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MANUFACTURING SITE CHANGE EXEMPTIONS FROM PRIOR APPROVAL

Executive Summary

MANUFACTURING SITE CHANGE EXEMPTIONS FROM PRIOR APPROVAL will be clarified in an FDA guideline on nonsterile drugs. The agency will attempt to define what changes are exempt and what changes represent "material differences" in drug manufacturing requiring prior approval. Availability of the draft guideline is expected to be announced in the Federal Register this summer for public comment. The guideline will contain sections on equipment and reprocessing and is intended to make it easier for companies to upgrade manufacturing. FDA's Center for Drug Evaluation & Research formed an in-house task group to develop the draft guideline. The task group included members of the Office of Generic Drugs, the Office of Compliance and the Offices of Drug Evaluation. One type of situation that may be exempted from prior approval is the addition of another processing line that uses the same or comparable equipment. In an April 7 letter to the Pharmaceutical Manufacturers Association, CDER Director Carl Peck said that FDA is declining PMA's request that the agency revise 21 CFR 314.70(b) and (c) to add an exception to the regs so that prior approval would not be required for a sponsor of an approved NDA to use a different facility to manufacture, process or repackage a product. PMA made its request in a Dec. 21, 1992 citizen petition. Change in manufacturing site of drug substances can be made without prior approval and PMA "recommends that the same conditions apply to a drug product as for drug substance," the petition says. PMA maintained that such an amendment to the regs "will reduce the heavy backlog of manufacturing supplements requiring FDA approval." In March 16 comments to FDA, the National Association of Pharmaceutical Manufacturers said that it "generally supports the goal of the PMA petition to eliminate the need for prior approval of changes in sites of manufacturing or other processing." Peck informed PMA that "while we appreciate your interest in streamlining FDA's regulatory requirements, we respectfully decline to grant your request." The FDAer pointed out that the agency considered a similar request when it issued NDA regulations in 1985 but decided to continue requiring prior approval for such changes. "FDA continues to believe that there are important distinctions between drug products and drug substances that warrant prior approval for changes in the manufacturing site or method of manufacture for a drug product," Peck said. "For example, drug substances typically go through additional manufacturing processes to become finished dosage forms whereas drug products, by definition, are finished dosage forms," Peck noted. "Drug products also tend to be more complex than drug substances, so additional safeguards are needed to maintain product quality. This is especially true for some drug products, such as sterile drug products and controlled-release products, when manufacturing site changes are contemplated." Peck told PMA that "we also disagree with your assertion that a regulatory change would reduce FDA's backlog. Even if your request were granted and the agency permitted such changes without prior agency approval, FDA would still be obliged to review those supplements." However, Peck said, FDA encourages companies to advise the agency early about changes to expedite approval. Approval times resulting from such cooperation "can be as low as one month from the time of submission." Although FDA has decided not to amend the regs to exempt changes for "all drug products from the prior approval requirement, the agency is currently considering whether to amend 21 CFR 314.70 to exempt some manufacturing changes and other changes to certain drug products," Peck said. FDA's "use of pre- and post-approval inspection, as well as its greater expertise in bioavailability matters, has prompted the agency to re-examine the requirements."
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