When an FDA investigator walks into your facility informing that they are going to conduct an inspection, a tense moment may arise even at the most cGMP (Current Good Manufacturing Practices) compliant facility. Paging the employees to inform them of the presence of FDA at the facility is a common occurrence so that they are prepared to face the investigator or a team of investigators. However, being prepared all the time for such a moment can bring the anxiety down to some extent. FDA publishes its Investigations Operations Manual (IOM)¹ annually and Chapter 5 represents “Establishment Inspections” which provides complete details for the investigators to follow during an FDA inspection. In this article, we are highlighting the types of FDA inspections that are conducted at a pharmaceutical facility focusing on drugs. Generally, the Office of Regulatory Affairs (ORA) conducts the inspections, however, it is not uncommon for the Center for Drug Evaluation and Research (CDER) personnel to join or independently conduct FDA inspections, particularly during Pre-approval Inspections.

1. Types of FDA Inspections

FDA conducts four types of inspections in a pharmaceutical facility to help protect consumers from unsafe products. They are as follows:

Surveillance Inspections. These cGMP inspections are conducted on a routine periodical basis of a regulated facility. These are also called cGMP or routine inspections and cover both domestic and international facilities. These inspections cover the pharmaceutical systems, namely, Quality, Facilities & Equipment, Materials, Production, Packaging & Labeling and Laboratory Control.

Pre-approval Inspections (PAI). These inspections are conducted after a company submits an application to FDA to market a new product. These inspections are performed to contribute to FDA’s assurance that a manufacturing facility named in a drug application is capable of manufacturing a drug, and that submitted data are accurate and complete. There are three primary inspection objectives of a PAI, which are, Readiness for Commercial Manufacturing, Conformance to Application and Data Integrity audit.

Post-approval Inspections. These inspections are conducted for products marketed under a recently approved application. The main objectives of these inspections are to assure that any changes in manufacturing and process control are in compliance with cGMP regulations and to assure that all changes are documented in supplemental applications or annual reports. These assignments are issued by CDER based on recommendations and risk.

For Cause or Directed Inspections. These inspections are harder to prepare for and the investigator may have a specific assignment that is not publicly available. Requests for for-cause inspections can be initiated by Office of Regulatory Affairs (ORA), CDER sub-offices, namely, Office of Process and Facilities (OPF), Office of Surveillance (OS), or Office of Compliance (OC). Once the initiating office determines a for-cause inspection is warranted, the office prepares an assignment that sets forth the areas of required coverage which may or may not include surveillance program coverage.

2. Difference Between Domestic and International Inspections

The main difference between domestic and international inspections is that FDA will issue a Form FDA 482 Notice of Inspection to a domestic firm but will not issue to an international firm. The other major difference normally observed is the time period of the inspection. A domestic inspection may easily extend beyond a week, but an international inspection normally will last for five days but may extend in case of a sterile facility or in case of for-cause inspections.

3. Have a Written Procedure

Having a written procedure that will be followed during a regulatory inspection, including one by FDA, will be of tremendous help for the responsible employees of the firm for a smooth and successful inspection.

4. Assign an Inspection Preparedness Team

An inspection preparedness team with an inspection coordinator should be assigned to ensure all relevant activities and documentation are tracked, completed, and evaluated in a timely manner. The inspection coordinator holds regular meetings with the aid of operation plans to ensure preparations for inspection are running smoothly and issues are resolved in a timely manner.

