INNsight article by Alan Klein, December 2014

Late last month, the FDA issued its long awaited final “Guidance for Industry: Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug [Facility] Inspection.” Charged with domestic and foreign plant inspections to ensure compliance with the agency’s current Good Manufacturing Practices (cGMPs), the FDA issued its Guidance to delineate the circumstances occurring during the inspection process that may result in a drug being deemed “adulterated” under the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA). As reported in the media over the past several years, FDA inspections have resulted in many import bans imposed upon foreign drug manufacturers, the closing of pharmaceutical facilities and other FDA sanctions. In its Guidance, the FDA seeks to provide benchmarks of when an inspection facility, by the active or passive conduct of its personnel, may be found to have unreasonably delayed, denied or limited the agency’s inspection authority.

FDA’s Statutory Authority for Plant Inspections

Section 704(a) of the Food Drug and Cosmetic Act (FDCA) gives FDA’s designated and specially trained personnel the authority to conduct drug facility inspections at reasonable times, within reasonable limits and in a reasonable manner. Such inspections are critical, mandated events to ensure that drug manufacturers and others involved in making, testing and distributing drug products in the United States comply with applicable law and regulations. While prior notice of a plant inspection is not required by law, in practice the FDA provides such notice for certain kinds of inspections such as those involving pre-approval and pre-license inspections and most inspections of foreign facilities. By and large, for-cause and routine surveillance inspections are not pre-announced.

The Guidance at a Glance

Although FDA Guidance documents do not have the force of law and constitute what the agency typically describes as its “current thinking on this topic,” most experienced pharmaceutical industry professionals listen carefully to the agency’s recommendations because its staff often implement Guideline suggestions in the performance of their responsibilities. In the current Guidance, for example, the FDA “defines” the range of actions or inaction, or other circumstances, which it may deem a company’s delaying, denying or limiting an inspection sufficient to risk enforcement action, including, but not limited to, its drug product being found “adulterated” under the FDCA.

In a series of examples of conduct which the FDA discourages and may find unreasonable, the Guidance provides industry participants with a generalized but important range of active and passive behaviors suggestive of a company impeding the agency’s inspection. If, without a reasonable explanation, a company does not agree to a plant inspection start date, or seeks to cancel an inspection, or fails to respond to FDA efforts to contact designated company personnel, the resulting delay may constitute an FDCA violation.

Similarly, if, during an investigation, and without reasonable explanation, the FDA inspector is denied access to an area of the facility that is fully operational, or is denied direct observation of a manufacturing process, or timely access to either necessary documentation or responsible individuals, these, too, may be deemed sanctionable conduct. Efforts, also, to preclude the inspector from collecting statutorily authorized samples (such as finished product, raw materials, in-process samples, and reserve samples for use in bioequivalence and bioanalytical studies) may expose the company to the issuance of a warning letter or more severe FDA enforcement measures.

Likewise, a facility that discontinues all manufacturing for the duration of an inspection, without reasonable explanation, or denies the inspector access to the facility, or dismisses its staff for the day and represents to the investigator that the facility is not producing product, has engaged in potentially sanctionable behavior.
Although there is no statutory authority for the FDA taking photographs at inspection facilities, the agency believes, as stated in its Guidance that “photographs are an integral part of an FDA inspection because they present an objective and contemporaneous representation of facility conditions.” Accordingly, in the Guidance the agency cautions drug companies that denying or impeding an inspector’s taking of photographs “may be considered a limitation” if the investigator determines that the photographs are “necessary” for the “effective conduct” of the inspection.

What are the Takeaways for Industry from this FDA Guidance?

On the positive side, the Guidance includes helpful information to drug companies describing “reasonable explanations” for delays, denials and limitations of FDA inspections. Delays may be understandable, for example, if manufacturing is not regularly or consistently occurring at a plant. Likewise, there may be excusable delays in producing requested records if the quantity is large or English translations are not readily available. Also, if appropriate personnel are not immediately available to respond to the FDA inspector’s questions during an unannounced visit, or if the plant is closed for scheduled maintenance when the inspector arrives, a manufacturer likely will not face enforcement action.

With potentially serious ramifications flowing from anyone impeding an FDA site investigation, the Guidance furnishes a valuable reminder of the necessity for a drug company to have written procedures in place addressing inspection issues. These include who is authorized to speak on behalf of the company during an FDA inspection, whether there are any restrictions regarding the taking of photographs of manufacturing processes, and the procedures to be utilized for the prompt assembly and production of records maintained both onsite as well as offsite relating to subjects likely to arise during the inspector’s visit and interview of company personnel.

Alan Klein
December 2014

AKlein@duanemorris.com