IVD Technology Magazine | IVDT Article Index
Originally published March, 1997
GMP inspectional consistency: A plan for the future
Leif Olsen and Patricia Shrader
Inspectional inconsistency may be real--but it isn't inevitable. Working together, FDA and industry can take action to check inspectional problems at their source.
Inspectional inconsistency is an issue that has had a profoundly negative impact on both individual manufacturers and the medical device industry as a whole. In order to better understand this problem, the Baltimore IVD Roundtable last year created a working group on inspectional consistency, giving it the tasks of identifying instances of inconsistency, describing the causes that led to them, and recommending corrective actions (see box, page 52). The working group's inquiries brought together more than a dozen examples in which FDA inspectors had been inconsistent in their inspections of device manufacturers. Together with an extensive introduction to the problem of inspectional inconsistency, these examples were presented in the last issue of IVD Technology (January/February 1997, pp. 4451). In this issue, we turn to the working group's remaining objectives, beginning with the search for causes.
Sources of Inconsistency
It is one of the key tenets of current quality systems that the root causes of any problem must be identified before appropriate corrective actions can be determined. It was in this spirit that the Baltimore working group began its evaluation of the examples of inspectional inconsistency that it received from medical device and diagnostics manufacturers. The result was the following list of problems and errors that appear to be the most common causes of inspectional inconsistency.
Lack of Common Understanding. Perhaps the most significant sources of inspectional inconsistency revealed by the working group's report are an incorrect interpretation of regulatory requirements and a lack of a common understanding of those requirements on the part of FDA and industry. Ultimately, the source of these problems can be traced to a lack of training on the part of both FDA and industry.
Although a wide variety of resources exist for training industry personnel, not all of these are equally available or reliable. Clearly, the most authoritative source of information is FDA, but in this era of shrinking budgets even it may be hard-pressed to come up with adequate funding to support its educational activities. As a result, there is often inadequate distribution of critical information among companies that do not know how to find it themselves--a fact that can have a chilling effect in an industry where many companies are small and relatively unsophisticated with respect to regulatory affairs. The difficulty involved in identifying authoritative training programs contributes to the fact that FDA and industry do not currently share a common understanding of the good manufacturing practices (GMP) requirements.
Inadequate training of FDA investigators, field office personnel, and device center staff is also a source of this problem. In the past, industry has only infrequently been involved in training investigators and has never been asked to participate in internal training for center personnel. This is unfortunate, for while field investigators have ample opportunities to visit numerous companies and observe their practices, center personnel generally do not. As a result, these personnel may not have the same level of awareness of current industry practices as investigators and industry personnel.
Misuse of Guidances. Secondary to the issues of misinterpretation and incorrect information is the inappropriate use of FDA guidelines and guidance documents. All too often, FDA investigators treat guidance documents as though they embody the single best means for achieving a certain end. The source of this problem is twofold: failure to understand the correct application of guidance documents, and inability to determine whether an alternative procedure is acceptable. Again, both of these causes can be traced to lack of training and failure to understand current industry practices.
Lack of Centralized Review. Another source of inspectional inconsistency is the lack of centralized review of FDA-483s and warning letters. Among members of the medical device industry who contributed to the working group's report, there was general agreement that regulations were more uniformly interpreted when the Center for Devices and Radiological Health (CDRH) was responsible for reviewing every recommendation for enforcement action that originated in an inspection.
However, contributors to the report also recognized problems with the way that centralized review was previously administered. Industry representatives acknowledged that centralized review sometimes had the undesirable effect of delaying enforcement action in cases where it was merited. Meanwhile, some FDA representatives indicated their belief that CDRH was sometimes unjustifiably more lenient than inspectors in the field in determining when enforcement action was necessary.
Overzealous Investigators. On occasion, companies may encounter overzealous FDA investigators. Although they are few in number, such persons cause difficulties by engaging in a variety of counterproductive behaviors, including presenting as requirements information contained in guidance documents, insisting that state-of-the-art practices are those that the particular investigator thinks is appropriate, and bullying or threatening companies. It is not uncommon for the observations appearing on an FDA-483 issued by an overzealous investigator to be quite different from those recorded by other investigators. In addition, overzealous investigators may more frequently recommend enforcement action against companies and may portray companies as being less cooperative or less knowledgeable than they actually are.
The Baltimore IVD Roundtable Working Group on Inspectional Consistency
The Baltimore IVD Roundtable is a group of FDA and IVD industry trade association representatives that meets quarterly to identify and discuss issues of interest to the diagnostics industry and to the medical device industry generally.
At its summer 1996 meeting, the Baltimore IVD Roundtable formed a working group to address the issue of inspectional consistency with a focus on the IVD industry. Members of the working group include Ken Shelin (Baltimore district office, FDA), Leif Olsen and Ray Watkins (Association of Medical Diagnostics Manufacturers), Paul Touhey (Medical Device Manufacturers Association), Bill Gilbert (Independent Reagent Manufacturers Association), and Pat Shrader (Joint Council of Immunohistochemical Manufacturers).
