When an FDA investigator walks into your facility and informs you 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, operating in a state of being always inspection ready can bring the anxiety of the employees at the site down to some extent. FDA publishes the Investigations Operations Manual (IOM) annually and Chapter 5 of the IOM covers ‘Establishment Inspections’ which provides complete details for the investigators to follow during an FDA inspection. In this series of blog posts, we will be focusing on drug inspections and will cover a number of items that firms should be aware of and have prepared in advance to be assured that they are always inspection ready.

Types of FDA Inspections

FDA conducts four (4) types of inspections in a pharmaceutical facility to help protect consumers from unsafe products. They are:

  1. Surveillance Inspections: These cGMP inspections are conducted on a routine periodical basis of a regulated facility. These are also known as cGMP or Routine inspections and cover both domestic and international facilities. These inspections cover the six (6) pharmaceutical systems, namely, Quality, Facilities & Equipment, Materials, Production, Packaging & Labeling and Laboratory Control.
  2. 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 assure FDA 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 (3) primary inspectional objectives of a PAI, which are: Readiness for Commercial Manufacturing, Conformance to Application, and Data Integrity audit.
  3. 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 all 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.
  4. For-Cause or Directed Inspections: These inspections are harder to prepare for and the investigator may have a specific assignment that is not available to the public. Requests for for-cause inspections can be initiated by Office of Regulatory Affairs (ORA), or CDER sub-offices, namely, Office of Process and Facilities (OPF), Office of Surveillance (OS), or Office of Compliance (OC). Once the initiating office determines that 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.

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 PAIs.

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 that document to an international firm. The other major difference normally observed include the time period of the inspection. A domestic inspection may easily extend beyond a week, but an international inspection normally will last for five (5) days but may extend in case of a sterile facility or in case of for-cause inspections.

There has been a lot of recent debate among lawmakers and the GAO (Government Accountability Office) regarding the need for unannounced foreign inspections. Despite their being some logistical issues to perform these, nevertheless, as of April 2022, FDA has resumed these in certain geographic regions (India). They have not been able to do so in China due to Covid restrictions remaining in place there.

Have a Written Procedure

Having a written procedure in place that will be followed during a regulatory authority inspection (including that of FDA) will be of tremendous help for the responsible employees of the firm in order to assure a smooth and successful inspection.

Assign an Inspection Preparedness Team

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

Documents Preparedness

There are some documents commonly requested by the FDA investigators and keeping them constantly and consistently available and updated can help the firm focus on other items that might be requested during the inspection that are not anticipatable. 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
  • List of products
  • 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 a firm will be asked to provide FDA with other procedures as well. It is a good idea to decide who makes and who keeps copies of documents requested by FDA well in advance of FDA being onsite. Screen records prior to giving them to the FDA but do not delay delivery. If a delay in unavoidable, explain the reason for the delay. Also, only provide the exact documents that they requested and nothing else. Remove post-it notes, hand-written comments or extra pages. Make two (2) copies of each document provided to the FDA – one (1) the FDA and one (1) for the site. Mark each set as “Copy” and “Confidential”. Guard originals vigilantly and keep the originals close until they can be filed and stored properly. Have a robust system in place to trace and recover documents and to ensure return to originating department.

Keeping the Facility Ready

It is critically important that you always keep your facility in a presentable form to an FDA investigator, even when FDA is not on site. As soon as is practicable, inform employees of an upcoming or ongoing inspection. Unauthorized pages or copies of procedures on desks or walls should be avoided. Label everything – 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 that there is an “Out of Service” sign displayed. Repair damaged areas – 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.

Qualified consultants can provide inspection preparedness training and help ensure that your facility is always inspection ready. In the next installment, we will describe best practices for personnel interfacing with during an inspection, points to consider regarding conduct when interacting with FDA, and dos and dont’s of responding to FDA questions and document requests during an inspection.

Stay tuned for part 2!