FDA Finalizes Guidance About Delaying, Denying, Limiting, Or Refusing An Inspection

By Adish Bhatnagar, independent consultant and freelance GxP auditor

The United States FDA issued a final guidance in June 2024 on the circumstances that constitute delaying, denying, limiting, or refusing a drug or device inspection.¹ The guidance covers facilities that are subject to drug or device inspection under section 704² of the FD&C Act and supersedes the October 2014 guidance titled Circumstances that Constitute Delaying, Limiting, or Refusing a Drug Inspection, which is withdrawn. The latest revised guidance is the final version of the draft guidance that was issued in December 2022 by FDA. There is no change in title of the guidance document from the draft guidance issued in December 2022.

The guidance¹ lays down the following examples of delaying, denying, limiting, or refusing a drug or device inspection.

Delay In Inspections

Delays may occur for many reasons, some of which are beyond the control of the facility. FDA will consider reasonable explanations for behavior that may otherwise be considered to be delaying, denying, limiting, or refusing an inspection. However, where an owner, operator, or agent causes the unreasonable delay of an inspection, this may cause the drugs or devices manufactured, processed, packed, or held therein to be adulterated under section 501(j) of the FD&C Act.

Delay Scheduling Pre-announced Inspections

Examples of delay in scheduling a pre-announced inspection that may cause drugs or devices to be adulterated under section 501(j) of the FD&C Act include, but are not limited to:

• A facility will not agree to an announced inspection start date and does not give a reasonable explanation for its failure to do so.
• After scheduling an inspection, a facility requests a later start date without giving a reasonable explanation.
• A facility fails to respond following FDA’s attempts to contact the facility’s designated contact(s).

Delay During An Inspection

Examples of delays during an inspection that may cause drugs or devices to be adulterated under section 501(j) of the FD&C Act include, but are not limited to:

• 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 and is an area of the inspection site that FDA has authority to inspect, without giving a reasonable explanation.
• A facility leaves the FDA investigator in a conference room without access to necessary documentation or responsible individuals for an unreasonable period of time that interferes with the investigator’s ability to complete the inspection.
• A facility agrees to the pre-announced inspection date, but when the investigator enters the facility, the necessary facility personnel are not available, or the firm’s management informs the investigator that operations are shut down, without providing a reasonable explanation.

Delay During An Inspection

Examples of delays in producing records that may cause drugs or devices to be adulterated under section 501(j) of the FD&C Act include, but are not limited to:

• During an inspection, the FDA investigator requests, within a reasonable time frame, records that FDA has authority to inspect, but the facility fails to produce the requested records within the time frame requested by FDA, without reasonable explanation.
• FDA requests records pursuant to section 704(a)(4) or 704(e) of the FD&C Act, but the facility fails to produce the requested records in a timely manner, without reasonable explanation.

Denial Of Inspection

Examples of behavior that may constitute a denial that may cause drugs or devices to be adulterated under section 501(j) of the FD&C Act include, but are not limited to:

• A facility rejects FDA’s attempt to schedule a pre-announced inspection.
• Upon arrival at the facility, the facility does not allow the FDA investigator to begin the inspection.
• A facility does not allow the FDA investigator to inspect the facility because certain staff members are not present, without a reasonable explanation.
• A 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.
• A facility sends staff home for the day and tells the FDA investigator that the facility is not producing any product.

Limiting Of Inspection

Limiting Access To Facilities And/Or Manufacturing Processes

Preventing an authorized representative of FDA reasonable access to an area of the site that FDA is entitled to inspect may be considered limiting the inspection. This includes the refusal to disclose or permit observation of the manufacturing processes or permit access to site personnel. Examples include, but are not limited to:

• A facility orders the discontinuation of all manufacturing for the duration of the FDA inspection, without a reasonable explanation.
• The firm interrupts production activities to prevent FDA investigators from observing production operations.
• A facility limits FDA’s direct observation of the manufacturing process, in whole or in part, to an unreasonably short amount of time, thus preventing FDA from inspecting the facility as is usual and customary.
• A facility limits direct observation of portions of the manufacturing process, without reasonable explanation.
• A facility unreasonably restricts entry to a particular portion of the facility, without reasonable explanation.
• Staff at a facility causes the FDA investigator to leave the premises before the inspection is completed, without reasonable explanation.

