by James A. Hartman, Retired GMP Institute Senior Consultant
The touch on the shoulder and the whispered words, "Wake up, there's someone in the house!" cause the homeowner to feel a sudden spasm in the pit of his stomach and a dryness in his throat, followed by a sensation that "something is expected of me, but I'm not sure just what." The householder finally awakens as he realizes that all of the precautions he has taken to exclude unwanted intruders have gone for naught.
All too often, the same initial reaction is exhibited by the plant manager whose assistant has just whispered "There's an FDA inspector in the lobby." Unlike the homeowner, however, the plant manager should then feel only that the time has come to "test the system" and hence to find out just how good the preparation for FDA's visit has been. For the FDA inspector, far from being an intruder, has a legal right to be in this plant, and the results of his or her inspection will depend largely on three steps that the firm should already have taken. In short, it is assumed that the firm has (1) designed and installed effective quality assurance systems and procedures; (2) implemented an internal audit program to ensure that the desired results are being obtained on an ongoing basis; and (3) made arrangements to guarantee that regulatory inspectors will be courteously received and adequately looked after during their visits, and that appropriate follow-up action will be taken at the conclusion of each visit.
Many companies manage steps one and two very nicely but then stumble at step three. This is unfortunate, as there is unquestionably a need for policies and procedures that will bring a high level of professionalism to the task of hosting visitors. Consequently, this article will describe the best composite practice a device manufacturing firms in the highly critical area of hosting regulatory inspectors.
Assuming that a firm's total GMP/quality assurance program is adequate, there are several steps that management must take to supplement the three steps that have already been delineated. Specifically, the firm must (1) accept the inevitability of inspections and assume that they will occur at the most inopportune time; (2) learn as much as possible about the why, how, who, when, and what of inspections and about the legal rights of the firm; (3) develop a corporate policy and a set of procedures governing inspections, and include positions on potentially controversial issues; (4) designate and train inspection coordinators to serve as hosts at each facility; and (5) analyze the results of each inspection to determine how the program can be strengthened for the future.
Why Are Inspections Conducted?
Preparations for hosting regulatory inspectors must begin with an understanding of the purpose of inspections. The objective in this case is expressed quite clearly in FDA's Inspection Operations Manual. Section 546.2 of this manual, which relates to medical devices, states that the objective of a device inspection is to "identify dangerous or otherwise violative units in order to protect the consuming public." (italics added). The emphasis here is on ensuring the fitness for use of the product and securing the correction of deficiencies found in regulatory audits.
Formulating a Written Policy
Given the aforementioned objective, together with the obvious requirement that a company be prepared to explain and defend its internal procedures, it becomes evident that a firm's inspection-response program must encompass certain key elements - the most important of which are written policies and procedures on issues pertaining to inspections. Translation of such matters into writing ensures that all relevant policies will be well thought out and that senior members of company management will approve both the policies and their implementation. In addition, standard operating procedures in written form can be readily communicated to all who are involved in hosting regulatory inspectors, thus ensuring uniform application of such policies throughout the firm. Finally, written policies and procedures provide a basis for periodic review as regulations and other factors change through the years.
In formulating its corporate policy toward inspections, the firm should make it clear that there will be full cooperation within the law with all properly constituted inspections. "Full cooperation" means just that - it includes complete responses to valid questions, a lack of defensiveness, an openness to the investigator's point of view, and, in general terms, projection of a professional and businesslike attitude. The written policy must, in addition, clearly state who is responsible for coordinating inspections in each facility; this can be defined in terms of a specific position in the organization or by the name of an individual. The procedures must then delineate the method that is used to select and train such personnel.
It should be noted, however, that no matter how well trained inspection coordinators may be, there will come a time when some help will be needed from others in the organization. Thus a firm should establish procedures to ensure that representatives of the corporate quality, regulatory affairs, and legal departments are immediately informed that an inspection is taking place and are told what the purpose of that inspection is. These individuals and other corporate staff and management personnel may have to be available for consultation; indeed, in some companies, quality assurance and regulatory affairs management personnel actually come to their plants to take an active part in the inspection process. Obviously, the more thorough a firm has been in preparing for inspections, the less necessary it will be for such individuals to be come actively involved in this way.
Formulating Positions on Controversial Issues
A good approach toward reducing dependence on staff groups is to arrive at corporate positions on potentially controversial inspection related issues. Failure to adequately consider such issues in advance can result in the firm's relinquishment of information to which the regulatory agency is not entitled. On the other hand, an unnecessarily restrictive position on an issue can cause a firm to appear uncooperative or result in a charge or refusal in part to permit an inspection. Although a firm should consult with its lawyer on the legal issues involved in such matters, some simple rules can be suggested.
