The Case for a Global DMF System

Standardized global regulatory practices will provide numerous benefits for industry.


Maxine M. Gallagher,
vice president of regulatory affairs, the Americas,
West Pharmaceutical Services

The global economy, reduction of trade barriers, an enlightened industry, e-commerce, and electronic documentation practices have contributed to the globalization of all aspects of healthcare, including regulation. The need for standardized global regulatory practices resulted in the International Conference on Harmonization (ICH) and the subsequent Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD). The CTD's introduction states:

"A common format for the technical documentation will significantly reduce the time and resources used to compile applications for registration of human pharmaceuticals and will ease the preparation of electronic submissions. Regulatory reviews and communication with the applicant will be facilitated by a standard document of common elements. In addition, exchange of regulatory information among regulatory authorities will be simplified."

One document not addressed by the ICH guidelines is the Drug Master File (DMF) used in the United States, Canada, Europe, and Australia. A DMF is a voluntary document that contains proprietary or trade secret information about raw materials, packaging components, or processes used in the production and control of drug and biologic products. A DMF allows communication from the manufacturer directly to the regulatory agency and incorporates reference information documenting the safety and efficacy of drug product components, processes, and controls. In the United States, four categories of DMFs are defined, including Type III for packaging components and systems. Canada defines four categories of DMFs, including Type II for packaging materials.

The use of DMFs is mentioned in the FDA draft guidance "Common Technical Document--Quality; Questions and Answers/Location Issues." However, because the three regions of the ICH have different systems, the applicant is required to consult the relevant competent authority in the filing region regarding DMF use. Given the variation in the requirements for each ICH region, it might be appropriate to define and incorporate the use of DMFs into the CTD.

In March 2002, a DMF workshop was held in Washington, DC, to discuss the use of all types of DMFs in the U.S. regulatory process. An increasing interest in the content of Type III DMFs and their part in the application process resulted in the presentation of a draft document, "Proposed Guidelines for Type III DMFs." This document was written by representatives active in the pharmaceutical and biologic packaging industries. It focuses on the content, format, and use of packaging DMFs in conjunction with the regulatory application. This guideline has been sent to the FDA Center for Drug Evaluation and Research's Office of Pharmaceutical Sciences for review and comments. The guideline and proceedings of the workshop can be viewed at the DMF workshop Web site,

The International Pharmaceutical Excipient Council has proposed a DMF system for excipients to the ICH. A recent European agency for the Evaluation of Medicinal Products proposal suggests that the DMF procedure should also be extended to novel excipients and/or plastic materials. The U.S. Type III DMF subcommittee who authored the "Proposed Guideline for Type III DMFs" supports this recommendation and proposes that a similar system be instituted for packaging components and packaging systems as part of the CTD process. A standardized global DMF system for packaging components and packaging systems will provide numerous benefits to regulatory agencies, drug and biologic manufacturers, and packaging suppliers. It would do the following: 

  • Reduce the opportunity for subjective interpretation due to specific regional or jurisdictional requirements.
  • Increase the amount of safety and efficacy data presented for packaging due to the confidentiality afforded the holder.
  • Reduce or eliminate the need for supplying patent or proprietary data via confidentiality or other contractual agreements between supplier and applicant.
  • Provide a mechanism to standardize the packaging information required to support products submitted using the CTD format.
  • Allow for a standardized approach to the review of packaging materials and packaging systems to determine adequacy for their intended use when combined with a technical guidance modeled after the "Proposed Guideline for Type III DMFs" developed by the Type III DMF Subcommittee.
  • Provide a venue for sharing information by the ICH regions once a DMF has been reviewed.
  • Provide for shortened review times if a previously reviewed DMF is referenced in the CTD, especially for frequently referenced packaging materials.
  • Standardize requirements for approval of various types of changes to packaging materials, components, or systems, resulting in a significant reduction in regulatory filings by eliminating packaging supplements or reducing the reporting categories of variations.
  • Facilitate the change notification process between DMF holder and applicant by communicating changes affecting multiple customers via a single letter referencing the DMF. 

The ICH has provided a forum for regulatory agencies to discuss and standardize data and practices associated with evaluating and documenting the safety, efficacy, and quality of drug and biologic products. While some FDA guidances define the criteria required for assessing the safety and efficacy of the container closure system and its component parts, the data outlined in the CTD are general. It is difficult to define the level of information required in the CTD since it may differ depending on the ICH region, the type of packaging, the nature of the product, and/or the applicant. Incorporating a standardized global DMF system for packaging materials, components, and packaging systems into the CTD will provide a level of specificity needed by applicants and holders.

The landscape of regulatory affairs is changing daily. No longer can applicants afford to speculate on whether the contents of their regulatory applications will be acceptable to each ICH region. In the same way that harmonized standard applications in the CTD simplify and facilitate regulatory reviews, a standardized DMF process defined within the CTD will simplify and facilitate global communication with applicants and holders. It will also promote worldwide exchange of regulatory information among regulatory authorities.

Definitive guidance and mechanisms that assist applicants, DMF holders, and reviewers in moving applications through worldwide regulatory reviews are needed. DMFs for packaging have a proven track record in the United States and Canada. The ICH strives to facilitate regulatory reviews and communication with the applicant via a standard document of common elements and to simplify the exchange of regulatory information among regulatory authorities. It is proposed, therefore, that the ICH consider implementation of a DMF process for container closure components and systems within the CTD. 

Maxine M. Gallagher is vice president of regulatory affairs, the Americas, West Pharmaceutical Services Inc. (Lionville, PA). This article was submitted on behalf of the Type III DMF Subcommittee.

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