5. Documents to Keep Ready

There are some documents commonly requested by the FDA investigators and keeping them ready can help the firm focus on other requested items during the inspection. Some of the commonly requested documents include, but are not limited to the following:

• Initial overview presentation of the firm
• Site Master File
• Organization Chart up to Operator or Analyst level
• SOP Master Index
• Training procedure
• Recall procedure
• Batch numbering procedure
• List of deviations, change controls, OOS, complaints investigations and CAPAs since the last inspection
• Responses and CAPAs to prior FDA 483 Observations

It is almost certain that you will be asked about other procedures as well. Decide who makes and who keeps copies of FDA requested documents. Screen records before giving them to the FDA but do not delay delivery. If unavoidable, explain the reason for any delay. Only provide documents that FDA requests. Remove post-it notes, hand-written comments or extra pages. Make two copies of each document provided to the FDA—one for the FDA and one for the site. Mark each set as “Copy” and “Confidential.” Guard originals and keep originals nearby until they can be filed and stored properly. Have a system to trace and recover documents and to ensure their return to the originating department.

6. Keeping the Facility Ready

It is important that you always keep your facility in a presentable form to an FDA investigator. Inform employees of the upcoming or ongoing inspection. Unauthorized pages or copies of procedures on desks or walls should be avoided. Label everything—ensure equipment and signs are displayed properly, identify manufacturing equipment, and calibration stickers must be current. Remove items or equipment that are out of service; otherwise, ensure an “Out of Service” sign is displayed. Repair damaged areas—ensure there are no cracks on the walls or floors; paint damaged areas. Dispose of as much Hold and Reject material as possible. Review status labeling in all storage areas.

7. During the Inspection

A brief introductory presentation showing the history of the company, compliance history, organizational chart, headcount, hours of operation, list of products, list of major equipment and software and facility layout can be made on the first day. This will help the investigator get familiar with your site before walking into the facility for inspection. Also, the inspection will include a facility tour which will most likely happen on the first day of the inspection.

Present the FDA investigator’s question to site personnel in the “Backroom” and prepare responses before meeting with the FDA investigator. Ask for clarification if a question or request is vague. Listen carefully to what you are asked and respond directly to the question. Make sure you understand the question before you answer. Answer questions accurately and succinctly and do not elaborate or guess. Do not delay, deny, limit, or refuse an FDA inspection as it may lead to further actions by the agency as they are considered prohibited behaviors and may cause a drug to be considered adulterated as described in the FDA guidance document, titled, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection.²

8. FDA Documents Request

It is not uncommon to receive a document request from the FDA investigator, particularly before an international inspection. If you receive such a request and you have doubts, ask for clarification. Some investigators ask the firm to have all the requested documents ready on the first day of the inspection. Preference among FDA investigators in collecting documents varies to a large extent, some preferring electronic documents, and some preferring hard copies, and others preferring both formats. It is common for FDA investigators to request electronic documents in a CD, DVD or USB format.

9. Documenting the Investigator’s Request

It is a good practice to document all the requests made by an investigator during the inspection. Document Room staff roles and responsibilities should include:

• Recording, prioritizing and tracking of document requests
• Retrieving and reviewing documents
• Sorting documents
• Staging documents for investigator review
• Esuring that complete records and copies are kept of all documentation provided to the investigators
• Tacking all documents entering and leaving the inspection room

10. Backroom Support

Although it might seem like all the important activities occur in the front room, the effectiveness of the backroom management is the key deciding factor in most successful inspections. In fact, the backroom is also called as the “war room.” A well-prepared and well-organized backroom is one of the most crucial elements of FDA inspection management, enabling your firm to act quickly and appropriately to any FDA investigator’s request. Qualified consultants can provide onsite support during FDA inspections, assist in backroom management, and provide inspection preparedness training.

11. General Conduct During FDA Inspection

Here are some general recommendations for the employees to follow during the inspection:

•  Escort the FDA investigator to the conference room upon arrival
•  The senior most person on site to receive Form FDA 482 (only for domestic) and verify accuracy of FDA 482 contents; will also receive FDA 483 at the closing of the inspection, if issued
•  Explain site rules including safety rules
•  Make sure site personnel are available when FDA investigator arrives daily
•  At start of the day, ask for the agenda for that day
•  Request daily wrap-up for discussing any potential FDA concerns
•  Periodically ask investigator if he/she has received the information requested
•  Avoid unrelated discussions in the room with FDA investigator as this may distract the FDA personnel
•  FDA concern is valid, acknowledge and commit to correct in a timely manner
•  Provide evidence of corrections made during the inspection
•  It is proper to provide information on corrective actions to FDA 483, if appropriate