Lists of Records
Above all, lists of records should be prepared, and these lists should be divided into three categories: (1) those to which the agency is entitled by law; (2) those that need not be shown from a legal standpoint but could be shared if they are clearly in the best interests of the firm; and (3) those that would not be shown under any circumstances. The location and form of the records in the first two categories should be indicated in these lists so that the coordinator can readily retrieve any of the records. At times, however, an effort should be made to limit the quantity of records delivered to the inspector. For example, if the goal is to demonstrate that the firm is involved in interstate commerce, FDA need not review all of last year's distribution records. If however, one is concerned about the adequacy of the product-retrieval record system, an in-depth review may be appropriate. In either case, a note should be made as to which records were seen by the investigator.
Most firms allow FDA access to company copying machines if the agency wishes to make a reasonable number of copies of appropriate records. Inspectors may offer to pay for copies, but this is seldom required unless the number of copies to be made is quite large. It may be preferable to have someone make copies for the inspectors, so that a second copy can be made and kept for attachment to the inspection coordinator's report. Some companies request that investigators initial and date the back of each original that is copied.
All sensitive information should be marked confidential, and this fact should be called to the attention of the inspector so that there is a reasonable chance that the information will not be disclosed under the Freedom of Information act. Such claims can be made in advance or at the time of the inspection, but too many claims of confidentiality tend to invalidate the whole process.
Samples of Items.
Most companies are willing to provide FDA with a reasonable quantity of samples of small items at no charge. A common limit beyond which payment is requested is $50.00. Most companies also make it a policy to retain duplicate samples for their own use. The inspector should be asked what testing will be done on the samples so that this testing can be duplicated in the firm's laboratory. A firm might also ask for the results so FDA testing so that a comparison can be made with company data.
Photographs on Inspections.
The question of a policy on photographs is complex and widely debated. A firm should nonetheless formulate some policy on this issue, because sooner or later an investigator will wish to take photographs during an inspection. More and more companies are clearly stating, as part of their initial interview, that a "no-photographs" policy exists.
Questioning Non management Personnel.
Regulatory inspectors may wish to question nonmanagement employees, and this can become a concern. A good policy is to state, "No questions on the job if there is any risk of interference with the task being performed." A firm can offer to have an individual temporarily relieved so that a discussion can take place away from the job site. However, it should be made clear that questions outside the individual's sphere of responsibility will be intercepted by the inspection coordinator, who should be present at all such interviews.
The Inspection Coordinator
The role of the inspection coordinator is a highly critical one. For this reason, each large facility should have a primary inspection coordinator and at least two backup personnel. In a smaller firm, the manager usually carries the responsibility of inspection coordination, but a backup person should be designated in the event that the manager cannot be present at an inspection. In larger facilities, the best candidate for the primary role is the plant's quality assurance manager. Many firms insist that the plant manager coordinate the inspection, but this individual may not be sufficiently familiar with the details of day-to-day plant operation.
The responsibilities of the inspection coordinator seem quite simple but are in fact highly complex. The coordinator's first duty is to stay with the inspector at all times. One exception to this rule might occur when the inspector is involved in a lengthy review of records, for which purpose he or she must remain in a conference room. Even in this situation, however, the coordinator should be available to explain or interpret items.
The coordinator must also provide the firm with a consistent approach toward problems and procedures; in this way, he or she can minimize the chance that contradictions will arise. It is also quite useful to have a second person accompany the inspector at all times; a good choice for this duty is one of the backup coordinators. This individual is valuable in that he or she can leave the inspection group for various purposes - e.g., to obtain information that is not at hand or to inform others of the progress of the inspection. Key managers of various departments should also be involved; however, if too many people are present, the inspector may feel that management is unduly concerned with the outcome of the inspection or that the firm lacks confidence in its coordinator. The coordinator must always remember that he or she is the company, as far as the investigator is concerned; indeed, a firm's attitude toward regulatory compliance will be judged largely on the basis of the coordinator's attitude. The coordinator must therefore be able to speak with authority and confidence, and yet, when necessary, be willing to say, "I don't know; I'll arrange to get the information for you," or simply, "That is beyond my authority."
The coordinator must also interact with other company employees - those working in the plant as well as those in staff groups. Questions posed by the inspector must be guided to people with both the knowledge and the verbal skills to answer them, and inappropriate questions must be challenged immediately. The coordinator must communicate inspection results on a continuing basis; then, once the inspection has been completed, he or she should summarize the results more formally.
Any individual who hopes to assume all of these responsibilities must possess knowledge and skills in several areas. Above all, he or she must thoroughly comprehend the Federal Food, Drug, and Cosmetic Act and its relevance to the products being inspected. An understanding of the current good manufacturing practices and other regulations is equally important. Finally, the coordinator must understand both FDA's inspection authority and the approach that the agency takes during inspections; to do so, he or she can attend internal or outside seminars and peruse the FDA Inspection Operations Manual, which is available under the Freedom of Information
Other important areas of knowledge include (1) company policies and procedures, particularly those relating to potentially controversial issues; (2) All aspects of plant operation and of the quality assurance system (particularly important here is the rationale for the choice of a certain approach when the regulations permit options by using words such as adequate or sufficient); and (3) inspection do's and don'ts.
