The document summarizes regulatory considerations for pharmaceuticals in Japan, including manufacturing, packaging, labeling, and post-marketing surveillance. For manufacturing, drugs must be approved by the Ministry of Health, Labor and Welfare and manufacturers must be licensed and follow good manufacturing practices. Packaging and labeling must contain specified information and any changes require relabeling. Post-marketing surveillance involves adverse event reporting, drug reexaminations every few years to reconfirm safety and efficacy, and reevaluations based on current medical knowledge.

1. REGULATORY
CONSIDERATIONS IN
JAPAN
BY- AARTIVATSA
(MPHARMA,DRA; 2ND SEM)
2239805

2. TABLE OF CONTENT:-
Regulatory Considerations for
• Manufacturing,
• Packaging and Labelling of Pharmaceutical
• Post Marketing Surveillance

3. Regulatory Considerations for
Manufacturing of Pharmaceuticals
• Manufacturing/marketing refers to selling or delivering the manufactured or
imported drugs.
• There are various provisions in the Pharmaceutical Affairs Law so that the drug
manufacturer/market authorization holders takes all responsibilities from
manufacturing to post-marketing affairs.
• Marketing/ Manufacturing of Pharmaceuticals are approved from Ministry of
MHLW.
• The approval and licensing system has been revised in the amened Law and
manufacturing(import) approvals become marketing approval from April 2005.

4. Contd.
• License of manufacturer/market authorization holder is necessary.
o obtain license by demonstrating that the business entity is capable of responsible
manufacturing, quality control and post-marketing safety control of pharmaceutical products.
• License (accreditation) of manufacture is necessary.
o License (accreditation) of manufacture is obtained by showing that the party concerned has
capacity to manufacture drugs.
• Manufacturing/ marketing approval is necessary.
o It is necessary to collect the data related to drug quality, efficacy and safety and have those
reviewed and approved by the MHLW.

6. Marketing approval requirement for
Pharmaceutical Products (Section 2, Article 14
of the Law)
• License of manufacturer/market authorization holder.
• License (accreditation) of manufacture at the manufacturing site.
• Absence of problems in drug quality, efficacy and safety.
• Compliance with Good Manufacturing Practice (GMP) at the manufacturing site. (the
license renewal is necessary in every 5 years).

7. Approval items specified in the approval; certificate are as follows:When a change is made
on approval items expect for brand name, a partial change application or slight modification
notification has to be submitted.
• Brand Name
• Ingredients and quantities, or nature
• Manufacturing process
• Dosage and administration
• Indications
• Storage conditions and shelf life
• Specifications and testing methods
• Manufacturing plant of item to be marketed
• Manufacturing plant of the drug substance.

8. Good Manufacturing Practice(GMP):
• In manufacturing plants with manufacturing business license or overseas manufacturer
accreditation, compliance with the criteria in GMP that specifies Standards.
• In consideration of ClinicalTrials including early Exploratory stage, the GMP for
investigational products was amended on July 9, 2008 to assure quality.
Items to be kept in mind for on-site inspection :
• To provide the manufacturer with necessary information such as JapaneseGMP
Ordinance, etc.
• To prepare document enabling confirmation of the agreement between the manufacturer
and JapaneseGQP Ministry Ordinance.
• To translate material.
• To prepare an efficient review schedule.

9. Foreign Manufacturer with
Manufacturing Approval
Designated Manufacturing/
marketing business license holder
in Japan
MHLW
2.
Manuf
acturin
g
approv
ed
applic
ation.
1. Designation of
manufacturing/marketing business
license holder
3.
Restricive
approval
of drugs
manufactu
red
overseas
4. Manufacturing/
marketing order
5. Manufacturing and
marketing

10. Packaging and Labelling of
Pharmaceuticals:
The regulations of packaging and labelling of medicinal products is set out by the PA
Laws.
The Primary Authority to enforce the regulation of packaging and labelling =
MHLW.
• The package inserts must contain indications, dosage/administration, precaution,
and precaution for handling.
• According to PAL amended on April, 2005, a new regulatory category for
prescription from a physician and labelling “CAUTION”.
• The law for Partial Amendments of the PAL enforced on June 1, 2009 mandates
non- prescription drugs to be classified into one of type 1,2,and 3 according to the
risk and to bear a label indicating the type.

11. Contd.
• In addition, barcode labeling of prescription drugs was partially mandated in July
2015 to prevent medical accidents due to misunderstandings, ensure traceability,
and improve the efficiency in prescription drug.
• In the revised Pharmaceutical Affairs Law enacted on November 25, 2014. the new
package insert notification system was introduced to enhance safety assurance
measures. Manufacturing/marketing authorization holders must prepare package
inserts based on scientific knowledge and information obtained from latest
literatures, etc. to provide related information.