Limiting Photography

Examples of potentially reasonable explanations that might result in the drugs or devices not being deemed adulterated under section 501(j) of the FD&C Act include, but are not limited to:

• The chemical properties of products manufactured at the facility are such that taking photographs would adversely affect product quality.
• The facility can document that taking photographs of any raw material or assembly would adversely affect product quality.

Limiting Access To Or Copying Of Records

The ability to access and copy records is a critical aspect of FDA inspections. Not allowing an authorized representative of FDA access to or copying of records that FDA is entitled to inspect by law, including not providing records, may be considered limiting an inspection. Examples of limiting access to records include, but are not limited to:

• A facility refuses to allow the FDA investigator to review the facility’s shipping records that FDA has authority to inspect.
• A facility provides some, but not all, records requested by the FDA investigator that FDA has authority to inspect.
• A facility provides the FDA investigator the requested records that FDA has authority to inspect, but they are unreasonably redacted.
• A facility refuses to provide records that FDA requests pursuant to section 704(a)(4) or 704(e), or such records are unreasonably redacted.
• A facility maintains electronic records but omits or limits the data contained in the electronic records when providing electronic copies of the records to FDA. This includes but is not limited to actions such as removing data columns in Excel, removing data from the electronic record when providing the record to FDA, exporting data into reports without including all of the data fields (unless otherwise requested by FDA), or locking the electronic worksheet so that the data cannot be searched, sorted, or analyzed by FDA.
• A facility identifies an electronic record as the original but does not provide an electronic copy of that record (or data query) to FDA pursuant to FDA’s request.

Limiting Samples

Preventing an authorized representative of FDA from collecting statutorily authorized samples may be considered limiting the inspection. Examples of sample limitations include, but are not limited to, declining to allow or impeding FDA from collecting the following types of samples: environmental samples, finished product samples, raw material samples, in-process material samples, reserve samples in bioequivalence and bioanalytical studies, and labeling.

Refusal To Permit Entry Or Inspection

FDA interprets the term “refuses to permit entry or inspection” to include not only active but also passive behavior and inaction by the owner, operator, or agent of a facility that results in an authorized representative of FDA not being able to enter or fully inspect the facility. For purposes of this guidance, such an owner, operator, or agent shall be considered to have refused to permit entry or inspection if such owner, operator, or agent fails to take steps to permit an inspection of a facility. Examples include, but are not limited to:

• Without reasonable explanation, the facility bars the FDA investigator from entering the facility or certain areas of the facility by, for example, not unlocking the areas or taking other necessary actions that would permit access by the investigator.
• Following FDA’s attempt to contact the facility’s designated contact(s) to schedule an inspection, the facility fails to respond.
• The facility does not answer calls from the FDA investigator, despite clear evidence of the presence of employees engaged in job-related functions.

Navigating These Circumstances Moving Forward

Individual organizations can prepare an internal standard operating procedure against any unforeseen circumstance that constitute delaying, denying, limiting, or refusing a drug or device inspection.

References/Notes

1. Find the complete guidance at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/circumstances-constitute-delaying-denying-limiting-or-refusing-drug-or-device-inspection
2. Section 704(a) of the FD&C Act provides FDA authority for inspections, specifically providing authority for duly designated officers or employees of FDA to enter, at reasonable times, and inspect, at reasonable times and within reasonable limits and in a reasonable manner, facilities subject to regulation under the FD&C Act.

About The Author:

Adish Bhatnagar has been a freelance pharmaceutical consultant and GxP auditor since 2020. Hailing from India, he is a postgraduate in pharmaceutical analysis & quality assurance and has worked in a top multinational pharmaceutical firm of India. He has 14 years of experience in general quality management system (QMS), good manufacturing practices (GMP), good distribution practices (GDP), electronic compliance, risk management, and investigational impact assessment. Bhatnagar has extensive experience conducting over 370 remote and on-site audits of manufacturing facilities located in European and Asian regions, which include manufacturing facilities for drug products (clinical and commercial), active pharmaceutical ingredients (clinical and commercial), key starting materials, intermediates, excipients, packaging materials, medical devices, and good distribution practice audits.

[Editor’s Note: Check out our other recent guest column about the final guidance, “Making Good Decisions When FDA Investigators Come Knocking,” by John W.M. Claud, counsel, Hyman, Phelps & McNamara.]