What Not To Do When An FDA Inspector Comes Knocking At Your Door

FDA tweaks final guidance on what constitutes interference with FDA inspections to include examples of ‘reasonable’ explanations for sponsor delays; industry had requested many other changes.

FDA tweaked its final guidance on what constitutes interference with FDA inspections that may cause a drug to be deemed adulterated: it added examples of “reasonable” explanations for sponsor behavior that delays an inspection. But the agency largely ignored industry concerns that the document is overreaching.

The guidance, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection, describes numerous delaying tactics 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.

The final version, which FDA announced in an Oct. 22 Federal Register notice, is almost identical to the draft guidance issued in July 2013 (Also see "Door-Opener for Inspections: Guidance Lists Unacceptable Tactics To Hamper FDA Visits" - Pink Sheet, 19 Jul, 2013.).

Members of industry had numerous objections to the draft guidance, including its requirement that sponsors provide inspectors “reasonable access” to specified areas, particularly those for aseptic processing (Also see "Rx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.).

Worries About ‘Regulatory Creep’

The agency was required to issue the guidance under the 2012 FDA Safety and Innovation Act. The statute amended the Food, Drug, and Cosmetic Act (FDCA) to allow FDA to request records or information in advance of or in lieu of an inspection. And most worrisome to industry, it added language deeming a drug to be adulterated if 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 an FDA Law Blog post, Hyman, Phelps & McNamara attorneys Jay Cormier and Anne 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 require that certain personnel be present at the facility. They also question FDA’s use of the word “reasonable” to define situations that would justify the delay, denial, limitation or refusal of an inspection, saying the agency will likely be the one to decide what this means.

“The final guidance, thus unfortunately, creates issues rather than clarifies issues,” they 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, Conference Rooms Pose Inspection Risk

In comments on the draft guidance, the Biotechnology Industry Organization raised concerns about FDA inspectors taking photographs, noting that many companies have restrictions on photographs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

The final guidance gives a single example of a situation where limiting photography would not result in drugs being deemed adulterated: if “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 of facilities, and visible contamination of raw materials or finished products.

The document also states that leaving the 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. had asked FDA to clarify what constitutes “unreasonable” in this case, noting that there are circumstances in which the “necessary documentation” requested by FDA is in archives or located in off-site storage and it may take time 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 raised by industry. Most significantly, 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. The guidance does not address this request.

Another example of a reasonable explanation for holding up an inspection would be that manufacturing at the facility is not on-going, for example if it 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,” the guidance states.

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.