FDA's GMP dispute resolution pilot could allow drug inspectors a "short post-inspection delay" prior to issuing a Form 483 manufacturing report.

The agency is considering granting a 48-hour delay "to allow for clarification of issues and an opportunity to informally resolve disputes that occur late in the inspection process," as part of FDA's risk-based good manufacturing practices initiative.

A working group, formed as part of the GMP initiative, recommends FDA implement a 12-month pilot "that will allow rapid, objective resolution of scientific and technical questions and issues that may arise either during an inspection or as the result of an inspection."

"Occasionally, inspectional observations are recorded, or warning letters sent, that might have been avoided if the agency were able to consult with internal experts concerning central scientific and technical issues relating to advanced technology and innovative manufacturing processes," the working group said.

"This pilot would allow FDA to evaluate the process and to answer questions about the effects of the process on industry as well as on FDA. Criteria to evaluate the pilot will need to be developed with internal and stakeholder input," the agency said. FDA will seek further comment within 90 days.

"It is intended that the proposed process will not cause significant delays in product approval time, will not unduly burden agency resources, will only be used in situations that meet criteria set forth by FDA, and will not inhibit appropriate enforcement actions."

The working group made its recommendations in a progress report issued six months after FDA's announcement of the GMP initiative (¹ [A#00640340001], p. 3). FDA was understood to be targeting late February for release of the report (² Also see "GMP Dispute Resolution Concept Paper From FDA Expected In February" - Pink Sheet, 13 January, 2003., p. 4).

Other aspects of the agency's GMP initiative involve a shift from the field to the centers on authority to issue warning letters and involvement of product specialists on inspection teams (see ³ Also see "FDA GMP Initiative Shifts Warning Letter Review Back To Agency Centers" - Pink Sheet, 24 February, 2003.).

The 48-hour delay would be part of the first, informal stage dispute resolution process, which takes place during the actual inspection. In an informal manner, "investigators are encouraged to discuss observations relating to manufacturing quality as they are observed, or on a daily basis to minimize surprise, errors, and misunderstandings when the 483 is issued."

"The goal is to try to facilitate early resolution of those issues and technical disputes, rather than allow them to drag on," Center for Drug Evaluation & Research Office of Compliance Director David Horowitz said during a Feb. 20 conference call.

Under the existing inspections process, an applicant "may make changes in the manufacturer of or the control of the manufacturing process for the product to correct deficiencies identified during an inspection, even when the firm believes that corrective action is not consistent with available scientific/technical evidence or is based on an inaccurate observation."

The progress report notes that "industry may have adopted a 'don't use' or 'don't tell' approach to new manufacturing technologies" which may be due to "concerns about misinterpretation of data generated using new technologies."

Another issue with the current system is that "incorrect or scientifically invalid observations may become a part of the public record and become a de facto standard in the absence of a more specific agency guidance," the report says.

Other concerns identified by FDA's GMP working group suggest "that the purpose and legal intent of the 483, as well as the agency's process for developing and issuing it, may be unclear to some inspected entities and the public."

To address that concern, FDA is adding language to the 483 report that explains that its observations are "inspectional observations, and do not represent a final agency determination regarding your compliance."

"If you have an objection regarding an observation, or have implemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA," the new form says.

"The clarifying language will help industry and others understand better what the observations contained in a 483 represent" and will "help people understand that the Form 483 and the observations contained therein are just one piece of the overall inspectional compliance process," Associate Commissioner for Regulatory Affairs John Taylor explained.

The agency plans to include the disclaimer "promptly" for electronically generated forms, and "as soon as practicable" for paper forms.

After the informal stage, the proposal includes two escalating formal processes: 1) dispute resolution at the district and center levels; and 2) via a dispute resolution panel within the Office of the Commissioner.

If the dispute is not resolved during the informal process, a manufacturer can request a formal review by the district office "regarding the scientific basis for an observation" in a 483 report. If the company disagrees with the conclusions from the district panel, it can then seek an appeal to the dispute resolution panel.

The panel should be chaired by an OC representative and include representatives from CDER, the Center for Biologics Evaluation & Research, the Center for Veterinary Medicine, the Office of Chief Counsel, the Office of Regulatory Affairs, and possibly ad hoc experts, the working group suggested.

Criteria will need to be developed for "how and when a firm may ask for consideration by the [OC] panel," the group recommended. "The center, in consultation with the district, will determine whether the dispute meets the applicable criteria and is appropriate for review by the panel."

Outstanding issues yet to be resolved include determining a process by which to resolve internal disagreements within FDA; methods to disseminate information on resolved disputes; and criteria to determine whether an issue is appropriate for dispute resolution processes (i.e. "what is a scientific or technical issue?").

The dispute resolution system could reduce tensions between companies and FDA; industry has expressed concern that agency inspections can be capricious and inspectors may retaliate if companies challenge their findings (⁴ Also see "GMP Compliance Guidances Should Be Increased, Lilly’s Miner Says" - Pink Sheet, 22 April, 2002., p. 18).

GMP Dispute Resolution Pilot May Build In Delay Before Form 483 Is Issued

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