Effectively Managing FDA Inspections

Successfully managing an FDA inspection begins with the development of a clear company policy which defines the role and responsibility of all company employees during an inspection. Since the vast majority of FDA inspections are unannounced, it is imperative that employees be trained frequently on this policy.

The following are the key elements to prepare your company for a successful FDA Inspection.

Guidelines for Greeting the Inspector

• FDA personnel may arrive at the Company without prior notification. Company personnel must be prepared at all times for an unannounced inspection. Regular company business will continue as normal during the regulatory audit.
• When the investigator first arrives, he or she should be brought to the main office to provide identification and request entry into the facility.
• The receptionist shall ask the investigator to wait until the company liaison, the Director of Quality, is located and made available. In the event that the Quality Director is unavailable, the next available person as per your predefined policy should be located and summoned to meet the Inspector. The list usually includes the Director level or higher of the following functions:
  • Regulatory Director, Quality Assurance Manager, or Production Manager
• The company President must also be informed of the Inspector visit immediately.

Employee Conduct During an Inspection

• FDA inspections may not delve into Company financial, business, or planning information, or audits by or for the Company performed to self-monitor compliance such as internal audits.
• At all times during the course of an inspection, employees should be cooperative, avoid conflict, and terminate or redirect inappropriate discussions.
• Only information specifically requested by the investigator should be provided.
• The Company Representative should be the sole contact for requests of documents, samples, or information. The Company Representative will assist the investigator and make all reasonable efforts to meet appropriate requests.
• Cameras, video cameras and electronic recording devices should not be allowed during any part of the inspection. If, upon refusal to use these recording methods, the investigator obtains a court order to permit such use, the Company liaison will arrange for duplicates to be made by the Company of anything photographed or taped.
• Company employees shall notify the Director of Quality immediately if approached by an FDA investigator outside of normal business hours (i.e. after 5:00 p.m. and/or outside of the facility on the company grounds. The employee contacted should advise the FDA Investigator of the company’s inspection policy that authorizes employees to discuss company matters with FDA only during normal business hours. If the inspector wishes to remain on site, the employee should escort the Inspector to a conference room and remain with the Inspector until the proper Company Representative arrives to take over the Inspector visit.

Inspector Information Requirements

• The Company Representative shall immediately notify a designated individual, who in turn, will assure that all relevant managers and departments are aware that the FDA inspector is on the premises. Following notification by the designated individual, the Company Representative should proceed without delay to meet the FDA investigator and attend to his/her requirements.
• The FDA investigator must present a notice of Inspection (FD-482) and should offer proper FDA credentials upon request. If the investigator does not present a FD-482 or credentials, the investigator should not be allowed to begin the investigation until the investigation coordinator authenticates the person’s identity with FDA Field Operations.
• Any persons accompanying the investigator must provide identification along with their purpose for requesting entry and authority to enter.
• Should such persons not be affiliated with the FDA or another authorized governmental agency, the Company Representative must evaluate the circumstances and determine whether approval is granted to the facility.
• The names and affiliations of all persons entering shall be documented. The decision to allow entry to such persons shall be based upon the impact on the Company, including the disclosure of proprietary information and the effect on goodwill.
• Upon presentation of proper credential verification, entry must not be refused to the investigators during normal business hours. Once credentials have been approved for the investigator(s), reentry on subsequent days of the same inspection does not require additional approval.
• Under no circumstances should the investigator(s) be allowed to tour or inspect any areas of the facility without being accompanied by a Company escort.

Typical Protocol During an FDA Inspection

• Ideally, an empty conference room or office should be made available to the FDA investigator to review records and serve as the base of operation while the inspection is being conducted.
• The Company Representative shall attempt to determine from the investigator the scope and purpose of the inspection. This allows the Company Representative to organize the visit properly to determine the approximate length of time the Investigator will need to be on site to complete their assigned visit purpose. During the visit, the Investigator will need to do a proper document review, conduct appropriate interviews, and other inspection activities. Keep in mind that the Company Representative will also need to provide adequate time for a brief company orientation and allow time to answer any other questions the Investigator may have in order to conduct the Investigation.
• Company policies and procedures that will or may have an impact on the inspection shall be reviewed with the investigator including: Access to restricted areas, restricted behaviors including the wearing of lab coats (in required areas), the absence of food or eating in animal labs, no smoking, etc., policy prohibiting the use of cameras, tape recorders or other audio and/or photographic equipment, requests for copies, materials, and/or drug samples must be made through the Company Representative.
• The inspection usually involves a combination of physical plant inspection and document and record review, including complaints, production records, QC records and storage and shipping records. The investigation may also delve into procedures related to equipment and process controls and vendor and design specifications. Employees shall cooperate in accommodating the investigator’s lawful requests while assuring that conditions necessary for the continuing conduct of business are not jeopardized.
• The Company Representative and assistant(s) accompanying the investigator must keep a detailed record of dates, times, areas inspected, any observations made, questions or remarks by the FDA investigator, and responses or remarks by any employee during the inspection. Duplicate copies of all material provided to the investigator shall be retained by the Company Representative.
• During the Inspection, the company liaison will request that the investigator(s) identify areas, procedures, or documents as they are discovered which are judged as not good practices. When corrections can be made during the inspection, the investigator(s) should be informed and shown that correction has been effected.
• After the FDA investigator has departed the facilities, the Company Representative shall provide a briefing to Senior Management at the end of each inspection day. If there were any findings during the days inspection, the company representatives will assemble the managers of the department(s) impacted by the noncompliance and will, when practical, prepare and implement the appropriate corrective preventive actions.
• The corrective preventive actions will be reviewed with the FDA inspection at the start of the next inspection day. The company’ s intention is to close out all noncompliances prior to the completion of the inspection. This will demonstrate to the inspector the company’s commitment to quality, as well, provide the company with the opportunity to review the proposed corrective action with the inspector and make any corrections should the inspector feel the corrective action is not appropriate.