12. • The information that must be contained on a drug container:
1. Name and address of the marketing company
2. Name of the drug and its serial number
3. Volume of drug in the container
4. Ingredients used to create the drug
5. Expiration date when the drug should be used.
• An enclosed instruction document must be provided
1. How the drug is to be used
2. Dosage
3. Ingredients of the drug.
4. The effectiveness of the drug, adverse effects, and the proper method of the storage
.
• Any changes about the information in the packaging and labelling ?
All packaging and labelling MUST ALSO BE CHANGED accordingly.

13. E- Labelling
• To provide better medical products safely, promptly and efficiently.
• To improve a pharmaceuticals provision system for patient's secure access in familiar
community.
• Package inserts shall basically be distributed electronically instead of being enclosed in
products.
• In addition to the electronic distribution, package inserts shall be provided in paper format
at the initial delivery of drugs/medical devices under the responsibility of a Marketing
Authorization Holder and in cooperation with a wholesaler, if needed. Also, a scheme shall
be built to provide information to access the latest package insert information shown on
the outer box of a product, and revised information is distributed to medical
institutions/pharmacies without fail in paper format or other forms.
• For OTC drugs that are directly purchased by consumers, package inserts shall be
continuously prepared in paper format and enclosed in products to make the information
available at the time of use

14. Post- Marketing Surveillance in Japan:
• Post-marketing surveillance (PMS) to assure the quality, efficacy and
safety of drugs after they go on the market and to establish proper
methods of use of drugs consists of three systems: the ADRs and
infections collection and reporting system, the re examination system,
and the revaluation system.
• The re-examination system for new drugs was introduced in the
October 1979 amendment of the Pharmaceutical Affairs Law, and
Good Post-marketing Surveillance Practice (GPMSP) came into effect
from April 1993 to assure proper implementation of PMS and also to
assure the reliability of such PMS data.

15. It Includes:
• GVP (GoodVigilance Practice)
• GPSP (Good Post- Marketing Study Practice)
• Paper Compliance Review and On-Site GPSP Surveys of Data for Re-examination
and Re-evaluation.
• Adverse Drug Reaction and Infections Reporting System.
• Periodic Infection Report for Biological Products.
• Re-examination System
• Re-evaluation System

16. 1. GVP: It establish standards for post-marketing safety management related
to the collection, evaluation, and assessment of proper use information on the
establishment of appropriate safety related organization and systems as one
of licensing requirements for the manufacturing, development and
implementation of relevant SOPs, marketed drugs, etc. and to the
implementation of measures for safety assurance.
2 . GPSP: Specifies items that are to be strictly complied with in order to
achieve appropriate post-marketing surveillance and studies conducted by
manufacturing/ marketing authorization holders, and to assure the reliability
of data submitted when applying for re-examinations or re-evaluation.

17. 3. Paper Compliance Review and On-site GPSP Surveys of Data for re-
examinations and re-evaluation.: Documents and data submitted for
reexamination and reevaluation of a drug are subject to paper compliance review
and on-site GPSP surveys in order to examine whether the materials for
evaluation have been collected in accordance with the standards specified by the
MHLW minister. Detailed procedures for the compliance review and on-site
surveys are available as “the Guidelines on Compliance Paper Reviews on
Approval Application Data for New Drugs”.
4. Adverse Drug Reaction And Infections Reporting System: Programs for
collecting and reporting safety information on drugs such as adverse drug
reactions include an adverse drug reaction reporting system undertaken by
pharmaceutical companies, the drug and medical device safety information
reporting system undertaken by medical personnel, and the WHO International
Drug Monitoring Program whereby drug safety information is exchanged among
various countries. (Collection and Reporting of Pharmaceutical Safety
Information).

18. 5. Periodic Infection Reports For Biological Products: With the revision of the
Pharmaceutical Affairs Law in July 2002, drugs manufactured from materials
derived from humans or other living organisms (excluding plants) that require
caution in terms of public health and hygiene are designated as biological products
by the MHLW. From July 30, 2003, the system of periodic infection reports was
introduced by which manufacturers of such biological products. In April 2017,
"Notification on the System of Periodic Infection Reports for Regenerative Medicine
Products and Biological Products“.

19. 6. Re-examination System: The reexamination system is aimed at reconfirmation
of the clinical usefulness of drugs by performing GPSP or GVP as one aspect of PMS,
through collecting information on the efficacy and safety of the drug during a
specified period of time after approval.This system was commenced in April 1980.
Based on the revision of October 1993, the reexamination period for orphan drugs
was extended to a maximum of 10 years.
7. Re-evaluation System: The reevaluation of drugs is a system whereby the
efficacy and safety of a drug, which has already been approved, is reconsidered on
the basis of the current status of medical and pharmaceutical sciences.This new
reevaluation system aimed at reevaluations of the efficacy and safety of all
prescription drugs was started in May 1988.These reevaluations are at first
performed by means of a review by the PAFSC.