Drug Master Files: Requirements and Challenges

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

However different countries have different requirements within the EU. The United Kingdom and The Netherlands will only accept electronic copies each in their own separate electronic format, while France requires both a paper copy and an electronic copy. France also requires special application forms to accompany the DMF as well as a letter certifying that the electronic version is identical to the paper copy. Several other countries are in the process of converting to the non-ICH (XML), non-eCTD electronic submissions (NeeS) electronic filing format (4). These include Belgium, Denmark, Germany, France, Hungary, Portugal, Spain, and Sweden. In addition, Canada and Australia have different DMF Type designations than the United States. Future international submissions will probably adapt the ICH-recommended XML format (5)

Table I highlights many for the world's health authorities'particular requirements for the submission of DMFs and ASMFs.

With the international movement to submit electronic documentation of marketing applications for the approval and sale of pharmaceuticals, DMFs submitted in many countries have yet to follow this trend. Although several EU countries have initiated the conversion to electronic copies of ASMFs, the majority of the world's health agencies are still requiring several bulky paper copies. In addition, many countries still do not assign a registration number to a submitted DMF or ASMF, which may cause confusion. This could become an issue in light of the pharmaceutical industry's trend to consolidate.

Although the CTD format has brought significant consistency to the preparation of DMFs and ASMFs, many different filing conventions still remain. The universal acceptance of a single electronic format and associated paperwork is still in the future.

Thomas Warden is president of Warden Consulting, 4312 Whippeny Dr., Fort Collins, CO 80526, tel. 970.225.9789, twarden4312@gmail.com

References

1. ICH, Organization of the Common Technical Document For Registration Of Pharmaceuticals For Human Use M4, Rev.4 (Brussels, Belgium, Nov. 2005) www.ich.org.

2. FDA, Guideline for Drug Master Files (Rockville, MD, Sept. 1989) http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122886.htm, accessed Aug. 24, 2009.

3. Personal communication, Sharon Brownewell, FDA, CDER, May 2009.

4. EMEA, EU Telematic Implementation Group – Electronic Submissions (TGes), Guidance for Industry on Providing Regulatory Information in Electronic format: Non-eCTD Electronic submissions, Ver. 1.4 (Strasbourg, France, Jan. 2008) www.cbg-meb.nl.

5. ICH, ICH M2 ENG, ICH Common Technical Document Specification, V. 3.2 (Brussels, Belgium, Feb. 4, 2004) www.ich.org.