The FDA is Here! A Primer on What To Expect

No matter how often you experience an FDA inspection, you always get butterflies in your stomach when you hear the phrase, "The FDA is here!" You, as the primary contact person, know what to expect because you have been through numerous regulatory inspections in the past.

Gerald E. Vince

Much of your concern is centered on everyone else who may have to meet with or provide information to the FDA investigator(s). Are they prepared and do they know what to expect and how to act? The following article is intended as basic guidance to people who have never experienced a regulatory inspection, as well as a reminder for all of those who have been through the inspection process before.

FDA'S HERE! --- WHY?

The agency can inspect a firm for a variety of reasons. Some of the major reasons for an FDA inspection are:

• General Inspection (Current Good Manufacturing Practices [cGMPs]/Quality Systems Inspection Technique [QSIT])

• Pre-Approval Inspection

• Post-Market Follow-up

• For Cause Inspection (suspected problem, recall, etc.)

• Sample collection

• Others (complaint handling, Prescription Drug Marketing Act, etc.)

WHAT HAPPENS FIRST?

A plan of action should be outlined in a formally approved standard operating procedure (SOP), which defines who is responsible for performing each duty during the course of an inspection. This SOP should detail actions which may be taken during an inspection in particular situations encountered (e.g., provision of photocopies) as well as other activities outlined here.

In general, the first responsibility is for the receptionist to notify the corporate primary contact and appropriate manager of the FDA personnel's arrival. It is imperative that management and staff who may be impacted are aware that FDA is on the premises. Managers and area supervisors must ensure that all personnel in operational areas are aware that FDA is presently in the facility.

During initial discussions with FDA investigators, the primary contact should check the credentials of FDA personnel, determine the purpose and probable length of the visit, and accept the FDA-482, Notice of Inspection issued by the investigators (or at times, an analyst and/or microbiologist). The contact person should maintain a courteous and professional attitude during the initial meeting and throughout the course of the inspection. It should be kept in mind that FDA investigators are just doing their job. Therefore, it is important that you project an air of cordiality and cooperation. An adversarial approach should be avoided at all times. You don't want to alienate the investigators and make the inspection uncomfortable for all, especially the firm under scrutiny. Keep in mind that the agency maintains establishment files, and to have a reputation as confrontational will not make life easier for your company.

During the initial meeting, it is highly recommended that a scribe and/or runner be called in to act as recording secretary and expediter for document retrieval and for contacting staff who may be required to participate during the course of the inspection. It is also recommended that you explain your firm's policy with respect to photography, tape recording, and the signing of affidavits.

The primary contact is the firm's inspection facilitator. The contact's rapport with the investigators is a key factor during the course of an inspection. It is important to keep in mind that one of this person's major responsibilities is to speed the inspection process. From the firm's perspective, the time spent during a regulatory inspection is a highly disruptive period.

INSPECTION ACTIVITIES

• Although the firm's contact person may guide the investigator, it is the FDA investigators who decide how they wish to proceed. It is important, however, that the primary contact reviews plans with the investigators to ensure that essential personnel are available at the appropriate time during your inspection. It is helpful to conduct a daily wrap-up for agency and company representatives who have been involved in the day's activities to review FDA's comments from this time period and the requirements for subsequent days. After these sessions, it is recommended that the firm's management meet to prepare for ongoing inspection requirements and to discuss any corrective actions which may be implemented to address investigator observations or concerns. If concerns can be addressed promptly, it will increase the likelihood of a smooth investigational process.

• FDA investigators tend to concentrate on areas of interest to them or as pre-determined by the local FDA office. Early on in the inspection, it may be useful for the firm's personnel to use their contact network to determine the investigators' specialty areas. If the firm is aware of the individual investigator's areas of expertise, much can be done behind the scenes to facilitate the inspection.

• Copies of documentation may be requested and people interviewed.

• All documents should be reviewed prior to sharing them with FDA investigators. It is recommended that a qualified employee familiar with the firm's systems and procedures be assigned to this task. If this is an anticipated inspection, such as a Pre-approval Inspection, preparations should include a corporate advanced review of all appropriate documents. This document review can prevent surprises such as misfiled documents and post-it notes attached to documents presented to investigators. A review also provides an opportunity to understand what problems and errors are present in the documents so they can be accurately explained to the investigators. Presenting documentation in a timely manner will expedite the inspection process and provide a positive impression to agency representatives.

• If FDA requests copies of specific documents, multiple copies should be made — one for FDA and others for the firm. The exact number of copies required should be pre-established and specified in all the firm's relevant procedural documentation.

Once again, timeliness is important. Wherever possible, the availability of clerical support and dedicated photocopying equipment is recommended.

• If samples of product or materials are requested, duplicate samples should be taken and retained by the firm. Often the investigator will request to observe the sampling process. Both FDA and the duplicate sample should be taken during FDA's observation of the process. It also is likely that copies of the labeling on material container(s) will be requested. Once again, duplicates should be taken for retention by the firm.

INVESTIGATION INTERACTION

It is very useful to conduct a training session for all operational personnel, including managers and supervisors, outlining the FDA inspection process and how to interact with FDA investigators. This course may be included as part of a firm's cGMP training program. Refresher courses should be conducted periodically, especially if no FDA inspections have occurred for extended time frames. Role-playing is effective in demonstrating how to act during an FDA interview situation.

