What Not To Do When An FDA Inspector Knocks At Your Door

FDA tweaks its guidance on what constitutes interference with facility inspections to include examples of “reasonable” explanations for delays, without addressing many industry concerns raised during a comment period. Created to provide FDA’s perspective on 2012 changes to federal food and drug law related to adulterated drug products, the guidance’s “sweeping” language suggests it could have relevance for inspections of cosmetic facilities conducted by the agency, attorneys say.

A final guidance from FDA describing interference with FDA inspections that may cause a drug to be deemed adulterated includes examples of “reasonable” explanations for sponsor behavior that causes delays, but largely ignores industry concerns that the document is overreaching.

The guidance announced in an Oct. 22 Federal Register notice, “Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection,” describes numerous delaying tactics employed by firms facing inspections, such as blocking access to facilities, sending staff home for the day and halting drug manufacturing when an investigator shows up at the facility.

In a same-day FDA Law Blog post, Hyman, Phelps & McNamara attorneys Jay Cormier and Anne Walsh note that “on its face, the final guidance does not apply to inspections of [non-drug] facilities, but the final guidance is written in sweeping terms.”

Specifically, FDA says the guidance “covers facilities subject to inspection under any of the authorities in section 704” of the Federal Food, Drug and Cosmetic Act, which governs inspections of food, drug, device, tobacco and cosmetic product facilities.

“Therefore,” the attorneys say, “it is reasonable to expect that FDA will take a similar approach for all FDA-inspected facilities.”

Among numerous other scenarios, leaving an investigator in a conference room without access to necessary documentation or responsible individuals “for an unreasonable period of time” would constitute an inspection delay that may cause drugs to be found adulterated.

The final version follows a July 2013 draft guidance to which industry stakeholders made numerous objections, including to a provision directing sponsors to provide inspectors “reasonable access” to specified areas, particularly those for aseptic processing (Also see "Rx Companies Push For Exemptions To Breadth Of FDA Inspections" - Pink Sheet, 21 Oct, 2013.).

HPM’s lawyers maintain that no legal basis exists for certain elements of the guidance that may be treated as binding requirements.

Concerns About ‘Regulatory Creep’

FDA was required to issue the guidance under the 2012 FDA Safety and Innovation Act, which amended the FDCA to allow FDA to request records or information in advance of, or in lieu of, an inspection.

Most worrisome to industry, FDASIA added language identifying a drug as adulterated when it is manufactured, processed, packed or held in a facility and the owner or operator “delays, denies, or limits an inspection, or refuses to permit entry or inspection.”

The final guidance notes that a potentially reasonable explanation for delaying investigator access to aseptic process areas would be having the investigator follow the facility’s documented gowning procedures.

In their blog post, Cormier and Walsh say the guidance extends FDA’s authority during inspections. They cite requirements that employees answer questions, produce documents that are not on-site or ensure that certain personnel are present at the facility as instances where “FDA’s expectations of facilities extend beyond the already substantial reach Congress delegated to FDA.”

The attorneys also question the agency’s use of the word “reasonable” to define situations that would justify the delay, denial, limitation or refusal of an inspection, predicting that FDA likely will decide how to interpret and apply the term rather than relying on objective legal standards.

“Because these determinations will be made in practice by investigators in the field rather than attorneys, FDA will likely become its own arbiter of reasonableness,” they suggest.

“The final guidance, thus unfortunately, creates issues rather than clarifies issues,” the attorneys write. “Whether FDA will ‘get away’ with the regulatory creep evidenced in the final guidance will depend on facilities holding FDA accountable to the four corners of the FDCA and not ceding ground to FDA.”

Photography Policies Pose Inspection Risk

In comments on the draft, the Biotechnology Industry Organization raised concerns about FDA inspectors taking photographs, noting many companies have restrictions on photographs to protect intellectual property. The group asked FDA to revise the guidance so that some limitations on photographs would not necessarily render drugs adulterated.

The final guidance gives a single example of a scenario where limiting photography would not result in drugs being deemed adulterated: when “the chemical properties of products manufactured at the facility are such that taking photographs would adversely affect product quality.”

The guidance says photographs are necessary to document evidence of rodents or insect infestation, faulty construction or maintenance of equipment or facilities, and visible contamination of raw materials or finished products.

According to HPM’s attorneys, “the issue of FDA’s authority in the realm of photographs is murky, at best.”

The document also states that leaving an investigator in a conference room without access to necessary documentation or responsible individuals “for an unreasonable period of time” would constitute an inspection delay that may cause drugs to be found adulterated.

Merck & Co. Inc. asked FDA to clarify what constitutes “unreasonable” in this case, noting that circumstances occur in which “necessary documentation” requested by FDA is in archives or located in off-site storage and time is needed to locate and retrieve the records.

The guidance says acceptable delays in producing records may be that a requested English translation is not readily available, that the records are being used for a manufacturing operation in progress or the volume of records requested is so large it takes “reasonable time to compile.”

The final guidance does not address several other issues industry raised. In what is likely the most significant of those, many stakeholders asked FDA to develop a formal process for notifying a company of its intent to deem products adulterated due to delaying, limiting or refusing an inspection and to establish an appeals process.

Another example provided by FDA of a reasonable explanation for holding up an inspection would be that manufacturing at the facility is not ongoing, for example if the site is running one manufacturing campaign per month.

In addition, drugs might not be deemed adulterated if “at the beginning of an inspection, appropriate personnel are not immediately available to accurately answer the FDA investigator’s questions,” but the issue is resolved later, the guidance indicates.

The guidance lists numerous other actions by sponsors that could impede an inspection and lead the agency to find their products adulterated. They include limiting or preventing collection of samples, including finished product samples, raw material samples and reserve samples in bioequivalence and bioanalytical studies; and falsely alleging that the facility does not manufacture, process, pack or hold drugs.