Guest Column | January 9, 2023

FDA Seeks Comment On Circumstances For Delaying, Denying, Limiting, Or Refusing An Inspection

By Mark Durivage, Quality Systems Compliance LLC

On Dec. 15, 2022, the FDA released for public comment Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection Revision 1. The proposed draft guidance document seeks to update the current guidance document Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection published in October 2014. The October 2014 FDA guidance will remain in effect until it is officially withdrawn.

Section 704 of the Food, Drug & Cosmetic (FD&C) Act authorizes the FDA to conduct inspections of facilities (establishments, factories, warehouses, and vehicles) “at reasonable times, within reasonable limits, and in a reasonable manner.” The FDA does not specifically define the term reasonable but does provide the following explanation: its inspection authority “extends to what is reasonably necessary to achieve the objective of the inspection.” The FDA works with facilities to conduct inspections to secure the information necessary to achieve the inspection objectives. The FDA will consider reasonable explanations for delaying, denying, limiting, or refusing an inspection. The FDA realizes delaying, denying, limiting, or refusing are actions that can be used singularly or jointly to obstruct an inspection. Delaying, denying, and refusing an inspection are discrete events. Delaying an inspection is causing the inspection to be postponed, whereas denying an inspection is the act of intention to avoid the inspection, and refusing an inspection is the act of prohibiting an inspector from conducting the inspection. Refusing an inspection, by default, will cause a delay.

Facility registration, reportable events, and reports of corrections and removals are used by the FDA for scheduling inspections. It is important for facilities to register and to ensure the information is updated when changes occur, such as, for example, the official point of contact. The FD&C Act prohibits the facility’s owner, operator, or agent from refusing to permit entry or inspection or refusing to permit access to or copying of certain specified records. The FDA considers drugs or medical devices adulterated if they have been “manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection,” per The Food and Drug Administration Safety and Innovation Act (2012) and the FDA Reauthorization Act of 2017.

Delay Of An Inspection

Delays in scheduling pre-announced inspections, during an inspection, and/or producing records may occur and are due to circumstances beyond the direct control of the facility. The FDA makes reasonable accommodations for local conditions, such as weather, security situations, holidays and other non-workdays, and scheduled manufacturing campaigns.

Examples of unreasonable delays in scheduling a pre-announced inspections include:

A facility will not agree to an announced inspection start date.
A facility requests a later start date after scheduling the inspection.
The FDA has attempted to contact the official contact of the facility to schedule an inspection and the official contact for the facility fails to respond.

A potentially reasonable explanation for a delay in scheduling a pre-announced inspection production at a facility is that production is not ongoing and the facility requests a different date.

Delays During An Inspection

When an owner, operator, or agent impedes an FDA investigator from performing the inspection in a reasonable manner before or during an inspection, this may be considered delaying the inspection.

Examples of unreasonable delays during an inspection include:

The FDA investigator is not allowed access to an area of the facility until later, although the area is operational.
The FDA investigator is left in a conference room without access to necessary documentation or responsible individuals for an unreasonable amount of time.
The necessary facility personnel are not available, or management informs the FDA investigator that operations are shut down when a pre-announced inspection was scheduled.

Potentially reasonable explanations for delays during an inspection include:

The FDA investigator must be trained on the facility’s gowning procedure and precautionary measures prior to accessing the aseptic processing areas to prevent contamination.
The FDA investigator is required to have Occupational Safety and Health Administration (OSHA) training before entering a particular area of the facility.

Delays Producing Records

FDA inspections rely on accessing and copying records to verify compliance, interstate commerce, and product labeling and promotion and to identify responsible parties. Examples of potentially reasonable explanations for delays producing records include:

The requested records require translation into English.
The requested records are currently being used in production that is in progress and accessing the records would unnecessarily disrupt the operation.
The records requested are sufficiently large as to require reasonable additional time to compile.
The records requested are stored off-site and require time to retrieve.

Denial Of An Inspection

Denial of an inspection includes statements or physical actions intended to avoid inspection or mislead, deceive, or impede the FDA investigator. Examples of denying an inspection include:

The owner, operator, or agent of a facility rejects the attempt to schedule a pre-announced inspection.
The FDA investigator is not allowed to begin the inspection.
The FDA investigator is not allowed to inspect the facility because certain staff members are not present.
The facility does not allow the FDA investigator to inspect the facility by falsely alleging the facility does not manufacture, process, pack, or hold drugs or devices.
The FDA investigator is told the facility is not producing any product and the staff is sent home.

Examples of potentially reasonable explanations for denying an inspection include:

Appropriate personnel are not immediately available to accurately answer the FDA investigator’s questions at the beginning of an unannounced inspection.
The facility is closed due to scheduled maintenance at the beginning of an unannounced inspection.

