Canadian API Type-I MF Guidelines

The Drug Master File (DMF) began in the United States. Today, a number of countries, including Canada, have adopted DMFs to help manufacturers of raw materials protect business secrets and to allow manufacturers of formulations to reference information in DMFs.

The Canadian pharmaceutical market has shown steady growth in recent years, and Health Canada is responsible for regulating pharmaceuticals to ensure public safety. In this article, we introduce the basic information, submission process and requirements of the Canadian API Type-I Master File (MF).

Introduction of Type-I MF

The Canadian Drug Master File is a voluntary submission that provides Health Canada with detailed information about the ingredients, containers or packaging materials of a drug product.

According to Canada's DMF classification, Type-I MFs are Active Substance Master Files (ASMFs), which include APIs, starting materials, intermediates, vaccine antigens, albumin, and others.

Type-I MFs allow API manufacturers to protect their intellectual property and proprietary information while providing technical information to other participants in the drug approval process, such as the final drug manufacturer. During the drug registration or approval process, pharmaceutical companies can cite these documents to demonstrate that their products meet relevant quality standards and regulations.

When a pharmaceutical company submits an application for drug registration to Health Canada, it will cite the relevant information in the MF, but will not have direct access to the details in the MF. Health Canada will review the MF directly to verify the accuracy and adequacy of the information referenced in the application.

When Is a Type-I MF Required?

A new Type-I MF submission is generally required in the following cases:

• Different active substances
• Different salts, complexes, and co-crystals of the active substance
• Different solubilized or hydrated forms of the active substance
• Different isomers or mixtures of isomers of the active substance
• Optically pure racemates of the active substance
• Optically pure enantiomers of racemic mixtures
• Enantiomers of the active substance
• Introduction of new and significantly different synthetic routes (leading to different specifications of the active substance)
• Different polymorphic forms (leading to very different physicochemical and/or pharmacokinetic properties)
• Any other change that results in the active substance having very different physicochemical and/or pharmacokinetic properties
• Sterility level of a non-sterile active substance
• Non-sterile grades of sterile active substances
• Changes/additions of raw materials from different animal sources (only if the safety of the active substance has substantially changed)

If you are unsure whether you need to submit a Type-I MF, please contact us.

Type-I MF Submission Requirements and Methods

As of January 1, 2020, new MFs must be submitted in eCTD format based on structural and formatting requirements.

Related Guidance

MF submission timing

MFs should be submitted between 2 months and 1 year prior to the submission of a Drug Submission, a Drug Identification Number (DIN) application, or a Clinical Trial Application (CTA) referencing these MFs.

Contents of the electronic file for MF registration

• Signed cover sheet
• MF agent authorization form (if applicable)
• MF application form
• BSE/TSE statement
• CEP and CEP certificate (for Type-I MF only)
• Letter of Access (LoA)

The Type-I MF shall include the following elements

• "Applicant Section" (Public Section): contains information that the MF holder considers to be non-confidential and is provided to the applicant, usually as part of a drug submission, DIN application, or CTA, with a LoA.
• "Restricted Section" (Confidential Portion): contains information that the MF Holder considers confidential and is submitted directly to Health Canada. Health Canada protects the confidentiality of MF Restricted Sections under legislation.
• Word and PDF copies of the Quality Overall Summary (QOS)
• Word document of the Certified Product Information Document (CPID)

Naming MFs

For Type-I MFs, the preferred name should be the common name of the API, such as the International Nonproprietary Name (INN), followed by any internal API brand names, processes, or codes.

Promoting and Evaluating MFs

When a MF is received by Health Canada, it will be

• Assign the MF an MF number and a File ID (for new MF registrations only)
• Verify that information, documents and forms are submitted in the correct format and that administrative procedures are in place

MFs are usually evaluated in conjunction with drug submissions, DIN applications or CTAs. For technical requirements for MFs, please refer to the applicable guidance documents below:

(1) Quality (Chemistry and Manufacturing) Guidance: New Drug Submission (NDS) and Abbreviated New Drug Submission (ANDS)

This guidance document details the requirements for the Quality section of NDSs and ANDSs for synthetic or semi-synthetic pharmaceutical ingredients and their related products. The guidance applies to both new and existing APIs and covers all aspects of stability, facilities and equipment, episodic pathogen safety assessment and manufacturing documentation. It follows the format of the Common Technical Document - Quality (CTD-Q) recommended by the International Committee for the Harmonization of Technical Requirements for Pharmaceuticals.

(2) Appendix - Quality (Chemical and Manufacturing) Guidelines: Questions and Answers

This appendix provides answers to frequently asked questions about the Quality (Chemical and Manufacturing) Guidelines. It discusses information on validating primary and secondary reference standards, the significance of the similarity factor f2 for comparing dissolution test results, testing drug products that require dilution prior to use, the need for analytical testing facilities to comply with GMP requirements, and data to support the transportation of high-risk APIs and intermediates for drug products. It also explains Health Canada's rationale for requesting the designation of Normal Operating Ranges (NORs) in conjunction with the Proposed Acceptable Ranges (PARs).

(3) Quality (Chemical and Manufacturing) Guidance: Clinical Trial Applications (CTA) for Drug Products

This guidance document assists submitters in the preparation of CTAs by detailing the quality (chemical and manufacturing) technical requirements of the Food and Drug Regulations, Part C.05. It includes resources and templates for quality summaries of chemical entities for the different phases of a clinical trial.

(4) Certified Product Information Document: Chemical Substances CPID-CE

The Certified Product Information Document (CPID) provides a variety of details about a pharmaceutical ingredient, including physical properties, manufacturing information, impurities, control of the pharmaceutical ingredient, and stability. It also covers pharmaceutical products, outlining composition, manufacturing and manufacturing process controls.

These documents are critical to ensuring compliance with Health Canada's regulatory requirements for drug submissions, and they provide a comprehensive overview of expectations for drug quality, manufacturing and control processes.

Proregulations is committed to helping you submit your Type-I MF to Health Canada correctly, timely and securely, while strictly protecting your intellectual property and trade secrets. If you are interested in our services or need more details, please contact us.