Currently the third-largest pharmaceutical market in the world, Japan presents many opportunities for foreign drug companies. Major factors such as a rising incidence of chronic diseases and a rapidly aging population have contributed to the pharmaceutical market growth. Excipient manufacturers can also benefit from these opportunities by registering their products via Drug Master Files (DMFs) in Japan.
Pharmaceutical excipients are inactive substances that are contained in a finished pharmaceutical product. Different roles of excipients in the drug formulation process include transporting the drug to the appropriate site in the patient’s body, preventing the active drug from being released too early, and facilitating the disintegration process of the drug into small particles. Excipients can act as binders, fillers, coatings, colorants, etc.
Filing a DMF in Japan provides excipient manufacturers with significant advantages since it protects the manufacturer’s confidential information and “know-how”. This article outlines the regulations and procedures that excipient manufacturers must comply with in order to enter the Japanese market.
REGULATIONS AND PROCEDURES FOR REGISTERING AN EXCIPIENT IN JAPAN
The Pharmaceuticals and Medical Devices Agency (PMDA) is responsible for the review, evaluation, and approval of excipient DMF applications. As the first step, foreign manufacturers need to assign an in-country caretaker (ICC), who will work as a representative of the company in Japan and will be responsible for the DMF submission. Foreign manufacturers cannot directly submit their DMF dossier. As of now, there are no government fees for DMF registration.
The contents of a DMF can be broken down into two parts: “Disclosed” (“Open”) and “Restricted” (“Closed”). Open parts include general information about the manufacturer and product, while restricted parts include confidential descriptions of the manufacturing process, process controls, control of materials, etc. The excipient manufacturer, also called “DMF holder”, can directly communicate “Disclosed” contents with the Marketing Authorization Applicant/Holder (MAA/MAH) of the finished drug product. On the other hand, in order to protect the confidentiality, the DMF holder should only communicate “Restricted” contents with their Japanese ICC.
There is neither approval nor disapproval of the DMF registration, which by itself is not a marketing approval. The PMDA will reference the data in the registered excipient DMF as part of the approval review of the drug.
After the DMF is registered, the PMDA will issue a DMF registration certificate and a duplicate of the registration application. The PMDA will also publish on their official website information such as the DMF registration number, basic information of the DMF Holder, registration date, the name of the registered item, and the registration category.
If there are any changes to the registered excipient, the manufacturer should notify the PMDA and the MAA/MAH of the drug product as soon as possible. In some cases, if the changes are considered too significant, the manufacturer will have to do a new DMF registration instead of a change submission.
PHARMACEUTICAL EXCIPIENTS APPLICATION DOCUMENTS
The application form and other submission documents submitted to the PMDA must be written in Japanese. Before submitting the application, applicants should make sure that all data and supporting documents are accurate and up to date. In case applicants have any inquiries or are unclear about certain steps in the application process, a simple consultation, via their Japanese ICC, with the PMDA can be helpful.
- Classification for registration (Type of drug substances, etc.）
- Name of the drug substances, etc.
- Name of the manufacturing site
- Address of the manufacturing site
- Ingredients, quantity, or essence
- Manufacturing method
- Standard and test method
- Information on stability
- Storage method and validity period
- Information on safety
- Category of license/registration of the manufacturer, or category of accreditation/registration of foreign manufacturer
- License number or registration number of the manufacturer, or accreditation number or registration number of the foreign manufacturer
- Name of the in-country caretaker
- Address of the in-country caretaker