Limiting An Inspection

An owner, operator, or agent of a drug or device facility who inhibits an authorized representative of the FDA from fully conducting an inspection without a reasonable justification may be viewed as limiting the inspection. Examples of limiting access to facilities and/or manufacturing processes without a reasonable explanation include:

During the FDA inspection, the facility halts or interrupts production operations.
Direct observation of the production process or portions of the production process is limited by the facility, preventing the FDA from fully inspecting the facility.
The FDA is restricted from entering portions of the facility.
The FDA investigator is either asked or forced to leave the premises before the inspection is completed.

Examples of potentially reasonable explanations for limiting access to facilities and/or manufacturing processes include:

The FDA investigator must be trained on the facility’s gowning procedure and precautionary measures prior to accessing the aseptic processing areas to prevent contamination.
The FDA investigator is required to have OSHA training before entering a particular area of the facility.

Limiting Photography

The FDA uses photographs as objective evidence of conditions observed at the facility, including evidence of rodent and insect infestation, faulty construction or maintenance of equipment or facilities, product storage, conditions, product labels and labeling, and visible contamination of components, containers, closures, or products. Impeding, resisting, or otherwise limiting photography by an FDA investigator without a reasonable justification may cause the drugs or devices manufactured, processed, packed, or held to be considered adulterated by the FDA if the photographs are determined by the investigator to be necessary to effectively conduct inspection.

An example of a potentially reasonable explanation for limiting photography may include that the act of photographing of raw materials or assemblies would adversely affect product quality.

Limiting Access To Or Copying Of Records

The FDA investigator is refused access to shipping records.
The FDA investigator is provided some, but not all, records requested.
The records requested by the FDA investigator are unreasonably redacted or not provided.
Data contained in electronic records are omitted or limited, including removing data columns, removing data from the electronic record, exporting data into reports without including all data fields (unless otherwise requested by FDA), or locking the electronic worksheet so that the data cannot be searched, sorted, or analyzed by FDA.
Electronic records are considered the original, but the facility does not provide an electronic copy of that record (or data query) to the FDA.

Examples of potentially reasonable explanations for limiting access to or copying of records include:

The requested records require translation into English.
The requested records are currently being used in production that is in progress and accessing the records would unnecessarily disrupt the operation.
The records requested are sufficiently large as to require reasonable additional time to compile.
The records requested are stored off-site and require time to retrieve.

Limiting Or Preventing Collection Of Samples

FDA inspections rely on collecting samples as objective evidence. Limiting, declining, impeding, or preventing collection of samples includes environmental samples, finished product samples, raw material samples, in-process material samples, reserve samples in bioequivalence and bioanalytical studies, and labeling during an inspection. The FDA does not provide any explanations it qualifies as reasonable for limiting, declining, impeding, or preventing collection of samples.

Refusal To Permit Entry Or Perform Inspection

Examples of active or passive refusal to permit entry or perform inspection or refusal by inaction include:

An owner, operator, or agent of the facility bars the FDA investigator from entering the facility or areas of the facility by not unlocking the facility or areas or taking other actions that would permit access by the investigator.
The FDA has attempted to contact the official contact of the facility to schedule an inspection and the official contact for the facility fails to respond.
The FDA investigator places calls to the facility and the calls are not answered despite clear evidence of the presence of employees engaged in job-related functions.

The guidance does not provide any explanations it qualifies as reasonable for refusing entry for an inspection.

Conclusion

Please submit written comments to Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Rm 1061, Rockville, MD 20852, or electronic comments to https://www.regulations.gov. Please reference docket number FDA-2013-D-0710 with all comments. Comments must be received by Feb. 14, 2023. For questions regarding this draft guidance document, contact the Office of Regulatory Affairs (ORA), Office of Strategic Planning and Operational Policy (OSPOP), Food and Drug Administration at ORAPolicyStaffs@fda.hhs.gov.

Delaying, denying, limiting, or refusing a drug or device inspection without a reasonable justification will result in a less than collegial atmosphere during an FDA inspection. Honest and open communications are paramount when interacting with the FDA. Nearly 100% of the time, honest and open communications will establish rapport with the FDA inspector(s).

Organizations subject to FDA inspections should establish and maintain an FDA Inspection Procedure and ensure that the appropriate individuals are trained. Perform mock FDA inspections annually and live each day as if the FDA is going to show up and begin an inspection. Check out previous articles for advice on how to prepare for an FDA inspection and what should you do after an FDA inspection?.

About The Author:

Mark Allen Durivage has worked as a practitioner, educator, consultant, and author. He is managing principal consultant at Quality Systems Compliance LLC, an ASQ Fellow and SRE Fellow. Durivage primarily works with companies in the FDA regulated industries (medical devices, human tissue, animal tissue, and pharmaceuticals) focusing on quality management system implementation, integration, updates, and training. Additionally, he assists companies by providing internal and external audit support as well as FDA 483 and warning letter response and remediation services. He earned a BAS in computer aided machining from Siena Heights University and an MS in quality management from Eastern Michigan University. He holds several certifications, including CRE, CQE, CQA, CSSBB, RAC (Global), and CTBS. He has written several books available through ASQ Quality Press, published articles in Quality Progress, and is a frequent contributor to Life Science Connect. You can reach him at mark.durivage@qscompliance.com with any questions or comments.

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