An FDA inspection consists of a “careful, critical, official examination of a facility to determine its compliance with certain laws and regulations administered by the FDA.” The Food Drug and Cosmetics Act gives FDA the authority for inspections—FDA employees may enter and inspect facilities under the jurisdiction of the Act. While FDA inspections are not known for being pleasant experiences, facilities violate the Act if they refuse to cooperate in the ordeal. In fact, drugs are deemed “adulterated” if the manufacturer or facility owner delays, denies, or limits an inspection, or refuses to permit entry or inspection.” FDA seemingly became aware of certain facilities looking for extra time to clean things up before the Agency came knocking. Now FDA can quickly penalize facilities that drag their feet.
The FDA last year offered draft guidance to the industry on the circumstances that would constitute a delay or refusal. Last week, FDA issued Final Guidance that includes specific examples of what the FDA would find to “reasonably” excuse what would otherwise be an unlawful delay or refusal.
New aspects the Final Rule added are in blue.
Delay of Inspection
(1) Pre-announced Inspection
FDA notes that generally, for drug products, pre-approval and pre-license inspections, and most inspections of foreign facilities are scheduled before an investigator arrives at the inspection site. FDA’s goal is to contact facilities within a reasonable time prior to the start date and will make reasonable accommodations for local conditions, such as weather or security situations, holidays, and other non-work days, and scheduled manufacturing campaigns.
FDA gives examples of delay in scheduling a pre-announced inspection that may cause drugs to be adulterated under section 501(j) of the FD&C Act. FDA notes they would find a potential violation where facilities don’t agree on a proposed start date or request later start dates without “reasonable explanation.” An example of a potentially reasonable explanation may include where manufacturing at the facility is not on-going, for example running only one manufacturing campaign per month and the facility requests a different date than proposed.
Notably, the Final Guidance changes the word “adequate” justification to “reasonable” justification in a number of instances.
(2) Delay During an Inspection
FDA notes that minor delays that result from good faith efforts by the facility to comply with FDA requests generally would not be considered unreasonable. However, FDA would potentially find a delay where a facility does not allow the FDA investigator access to an area of the facility until a specific future date or time even though the area is operational. FDA also notes an unexcused delay would be where a facility leaves the FDA investigator in a conference room without access to necessary documentation or responsible individuals for an unreasonable period of time.
An example of a potentially reasonable explanation would be where a facility does not provide the FDA investigator access to “aseptic processing areas until the investigator accommodates the facility’s documented gowning procedures.”
(3) Delay Producing Records
FDA notes that facilities may be found to delay where they fail to produce requested records within the timeframe requested by FDA, without reasonable justification. (changed from “adequate”)
Examples of potentially reasonable explanations include a delay in order to translate documents, where documents are being used for a manufacturing operation that is in progress, and where the volume of the records requested is sufficiently large as to require reasonable time to compile. FDA notes the facility should also ensure that the resulting delay is of a reasonable duration.
Denial of Inspection
FDA interprets the word “deny” to also include statements or physical actions intended to avoid inspection or to mislead or deceive the investigator. Examples include:
- A facility rejects FDA’s attempt to schedule an inspection;
- A facility does not allow the FDA investigator to begin a pre-scheduled inspection;
- A facility does not allow the FDA investigator to inspect the facility because certain staff members are not present.
- A facility falsely alleges the facility does not manufacture drugs.
- A facility sends staff home for the day and tells the FDA investigator that the facility is not producing any product.
Examples of potentially reasonable explanations for denying inspection might be where at the beginning of an unannounced inspection, appropriate personnel are not immediately available to accurately answer the FDA investigator’s questions. Also, where the FDA investigator arrives for an unannounced inspection, but the facility is closed due to scheduled maintenance.
Limiting of Inspection
FDA notes that limiting of inspection would be preventing “reasonable access” to the facilities. This would include where a facility orders the discontinuation of all manufacturing for the duration of the FDA inspection without a reasonable explanation or where a facility states that direct observation of the manufacturing process, in whole or in part, must be limited to an unreasonably short amount of time. The FDA notes that FDA personnel may require proper training or safety outfits before entering a particular area.
Limiting inspection also includes limiting photography, “an integral part of an FDA inspection,” limiting access to or copying of records, and limiting or preventing collection of samples.
FDA beefs up the photography section in the Final Guidance. Photos are allowed to record evidence of rodents or insect infestation; faulty construction or maintenance of equipment or facilities; product storage conditions; product labels and labeling; and, visible contamination of raw materials or finished products. “Impeding or resisting photography by an FDA investigator may be considered a limitation if such photographs are determined by the investigator to be necessary to effectively conduct that particular inspection,” notes the Guidance.
FDA states that a possible excuse to photos would be where “the chemical properties of products manufactured at the facility are such that taking photographs would adversely affect product quality.”
Refusal to Permit Entry or Inspection
FDA interprets this to include passive behavior and non-action by the owner, operator, or agent of a drug facility that results in the FDA not being able to enter or inspect the facility. For example: not unlocking certain areas; failing to respond to FDA’s attempt to contact the facility’s designated contacts; or not answering calls from the FDA investigator who is present at the facility, despite clear evidence of the presence of employees engaged in job-related functions.
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What immediately jumps out in the guidance is the repeated use of the word “reasonable.” While not entirely unexpected in FDA Guidance, the inspection documents use this word with tremendous frequency and begs the question, what is reasonable? FDA provides more instructions in its Final Guidance, but there is still some guesswork out there for facilities looking to avoid getting in trouble for “delaying” an inspection.
Regulatory Affairs has been providing good coverage of the inspection issue. Alec Gaffney noted that two Warning Letters against Chinese companies have shown up over delays and refusals:
In one letter to a Chinese pharmaceutical manufacturer, FDA said the company had refused to provide access to records regarding product sampling. FDA’s own subsequent testing found the products to contain an unidentified ingredient, sildenafil, which is approved in the US under the brand name Viagra.
A second letter cited yet another Chinese company for preventing FDA’s inspectors from accessing parts of the manufacturing facility. Requests for batch production records were repeatedly denied, FDA claimed. The few records that were provided to FDA indicated the company was using suppliers subject to FDAimport alerts, the agency said.
RAPS also published an interesting study looking at statistics on how FDA rates inspected facilities: (1) NAI – No Action Indicated; (2) VAI – Voluntary Action Indicated, and (3) OAI – Official Action Indicated. “NAI and VAI indicate that only minor objections were noted, whereas OAI indicates that significant objectionable conditions that warrant FDA sanctions were cited,” the report states. “So it’s the OAI inspections that make the headlines, and that no one wants to experience first-hand, but how often do these occur?”
OAIs are clearly in the minority. Notably, the number of OAI decisions have also gone down from 1014 in 2011, to 906 in 2012, to only 462 in 2013, though this may not represent the complete number of 2013 decisions.