12. Daily Wrap-up Meeting

According to the FDA’s Investigations Operations Manual (IOM), “Investigators and analysts should make every reasonable effort to discuss all observations with the management of the establishment as they are observed, daily, to minimize surprises, errors, and misunderstandings when the FDA 483 is issued. This discussion should include those observations, which may be written on the FDA 483 and those that will only be discussed with management during the closeout meeting. Industry may use this opportunity to ask questions about the observations, request clarification, and inform the inspection team what corrections have been or will be made during the inspection process. Investigators are encouraged to verify the establishment’s completed corrective actions as long as the verification does not unreasonably extend the duration of the inspection.”¹ As the IOM recommends FDA investigators are generally not averse to conducting a daily wrap-up meeting. The firm should ask for one.

13. Close-out Meeting

Make sure that the most senior person available at the facility is sitting at the table during the closeout meeting with the investigators. This is important in demonstrating that your firm is taking the inspection findings seriously and interested in learning the inspection outcome to address the deficiencies. The close-out may include sample collections, affidavits (domestic) and issuance of Form FDA-483 Inspectional Observations. In addition to the Form FDA 483, the investigator may also verbally discuss minor deficiencies with firm management and may include the discussion items under the “General Discussion with Management” heading in the Establishment Inspection Report (EIR).

14. Response to the FDA Form 483

The FDA will generally allow firms 15 business days to provide a response to the FDA 483 observations. If FDA receives a response to FDA 483 observations within 15 business days after the FDA 483 was issued, they will conduct a detailed review of the response before determining whether to take any regulatory actions.

Form a cross-functional committee immediately to formulate responses. Responses should be as specific as possible. If there is more than one part to the observation, respond to each part. The response to the FDA 483 should include corrections to any inaccurate statements in the FDA 483. Demonstrate, if possible, how and why the existing systems in question are in conformance with GLP/GMP and, therefore, not deficient. Provide a corrective action in the response and a realistic timetable for the completion for the corrective actions.

15. Inspection Outcome

The FDA inspection outcome of a firm can have substantial impact on the business operations of the company. The FDA inspections may be classified as No Action Indicated (NAI), Voluntary Action Indicated (VAI) or Official Action Indicated (OAI), in the increasing severity order depending on the outcome. When no Form FDA 483 ‘Inspectional Observations’ is issued it is classified as NAI. When a Form FDA 483 is issued it may be classified as VAI or OAI depending on the significance of the deficiencies. OAI classifications may lead to further regulatory actions like, Regulatory Meetings, Untitled Letters, Warning Letters, Import Alerts, Injunctions and Seizures. Irrespective of the classification each inspection will have an Establishment Inspection Report (EIR) written by the FDA investigator and a copy will be sent to the firm as per FMD-145 (Field Management Directive). The investigators are also expected to report significant discussions with firm management in the EIR.

References

1. FDA, 2023 Investigations Operations Manual (IOM), https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/investigations-operations-manual, web accessed on March 27, 2023.
2. FDA, Guidance for Industry: Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection, October 2014, https://www.fda.gov/media/86328/download.

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Tamil Arasu, Ph.D., is a Principal Consultant at Lachman Consultant Services, Inc. who brings a unique background of both U.S. FDA and pharmaceutical industry experience to Lachman clients. He is an expert in cGMP and ICH guidelines and had conducted FDA pharmaceutical inspections as lead investigator in more than 10 countries prior to joining Lachman Consultants. His expertise includes APIs, sterile and non-sterile pharmaceuticals involving complex formulations, and biological products. He is co-author on more than 20 peer-reviewed scientific research articles and co-inventor on multiple U.S. patents.