Drug Master Files: Requirements and Challenges

The author describes several issues in creating drug master files and active substance files for active pharmaceutical ingredients and intermediates.
Sep 02, 2009

This article covers the submission requirements and issues pertaining to drug master files (DMFs), also known as active substance master files (ASMFs) in the European Union (EU), for active pharmaceutical ingredients (APIs) and chemical intermediates (CIs). Some of the changes made and differences between the world's health authorities' requirements for these documents will be addressed, but this discussion does not cover requirements of blood products, biologics, veterinary drugs, excipients, homeopathic drugs or herbal substances and preparations.

DMFs and ASMFs are documents containing proprietary information concerning manufacturing facilities, production details and packaging. In the United States, Canada and elsewhere, DMFs may also cover proprietary support information and excipients. Prior to the initiation, acceptance and adoption of the International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) using their Common Technical Document (CTD) format, each of the major health agencies in the US, Canada, EU, Australia, and Japan had their own formats for the compilation of DMFs and ASMFs (1). With the adoption of the CTD format, the efforts for preparing a DMF have been simplified. The ICH CTD format has simplified the organization of DMFs for the world's major health agencies. However, there are still many differences in terms of application requirements, number of copies required and CTD Module 1 "Administrative Information and Prescribing Information" formats.

It's common knowledge that most health authorities are less than fond of dealing with DMFs and ASMFs. However, protecting proprietary and confidential information is paramount to all. Many countries still require paper copies of these documents. The size of DMFs and ASMFs easily approaches or exceeds 1000 pages. Each master file is made up of several volumes (CTD Modules) as well as duplicate copies. The resulting amount of paper documents that must be generated and securely stored becomes quite large and onerous. The adoption of electronic submission of these documents seems much more convenient. However, only certain European Union countries require electronic copies.

The way the different countries address the paper storage and handling issues brings into play major differences in how DMFs must be prepared to meet each specific country's requirements. For instance, the United States Food and Drug Administration requires two copies of each Type II DMF using the CTD format, but not in CTD module form. Instead, FDA requires one continuous document embracing the CTD formats without the distinction of an "Applicant's Part" or "Restricted Part." This is because FDA considers the entire DMF document confidential and does not have the same marketing application requirements that the EU requires for marketing approval. As a result, one prepares an FDA DMF combining the "Applicant's Parts" and "Restricted Parts" of Modules 2 and 3. FDA also requires one copy in black binders and one in red; and updates must only include the sections changed. The EU requires the entire document to be submitted. However, US marketing applications should be submitted in electronic CTD (eCTD) format. Additionally, FDA agency staffing issues have hindered the update of the DMF guidance document and one should contact the FDA drug master file staff regarding additional and suggested submission information (2, 3).



In the EU, different CTD Modules comprising the ASMF must be separate indicating Module 1: "Administrative Information and Prescribing Information" (administrative information is only required for an ASMF); Module 2: "Common Technical Summaries" ("Quality Overall Summaries"– QOS) with an "Applicant's Part" and a "Restricted Part" optional, and Module 3: "Quality" comprised of an "Applicant's Part" and "Restricted Part." Although the "Applicant's Part" is considered confidential, it contains information required for the applicant to include in their request for marketing authorization. The "Restricted Part" contains information that the ASMF holder considers extremely confidential and can only be shared with the health authority