DRUG MANUFACTURING EQUIPMENT CHANGES DO NOT REQUIRE PRIOR APPROVAL

DRUG MANUFACTURING EQUIPMENT CHANGES DO NOT REQUIRE PRIOR APPROVAL from FDA when changing "to equipment of the same design and operating principles from the same or a different manufacturer" or when changing "to the same equipment with a different capacity" provided that "the capacity should not exceed 10 times the test batch size," FDA explains in a draft guidance on manufacturing supplements. Such changes would "ordinarily" require only description in a company's annual report. The draft guideline, which applies only to non-sterile drug products, was published in the Dec. 12 Federal Register.

"Usually changes in volume require a change and validation of parameters such as mixing time and speed," the draft guideline states. "Such validation studies should reflect no change in product formulation or quantitative composition. The applicant should also perform comparative multiple-point dissolution profiles for solid oral dosage forms as part of the validation."

Changes in equipment that involve either "different design or operating principles" or "changes in the basic methodology of manufacturing" require a preapproval supplement, the guideline advises.

The draft guideline is in line with recommendations from FDA's Scale-up and Post-approval Changes working group. The SUPAC working group has been attempting to define FDA's interpretation of current regulations on the subject, and, with input from industry, is seeking to identify possible areas for changes in regulations. The Dec. 12 draft guideline clarifies the existing regs in three areas: equipment changes, site changes and reprocessing.

The SUPAC group first previewed its proposal on immediate release oral solid dosage form products during a September workshop sponsored by the American Association of Pharmaceutical Scientists. For equipment changes, the SUPAC proposal matches the formula spelled out in the draft guidelines. SUPAC further suggested that the annual report for changes to equipment of the same design and principal would include an updated batch record, while supplements for equipment changes would require stability data and a dissolution profile incorporating multi-media testing. On Dec. 9, the proposal was presented by the Center for Drug Evaluation & Research to industry representatives from the Generic Pharmaceutical Industry Association, the National Association of Pharmaceutical Manufacturers, the National Pharmaceutical Alliance, PDA and the Pharmaceutical Research & Manufacturers of America.

The Dec. 12 draft guideline clarifies that manufacturing site changes do not require prior approval of a supplement if the manufacturing process does not "materially differ" and the new site has passed a current good manufacturing practices inspection within the past two years. A supplement must be filed for such changes, but production at the new site can begin prior to FDA approval. Site changes that involve "materially" different production methods or a site that has not had a GMP inspection in more than two years require prior approval.

The guideline also lists several examples of changes that may be made to the physical facility which may be described in the annual report: "relocating processing areas or structures" within the existing facility or to an addition without materially changing the manufacturing process; "relocating equipment within the facility"; "relocating nonprocessing rooms or areas" within the facility; "adding new interior partitions or walls to increase control over the environment"; and "replacing or adding improved lighting" and "new surfaces to enhance cleaning."

During the AAPS workshop on SUPAC, several industry representatives remarked on the cost to companies of delays in approval for site changes ("The Pink Sheet" Sept. 19, T&G-4). The SUPAC proposal previewed at the meeting clarifies that site changes within the same campus also require a changes-being- effected supplement including a commitment for stability data.

For reprocessing a drug product that does not meet specifications, the Dec. 12 draft guideline states, "repetition of one step a single time per batch in the approved sequence of the manufacturing process" does not require a supplemental application and can be described in the company's next annual report. However, the repetition of a step should be "a random and infrequent event. If a manufacturer finds that a step must be consistently repeated to meet specifications, this constitutes a change in the manufacturing process and requires a preapproval supplement," the guideline states.

Companies should submit "proposed, detailed reprocessing procedures when requesting authorization to reprocess" either with the original application or in preapproval supplements, the guideline adds. FDA must approve the reprocessing procedures before the reprocessed products are released for shipment.

Comments on the guideline are due by March 14. FDA notes that "if a person chooses to depart from the practices and procedures set forth in the guideline, that person may wish to discuss the matter with FDA to prevent an expenditure of money and effort on activities that FDA may later determine to be unacceptable."