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GPIA PROPOSAL FOR FDA APPROVAL OF DRUG MASTER FILES TO SPEED ANDA REVIEWS IS BEING CONSIDERED BY AGENCY, RHEINSTEIN SAYS; CONCURRENT REVIEWS URGED

Executive Summary

A Generic Pharmaceutical Industry Assn. (GPIA) suggestion that FDA revise its ANDA regulations to allow for agency approval of drug master files (DMFs) in the same way as bulk antibiotics is being considered by the agency, Office of Drug Standards Director Peter Rheinstein said Jan. 15 at the Natl. Assn. of Pharmaceutical Mfrs. (NAPM) annual meeting. The assn. has suggested, Rheinstein said, that FDA establish a "separate approval [process] for drug master files. That is, a drug master file would be approved for the bulk supplier the same way that an ANDA is approved for the dosage form of a mfr." Rheinstein added that "we have looked at it at FDA and it looks like to us that the resource usage is about the same either way. So if there aren't objections to it we probably ultimately will put this into effect." The drug master file proposal is one of 10 separate items suggested by GPIA as part of what the assn. is calling an "ANDA action plan." The outline of the plan was discussed at a meeting in December between GPIA and FDA. According to a summary of GPIA's suggestions prepared by the assn., GPIA is recommending changes in the "procedures for raw material approvals to be patterned after the system used for bulk antibiotics. These procedures would include a formal approval process for drug master file submissions." Rheinstein said that in informal discussion with NAPM members at the meeting, he found "little disagreement" that the suggestion is a good one. He added that among bulk mfrs. he talked with, "it looks like there is only one bulk mfr. that doesn't like it. Most of the bulk mfrs. like it." Before implementing a change, FDA is inviting outside comment on the proposal. GPIA Urging That Methods Validation - A "GMP Function" - Be Removed As Condition Of Approval At the NAPM meeting, Purepac's Ed Plymack commented: "When you file an ANDA now, you do two things -- you ask for a sample of the raw material and you ask for a sample of the finished product. I have no objection to the finished product. I do have an objection . . . with an item . . . which is mainly bought from the same company . . . What you are doing is tying up more labs again routinely checking the same material, three or four times." NAPM General Counsel Milton Bass (Bass & Ullman) observed that a delinquent DMF can delay an ANDA approval. "You [FDA] don't act on a DMF until somebody submits an ANDA or NDA, and then [FDA] takes action to find out whether the material is meeting the reference standards as required." A separate DMF approval, he said, "would save a lot of time. Because if you set up an ANDA based on a new supplier [which subsequently fails FDA inspection] what you have done for your ANDA is completely wasted." FDA Compliance Director Dan Michels told NAPM that "there might be a lot of practical utility for doing it that way." He cautioned, however, that the conversion would "have to be looked at very hard by our general counsel's office. There are some peculiar differences between the antibiotic provisions in the statute as opposed to all other drugs. Frankly, I am not sure that it would be permissible under the act as presently written and [approved]. I am not suggesting that we are not going to explore it, but I don't want to hold out a completely green light here." The GPIA plan also includes a suggestion for the concurrent review of ANDAs. "Concurrent, rather than sequential, review of application components, especially reviews of chemistry and biostudies, but also including sample validation and approval of draft labeling. Chemistry reviews, like biostudy reviews, should be subject to a formal approval process." The assn. also called for "the removal of methods validation, a GMP function, as a precondition of approval. Finished dosage form samples would continue to be submitted with applications." A clearer distinction of supplemental applications which need prior FDA approval and those that do not should also be made by the agency, GPIA said. The assn. said it "will provide examples and illustrations of manufacturing changes which do not effect product specifications and should not require prior approval. In addition, there is a need for definition of the supporting data requirements for various types of manufacturing changes and a determination by FDA as to whether the policy for expiration dating, after manufacturing change, is the same for all divisions." GPIA suggested also that the administrative status of the Generic Drugs Division be upgraded to a full office, equivalent to the level of the NDA reviewing group. The suggestion echoes a suggestion by another trade group, the Proprietary Assn., which is urging that FDA's OTC drug unit also be advanced to "office" status. GENERIC PHARMACEUTICAL INDUSTRY ASSN.'s ANDA ACTION PLAN PROPOSAL The following suggestions were developed by GPIA and presented to FDA at a Dec. 3 meeting with FDA officials. The written proposal was drafted after the meeting and submitted to the agency. Procedures for raw material approvals to be patterned after the system used for bulk antibiotics. These procedures would include a formal approval process for DMF submissions. Concurrent, rather than sequential, review of application components, especially reviews of chemistry and biostudies, but also including sample validation and approval of draft labeling. Chemistry reviews, like biostudy reviews, should be subject to a formal approval process. Appointment of an administrative chemist to oversee the definition and establishment of product guidelines by chemistry reviewers and to ensure consistent application of guidelines. Changes in product guidelines, dictated by new information or scientific concerns, would be adopted and consistently applied by all reviewers. Removal of methods validation, a GMP function, as a precondition of approval. Finished dosage form samples would continue to be submitted with applications. The need for distinction between major and minor changes (Parke-Davis petition) and for differentiation between supplements which would require prior approval and those which could be covered in annual reports. GPIA will provide examples and illustrations of manufacturing changes which do not effect product specifications and should not require prior approval. In addition, there is a need for definition of the supporting data requirements for various types of manufacturing changes and a determination by FDA as to whether the policy for expiration dating, after a manufacturing change, is the same for all divisions. Immediate and particular attention to manufacturing site changes where there are no changes in product specs, equipment, etc. Establishment of expedited procedures for the approval of supplements requiring prior approval. Appointment of a new FDA liaison team to work with USP officials on the long unresolved issue of differences in USP and FDA dissolution specifications. Consideration of a single-product ANDA for drug entities with multiple strengths. GPIA would like to discuss this possibility in greater detail with the generic division. Upgrading to office status the division of generic drugs.

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