Many coordinators have found that a good way to prepare for an inspection is to put together a booklet or a reference folder - one that contains "refresher" type information and other material that may be required during the inspection. Such information can also be invaluable if it becomes necessary for one of the firm's backup personnel to host the inspector. It is recommended that the following items be included:
Undoubtedly, each firm can add to this list on the basis of its won experience. It should be noted, however, that if a firm's inspection coordinators prepare reference folders, a decision must b made as s to which items will be given to inspectors, which might be shown to inspector, and which will be for the exclusive use of the coordinator.
Another key area of preparation should involve everyone in the firm who might reasonably to contact the inspector. In short, all such individuals must be acquainted with the procedures to be followed during the inspection, and all must understand the role of the inspection coordinator. It is also useful to familiarize these individuals with a list of inspection do's and don'ts. Items such as the following are often included in such lists:
Although the reasons for most of these recommendations are self-evident, the last item warrants some additional comment inasmuch as it has some interesting implications. If a facility is located at some distance from commercial eating establishments, it is perfectly appropriate for the firm to offer an inspector the paid use of the company cafeteria. The concern here is more with uncontrolled exposure of the inspector to situations in which chance remarks might be overheard and misinterpreted. To avoid such situations, one can take the inspector to a separate table or eating area. Normally, however, the inspector will want to use this time to update notes, call the office, review the file, or perform other activities, in which case he or she will leave the facility during lunch hour.
In the same vein, it is highly recommended that clip-on badges be given to all visitors - not only to inspectors. Firms should also review all appropriate safety and sanitation requirements as part of the opening interview. Inspectors are usually very sensitive to internal rules in these areas.
One final task of the inspection coordinator is to provide appropriate follow-up and response. This should begin during the exit interview, which involves the plant manager, the inspector the coordinator, and other key management personnel. This meeting is highly critical to the whole process; thus, attentiveness, tact, responsiveness, and good note taking are musts.
At the meeting, the investigator reviews the results of the inspection, in addition, he or she may leave a 483 if potentially violative conditions have been observed. If corrections have already been made, these should be called to the attention of the inspector. A request to note the corrective action on the 483 can be made, but the inspector is under no obligation to comply with such a request. Finally, any misunderstandings about the facts of an observation must be cleared up at this point. Alternately, a firm may "agree to disagree" and may want to communicate the disagreement to the FDA district office. A good coordinator will resolve issues of this type during the inspection, thus avoiding confrontations in the exit interview.
After the inspector leaves, the coordinator should prepare a detailed report, including:
The inspection should be discussed with appropriate corporate staff groups; topics stressed should include the inspection's emphasis and any comments that were made. Calling together the appropriate line and staff managers to critique the inspection will also be of value. Such a meeting gives the firm an opportunity to further improve its compliance status and its handling of inspections.
A formal response should be made to the FDA district office on all 483s. Corrective actions taken should be described, and if there is disagreement with either the facts of an observation or the significance of these facts, such disagreement should be noted. It might be beneficial for a firm to request that its response be filed with the 483 and that this response be released if a request for the 483 is made under Freedom of Information regulations. It should be remembered that one of the stated purposes of an inspection is to secure correction of deficiencies. Prompt response on a 483, while not legally required, can help convince the agency of the firm's good intentions and can thus reduce the chances that further regulatory action will be taken.
FDA, too, does some follow-up. For example, a detailed establishment-inspection report is prepared by the agency and placed in the company file; this report is also available for release under FOI regulations. Some companies routinely request copies of this report - often through a third party, so that the company can determine how thoroughly proprietary material has been purged. Immediate requests for establishment-inspection reports are not recommended, however, since such requests alert other companies and organizations to the fact that an inspection has taken place. The question is one of balancing the risk of alerting competitors or the media to the inspection against the benefit of having the material. However, the firm should definitely obtain a copy of the establishment inspection report if it is discovered that someone else has already requested one.
This article has outlined, in abbreviated form, some of the more salient aspects of a rather complex and extremely important subject. As you develop your own plans for hosting regulatory audits, you can obtain further assistance from a variety of sources. Quality assurance and regulatory compliance personnel from other firms, for example, are almost always willing to discuss their policies and procedures. A number of GMP quality assurance consultants are also available, and these individuals can be very helpful. A manual covering this important area can be purchased through the organization that publishes the Pink Sheet and related newsletters, and the FDA Inspection Operations Manual can be obtained as well. And the Health Industry Manufacturers Association offers a film and an instructors' guide on the subject of inspections.
In summary, it could be stated that through preparation, development of written policies and procedures governing the handling of inspections, and care in the selection and training of coordinators are the keys to a successful inspection.