The following recommendations need to be considered by all personnel who might come into contact with the investigators:

• Relax. The investigator has a job to do, just as you do. He or she is not looking to point fingers.

• Answer questions truthfully and concisely.

• Only provide them with enough information to answer the specific question asked.

• Do NOT volunteer information. Personnel who enjoy talking about what they do or have done often say too much.

• Listen to and watch the contact person or designee for cues on how to proceed.

• If you don't know the answer to a particular question, say so. Do not "fake it." Investigators often double check responses with other people to ensure that the responses given are consistent. If you can obtain the requested data, indicate so to the investigators. Make sure you provide the desired information to the investigators as quickly as possible.

• FDA investigators often watch people performing their jobs. During facility tours managers or supervisors of areas being visited should accompany the investigators. Departmental personnel should follow all procedures as they have been trained to do, and if questioned why they do something in a particular manner, explain as best they can or defer to a supervisor.

THE INSPECTION CLOSEOUT

At the conclusion of an FDA inspection it is common practice to have a closeout or exit meeting with the investigators to review their findings, as well as their overall impressions of your firm's level of compliance with the relevant regulations and issues for which the inspection has been conducted.

This meeting should be arranged by the primary contact with sufficient advance notice to ensure that the scribe and key inspection participants are in attendance. Also, by allowing upper-level management to attend the closeout meeting, you will generate a positive impression of the company's commitment to regulatory compliance. During this meeting investigators will summarize their inspectional observations.

• If the investigators are satisfied, no documents are issued. There may be some discussions, though, concerning Q/A or Q/C system observations FDA representatives feel merit your attention, and these points may be addressed in their establishment inspection re-port. We recommend always verbally requesting a copy of the FDA inspection report, and then following up with a Freedom of Information request if your particular district does not voluntarily provide this document.

• If problems are perceived, an FDA-483 is issued and discussion of those points should be considered based on the nature of company policy and status or corrective actions.

The company may respond to FDA observations at this point, especially if an FDA-483 observation is considered inappropriate, contentious, or the observed non-compliance has been corrected. In the latter case, the investigators may sometimes choose to annotate the FDA-483.

It is essential that any promises made or action dates suggested by the firm at this meeting be kept. Keeping this in mind, many firms choose to advise the investigators that they will respond to each of the FDA-483 observations in writing.

DEFINING AN FDA-483

An FDA-483 is the Notice of Inspectional Observations, which lists those items/areas considered not to be in compliance with cGMPs. Although it is only representative of what the investigator considers a non-compliant area or issue, it does require careful evaluation by the inspected firm and must be responded to in writing, treating each observation in sufficient detail to address the concern. It is important to consider the global implications of each observation and respond from a system-wide perspective as well as from the individual example(s). The actual reply should come from the individual identified in the firm's SOP, but the draft response should represent input from all the affected units, and it should be reviewed and approved by senior management prior to issuance.

Additional Resources

FDA-483 AFTERMATH

After receipt of an FDA-483, the firm should provide a prompt, written response, outlining corrective actions or disagreement with specific observations, to the FDA district office and the investigators. If a center representative accompanied the inspection, that individual should also receive a copy of the response. A pre-established timeframe for issuance of the response should be set forth in appropriate procedures. As a general rule, many firms send at least a preliminary response within ten working days of issuance of the FDA-483. The agency will evaluate the document(s) and either indicate acceptance or non-acceptance of the individual responses. In the event of the latter, the firm should make every effort to resolve all issues with FDA to avoid issuance of a warning letter or further regulatory action.

FDA INSPECTION FOLLOW-UP

It is essential you deliver what you have promised to FDA in response to the FDA-483. All too often firms that do not follow through on the corrective actions promised find themselves in a situation where the FDA will invoke harsh regulatory or judicial measures. Establish a timetable and responsibilities for corrective actions. Most inspected firms find it beneficial to track these issues through their Corrective and Preventative Actions program. If promised corrective actions involve an extended period of time, periodic updates should be sent to the agency.

In addition, it is recommended that the inspection, FDA-483, and the firm's responses be used as a learning experience. FDA investigator have looked at your firm from an outsider's perspective, using their training and experiences at other firms during their inspection of your facilities. Their eyes may have seen things differently than yours. Much can and should be learned from an FDA inspection. To ignore the observations made by the new eyes would be a wasted opportunity for quality improvement.

A "Lessons Learned" session is an invaluable tool in communicating to staff what is being done and what can be done to correct specific issues identified during the inspection, as well as bring to light systemic problems that need to be addressed. Quite often these sessions can result in additional insight into problem resolution because the staff members that perform these particular functions understand the problem on a first-hand basis. This knowledge can be used in training personnel for managing future FDA inspections. Such training may include reviewing your internal procedures; preparing for pre-announced inspections by gathering documentation most likely to be reviewed by FDA and reviewing it to assure they are complete and as accurate as possible; and reviewing all pertinent FDA programs and guidance materials such as the appropriate compliance program(s) and inspectional guides.

Gerald E. Vince is a sr. consultant, Kendle Regulatory Affairs 301. 838.3120, fax: 301.838.3182, gvince@aacgroup.comDavid Barr is vice president, Kendle Regulatory Affairs 301.838-3120, dbarr@aacgroup.comMichael Burke is a sr. consultant, Kendle Regulatory Affairs 517.285.3572,mburke@aacgroup.com.