FDA Bulk Actives GMP Guidance Returned To Draft By ICH Foray Into GMPs

FDA's near-final guidance on good manufacturing practices for active pharmaceutical ingredients will return to the draft stage as a result of the International Conference on Harmonization's decision to begin work immediately on its own guidance on the subject.

The agency's guidance on active pharmaceutical ingredient GMPs, which has been in development since 1993, was "in final form and ready to be published," FDA Office of Compliance Director Stephanie Gray said at the University of Texas at Austin's International Industrial Pharmacy Conference Feb. 25.

"As a result of ICH's decision, we cannot publish our guidance in final form, but rather what was negotiated is that we will publish it again in a draft format requesting comments and it will essentially remain a draft format until ICH has its document," Gray explained.

At the ICH Steering Committee's meeting in Tysons Corner, Va., the first week of February, Europe proposed "that GMPs for APIs be harmonized within ICH, and that decision was taken," Gray reported (see preceding story).

ICH established active pharmaceutical ingredient GMPs as topic Q7A, "indicating that ICH may decide later to work more on GMPs," she added.

The ICH document will be developed by an extended expert working group including, in addition to the six ICH parties, the International Generic Pharmaceutical Alliance, the Pharmaceutical Inspection Cooperation Scheme, China, India and Australia, Gray said. The World Health Organization, Canada and Switzerland will observe.

Gray forsees "possible confusion" between the ICH document and FDA practice in the GMP area. "Previous standards of operation won't necessarily prevail," she said. While ICH guidelines are considered a "ceiling" for requirements, "we traditionally say that GMPs reflect current industry practice and are a minimum. So we'll need to be very clear...about what we mean."

An ICH document would be the third guidance on the subject. At a September 1996 Pharmaceutical Inspection Cooperation Scheme meeting in Canberra, the 30 countries participating "decided to work together to harmonize a GMP document for APIs," Gray recalled. In September 1997, a draft was issued.

While the U.S. continued to develop its own separate guidance, FDA joined with Australia, China, Switzerland and Canada in a working group to develop the PIC/S document. The European Union was "invited to participate but declined. Eventually they sent an observer, as did WHO," Gray noted.

ICH "recognized other important initiatives already underway in this field," the steering committee said. "With the ICH commitment to this project, it is hoped to expedite the development of a single international set of principles."

Bulk inspections also are covered by the U.S./EU mutual recognition agreement completed in late May/early June. Gray called the terms of the MRA allowing Europe to do preapproval inspections (the largest category of bulk inspections) for FDA "a major tradeoff." The EU will do preapproval inspections "in return for [FDA] receiving inspection reports," she explained.

"Europe generally has not done inspections of bulk or API operations," Gray observed. "They don't have statutory guidance. And so it would be very difficult for them to be considered or judged equivalent and be able to do these inspections, which was one of the major features of the negotiations."

One effect of the provisions, she continued, could be "less experienced or perhaps more superficial inspections in the way of foreign bulk raw materials."

The EU also proposed another GMP topic for ICH consideration at the steering committee meeting. "Europe proposed that the format of inspection reports be harmonized in the ICH," Gray reported. The format, which determines "what's required in an inspection, was not addressed in the MRA itself," she noted.

Japan did not want harmonized inspection reports to be determined in the ICH setting, Gray continued. Under Japan's MRA with the EU, "inspection reports are not going to be exchanged," she noted.