Announced or unannounced, an FDA investigator may show up at your door wanting to tour the laboratory, look at your files, talk to staff, and collect evidence of your compliance with GxP requirements.
What happens post-inspection will depend not only on clinical matters but how you handle the inspection process. This is why preparing for GxP inspections is a crucial responsibility for lab management.
GxP inspections and why they matter
FDA GxP regulations require producers of drugs, medical devices, laboratory tests, and other life sciences products to meet strict safety, product effectiveness, and data integrity standards:
- G—means “Good”
- P—means “Practice”
- x—is a variable referring to an aspect of operation subject to audit.
FDA GxP inspections of laboratories typically focus on:
- Good Clinical Practice (GCP), or safety and design standards for clinical trials on humans
- Good Laboratory Practices (GLP), or standards for research and development of drugs, devices, and biologics
- Good Manufacturing Practices (GMP), requiring or implementation of production quality management systems, processes, and standards.
When FDA investigators observe GxP violations, the individuals responsible often lose their jobs. The laboratory may also receive an FDA Form 483 warning letter. The FDA can even halt your operations until you correct the problem. In addition to delays and disruptions, noncompliance can lead to monetary penalties and unfavorable publicity.
Maintaining GxP standards is also integral to maximizing product quality and consistency, reducing risk of product failure, and preserving organizational knowledge, data integrity, and accountability.
The Three Kinds of GxP Inspection
Inspection procedures and objectives differ depending on the kind of inspection involved:
During a GCP inspection, investigators evaluate compliance with reference documents to verify that the data generated during clinical trials is reliable and that the subjects’ rights are being protected. They may also review standard operating procedures (SOPs) for managing clinical trials, development of protocols, and amendments and procedures for deviation, selection of investigators, and randomization of subjects.
During a GMP inspection, investigators inspect the building(s) where the product is manufactured to see if the facilities meet regulatory requirements. They also evaluate whether the equipment used to manufacture the product is properly designed, maintained, and cleaned and that appropriate health, safety and sanitation are in place to protect personnel.
GLP inspections vary depending on type of GLP audit:
The GxP inspection process
Effective FDA inspection management starts with an understanding of the inspection process:
Notification: The FDA may inspect without notification, such as when inspection is for cause, or you have a history of violations. If you get one, the notification will tell you when investigators are coming. Tip: Start dates are generally not negotiable absent of extraordinary circumstances.
Arrival: Like any visitors, FDA investigators will show up and meet your receptionist, secretary, or security staff. Best Practice: Ensure front-line personnel are prepared for investigators’ arrival and know whom to notify.
Opening meeting: Investigators will first meet with your “most responsible person”, who is legally responsible for the facility’s operation, to present their credentials and badges. Best Practice: You are not allowed to copy credentials or badges but may record investigators’ names and identification numbers.
The investigator will provide the FDA 482 Notice of Inspection and describe the inspection’s purpose and scope. Best Practice: If the inspection will last longer than a day, have the most responsible person ask investigators to provide a brief progress report at the end of each day.
Opening tour: FDA investigators typically do a quick walking tour to form a first impression of cleanliness, orderliness, etc. Best Practices: Keep the touring party small and prepare a brief (no more than 30 minutes) slide show presentation describing your laboratory, products, facility, key management personnel, etc.
Actual Inspection: Investigators will collect evidence of your compliance via visual observation, records review, interviews with subject matter experts (SMEs) , and collection and analysis of samples, photographs, videos, and audio recordings. Best Practices:
- Escort investigators at all times
- Make copious notes of everything they say and do
- Make a list of all documents investigators ask for and all documents you provide
- Keep copies of all documents provided.
Closeout meeting: After completing the inspection, investigators will go over the results and give you a list of any significant observations on the FDA-483 form. They will discuss each objectionable condition observed and let you agree or disagree. Any statements you make are on the record and may be used against you. Best Practices: The closeout meeting is crucial and should be attended by:
- The most responsible person (or next highest-ranking person if the former is unavailable)
- The escort
- Individuals responsible for corrective actions and
- Your legal counsel
Prepare staff for GxP inspections
To manage the inspection process, create an inspection response team with eight clearly defined roles:
Point of contact (POC): Start with the person that investigators will first encounter when they visit your facility. Responsibilities: Greeting the investigator professionally and notifying the inspection response and team leaders of the investigator’s arrival. Best Practices: Have trained POCs at each entrance investigators may use and script the POC’s reply and notification to team leaders.
Most responsible person: Under FDA regulations, this must be the individual who is legally accountable for the facility’s operations. Responsibilities: Meeting with investigators to receive their credentials, accept the FDA 482 and pledge cooperation, and being present at the closeout meeting. Best Practices: The most responsible person should not also be the leader of the inspection response team, unless your company is very small.
Response team leader: This is typically a laboratory or quality control manager, attorney, or other senior person. Responsibilities: Making final decisions on responding to investigators’, requests, deciding whether to release documents, and communicating with investigators via a spokesperson. Best Practice: The response team leader should have decision-making authority, deep familiarity with operations, and knowledge of FDA inspections.
SMEs: You need technical experts to provide nuts-and-bolts information about your systems and operations. Responsibilities: Being available to investigators for interviews during inspections. Best Practices: Having a SME for every aspect of your operations that is likely to come under scrutiny and choosing SMEs based not just on their knowledge but also their likely performance during inspection interviews.
Escorts: Their role is to accompany investigators at all times, look after their needs, guide them to the right places, connect them with SMEs, and tell the response team how the inspection is going.
Spokespersons: Include a high-ranking official who can speak to investigators on the company’s behalf. Responsibilities: Politely and legally refusing investigator requests and explaining the grounds for refusal. Best Practices: If possible, designate in-house counsel as spokespersons. While spokespersons should not also be escorts or most responsible persons, they may act as both spokesperson and response team leader.
Scribes: A relatively junior person who chronicles the inspection. Responsibilities: Taking detailed notes of everything investigators say and do and summarizing the notes at the end of each day.
Runners: Another junior position that involves locating documents, finding SMEs, letting department managers know when investigators are entering their area, and being available for other logistical tasks.
Perform a mock inspection drill
Once you assemble your inspection response team, you can assess its effectiveness by staging a mock inspection that simulates real inspection conditions. In addition to letting team members practice their roles, mock inspections enable you to preemptively identify and correct problems that may arise during an actual inspection.
The exercise should be as realistic as possible, with a mock investigator who knows the FDA inspection process asking the same questions, requesting the same documents, and looking at the same things a real FDA investigator likely would. Mock investigators should make careful observations and identify strengths and weaknesses of personnel and response mechanisms. Best Practice: Have outside people with knowledge of your laboratory’s systems, including their vulnerabilities and weaknesses, play the role of FDA investigator.
Surviving an FDA GxP inspection takes more than rigorous adherence to GxP requirements. It also requires the capacity to handle and avoid potentially crucial mistakes during the inspection process. By designating roles to specific individuals throughout the organization and implementing the best practices outlined here, lab managers can ensure their teams are always prepared for an inspection.