes on quality-related

information such as similarity of dissolution

behavior, bioequivalency and collaborative

development of generic drugs

Information Package of Quality of Prescription Drugs (Blue Book)


http://www.nihs.go.jp/drug/ecqaged/bluebook/list.html

Thank you for your attention
