FDA Issues Final Guidance on Good Manufacturing Practice for Active Pharmaceutical Ingredients

Date: Nov 02, 2001

On September 25, 2001, the Food and Drug Administration (FDA) announced the availability of the anticipated "Q7A Good Manufacturing Guidance for Active Pharmaceutical Ingredients" (66 Fed. Reg. 49028). The Q7A final guidance, developed with the support of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), has been in near final form for quite some time. In August 2000 the draft guidance was made available for public comment (65 Fed. Reg. 46936, August 1, 2000), and the final draft of the guidance was submitted to the ICH Steering Committee and endorsed by three participating regulatory agencies in November 2000.

The Q7A Good Manufacturing Guidance for Active Pharmaceutical Ingredients reflects FDA's sustained interest in ensuring the quality and safety of finished pharmaceuticals through the compliance of active pharmaceutical ingredient (API) suppliers with Current Good Manufacturing Practice (CGMP) requirements. The guidance is intended to reach all manufacturing operations from the receipt of starting materials to the labeling, storage and distribution of APIs. More specifically, FDA outlines requirements for quality review programs, personnel, manufacturing facilities and equipment, record keeping, material storage and sampling, process and laboratory controls, validation, packaging and labeling, and warehousing and distribution procedures. Specific requirements also are set forth in the guidance for APIs intended to be used in clinical trials, and those manufactured by cell culture/fermentation processes.

One change of note between the draft and final guidance is the discussion in the introductory "Objective" section of the guidance regarding the meaning of the word "should." In particular, the term "should" no longer "indicates recommendations that are expected to apply unless shown to be inapplicable or replaced by" an equivalent alternative, but rather now "identifies recommendations that, when followed, will ensure compliance with CGMPs." This new terminology is less prescriptive. It positions compliance with the Guidance as a "safe harbor" but leaves open the possibility that deviations which may not be fully equivalent to the guidelines may be adequate. Other than in the rare case of a legal challenge to an allegation by FDA of a CGMP violation, however, this is a distinction of little practical consequence.

We note that FDA's Part 11 regulations on electronic documents are not directly applicable to bulk manufacturers of APIs or excipients because any records in electronic form that are created, maintained, or transmitted under the Q7A Guidance are not records required "under any records requirements set forth in agency regulations." 21 C.F.R. § 11.1(b). (Emphasis added). Nonetheless, Q7A requires that "[a]ll documents related to the manufacture of intermediates or APIs should be prepared, reviewed, approved, and distributed according to written procedures. Such documents can be in paper or electronic form," (Emphasis added) and further adds that "[i]f electronic signatures are used on documents, they should be authenticated and secure." ICH Q7A GMP Guidance for API, Part VI.A (6.1). It is not clear what distinctions might exist between "authenticated and secure" documents and signatures and the 21 C.F.R. § 11.1(a) goal that electronic records be "trustworthy, reliable and generally equivalent to paper records and handwritten signatures executed on paper." Furthermore, while the Guidance refers to electronic signatures, albeit briefly, there is no provision in the Guidance that mirrors Subpart B of Part 11, that deals specifically with electronic records. No doubt FDA will look to Part 11 for the principles it will apply to determine whether the Q7A requirements have been met. This is analogous to how FDA has always looked to the GMP regulations for finished pharmaceuticals at 21 C.F.R. Part 210/211 when interpreting CGMP compliance for API.

FDA is collaborating with the Pharmaceutical Research and Manufacturers of America, the Generic Pharmaceutical Association, and the Parenteral Drug Association in sponsoring a series of workshops to discuss the application of the Q7A guidance to API manufacturing (66 Fed. Reg. 48883, September 24, 2001). The three-day workshops are intended to provide training for both FDA personnel and industry participants on CGMP compliance. Fees are being charged for registration in the workshops, the locations and dates of which are provided in the September 24 Federal Register notice. The Federal Register notice can be found at: http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2001_register&docid=01-23804-filed.