Information and Drug Sample Requests

• When copies of records or documents are requested, company personnel shall photocopy requested records and reports. FDA personnel should not be allowed to make copies nor are they allowed to take original data.
• Requests for access to and copies of records and reports related to pre-clinical and clinical data conducted under the provisions of an IND are permitted under FDA authority. All copies must be marked “CONFIDENTIAL.”
• All materials given to the investigator shall be documented and listed by document title and number. The Company Representative shall maintain a complete set of copied records and reports.
• No raw data or original documents may be taken off-site by the investigator. The original documents should not be written on by the investigator. Photocopies made on site may be released to the investigator, after being marked, as appropriate, as “Confidential” and/or “Proprietary.”
• Raw material, product samples or any other samples provided to the investigator shall be listed by name, lot or batch number, and quantity on the FDA form (FDA 484). The company shall retain a triplicate sample from the same lot for confirmatory testing. After the inspection is completed, a Freedom of Information Request shall be made to the FDA laboratory for a copy of their test results. The company may bill the FDA for samples taken.
• Actual labels and labeling, (e.g. package inserts) and packaging may be collected by the investigator. Duplicates should be collected for the Company Record of the Inspection.
• The investigator(s) may ask for customer names and shipping records of products sold. This information should be provided. However, complete customer lists should not be provided during a routine inspection since this is confidential business information.

Exit Interview Protocol

• Upon completion of the inspection, the Investigator will present a written FDA form (FDA 483) that contains a list of any negative observations that the investigator believes constitutes violation of Food and Drug law.
• Senior Management, the Company Representative and other company personnel with responsibility in the areas inspected should attend this meeting. The Company President should be present for the exit interview and review of a 483.
• Extensive notes of the meeting shall be taken by company personnel. Company Representatives must ensure that all 483 items are understood and should ask clarifying questions as appropriate.
• Any preliminary verbal response to a 483 observation should be brief. It is not appropriate to vigorously argue a point with the FDA investigator during the exit meeting. If corrective action on an observation has been taken during the course of the investigation, this should be duly noted at this time.
• If it is felt that a 483 observation is in error or the result of a misunderstanding or incomplete information, the proper documents that support the company’s position shall be presented for review at this time. If an issue remains unresolved, request the investigator to annotate the FDA 483 and his Establishment Report to reflect the differences.

Post Inspection Protocol

• The company Representative shall prepare a written report and maintain a file of the subjects, operations, documents, and activities that were inspected and/or performed during the FDA inspection.
• The file shall contain duplicate copies of all records copied and taken by the FDA investigator. The report shall be reviewed by senior management and maintained by QA and should contain the following:
  • Reference the date of inspection and name(s) of members of inspection team, reason for written response, response to each cited deficiency, including observations resolved/corrected during the inspection and observed by the Investigator(s), description of preventive and corrective action to be taken regarding each observation for those items not resolved at the time of written response and a schedule for completion, items still in dispute between the company and the FDA shall be addressed with necessary supporting information and documentation.
  • The Quality or Regulatory Director shall submit the written response to the FDA within ten working days of the exit interview.
• After the inspection, the FDA investigator will write a narrative report called the Establishment Inspection Report (EIR). The Quality Director shall send a Freedom of Information (FOI) request for both a purged (confidential information removed) and an unpurged copy of the EIR. This should be sent directly to the FDA Freedom of Information Office in Rockville, Maryland.
• The Quality Director shall review all information received from the FDA after the inspection and coordinate all communication with the FDA. Any incorrect information should be communicated in writing to document the company’s position.

In conclusion, a successful FDA inspection begins with operating your facility in compliance, detailing your inspection plan, training on the plan and having everyone in your organization understanding his/her role in the inspection. We wish you the best of luck in your upcoming Inspections!

About the Author

Ed is the President and CEO of PCI Synthesis (PCI), he serves as a co-chair of the New England CRO/CMO Council and sits on the Industrial Advisory Board for the Department of Chemical Engineering at UMass, Amherst. Ed is also a long standing member of the American Chemical Society and advises the Bulk Pharmaceutical Task Force of the Society of Chemical Manufacturer’s and Affiliates (SOCMA).

Do you have questions? Talk to Ed.