In order to provide a basis for further discussions between FDA and industry, the working group on inspectional consistency adopted the following objectives for its work:
- To identify and present examples of inspectional inconsistency in the medical device and diagnostics industry, including inconsistencies among districts and investigators, in order to demonstrate that inspectional inconsistency is a real rather than a perceived problem.
- To identify sources of inspectional inconsistency, in order to best identify appropriate corrective actions.
- To recommend steps FDA and industry can take to help ensure both the reality and the perception of greater inspectional consistency.
Working group members solicited information directly from their association members and from other sources. The information requested included examples of inspectional inconsistency as well as recommendations for FDA and industry efforts to address the issue. The analysis and recommendations summarized here are results of the group's efforts.
Recommendations
To address the causes of inspectional inconsistency revealed in its report, the Baltimore working group developed and discussed a wide range of potentially useful strategies. The sections that follow detail the recommendations that the group considered most likely to resolve the underlying issues and root causes of inspectional inconsistency. Where possible, the working group also included mechanisms to monitor the effectiveness of the proposed solutions.
Develop a Joint Mission. Although it is rarely acknowledged, the vast majority of industry employees and FDA personnel share a commitment to common objectives. A primary objective of both manufacturers and regulators is to ensure that high-quality products that meet customers' needs are available for distribution in the United States. In order to attain this objective, both industry and agency personnel have an interest in ensuring that regulatory requirements are understood and complied with.
To further these goals, the working group recommended that FDA and industry work together to develop a joint mission statement with respect to agency inspections. The mission statement should seek to ensure that both FDA and industry personnel will have ongoing access to the most up-to-date knowledge about standards of practice in the IVD industry. From this common ground, documented in clear and consistent terms, industry and agency personnel will be able to make better progress toward achieving their goals. The working group also indicated its willingness to provide industry participants to work on this project.
Ongoing Training. FDA and industry should be involved in ongoing training about FDA's regulatory requirements and inspectional practices. For instance, it would be extremely valuable to have clear statements about the correct application of FDA's quality system regulation and other guidances used by field investigators, the purposes of each document, the ends they are intended to achieve, and alternative means of achieving those ends. Industry could assist in this effort by providing examples of alternative methods that have been used successfully in such areas as process validation.
Equally important, FDA investigators must be trained to focus on whether the company undergoing inspection is achieving the result intended by the agency's regulatory requirements. If a company can demonstrate that it has satisfied the intent of the regulation, the method used to do so should be less significant. In this regard, FDA investigators should place greater emphasis on determining whether a company's quality systems are present and functioning adequately than on judging the "correctness" of the system's parameters.
In order to develop and maintain a common understanding of the agency's requirements and corresponding industry practices, joint training programs should be conducted for industry employees and FDA field and CDRH personnel. Materials used to train FDA personnel should be made widely available to industry.
FDA should identify and certify agency and industry specialists in IVDs who can serve as resources for companies, field investigators, and CDRH personnel. These individuals could also serve as coordinators and clearinghouses to ensure consistent interpretation of IVD-related requirements and inspectional consistency, as discussed further below.
FDA and industry should work together to develop a checklist for conducting inspections of IVD manufacturers. The checklist should identify areas of particular importance for IVD quality systems and provide sufficient detail to ensure that inspections that are conducted by FDA investigators or third-party inspectors can be consistent. The working group is willing to participate in the development of such a checklist.
Guidance Documents. Inappropriate use of guidelines and guidance documents is a problem that FDA has already recognized and for which corrective action is under way. Although guidance documents may present an acceptable method for accomplishing a desired goal, it is important that both agency and industry personnel understand that such documents do not constitute regulations or requirements. The working group believes that FDA intends to address this issue through training, but encouraged it to solicit the active participation of industry in that training.
Centralized Review Process. Although the device center's Office of Compliance used to conduct centralized reviews of field inspections, resource constraints made this process take longer than the agency considered acceptable. As a result, the agency discontinued centralized review in order to permit field offices to take enforcement action more rapidly when necessary.
Although FDA's resources continue to be limited, the working group believes that the agency should reestablish a regularly scheduled, centralized review process for evaluating the results of inspectional activities. To address the issue of resources, the group recommended that industry representatives be permitted to participate in the review process.
The review process should include a mechanism for providing feedback on the consistency of inspectional observations and follow-up enforcement actions. With respect to FDA-483 observations, for instance, the working group could establish an industry panel that would meet regularly to review inspectional observations for companies in the same industry segment or, if appropriate, across industry. The industry panel would provide its analysis to appropriate individuals at FDA (for example, the associate commissioner for regulatory affairs and the director of the device center) to ensure that it is available both to headquarters and to district offices. The results of such reviews should be publicly disseminated using appropriate mechanisms.
Although it would be optimal to provide a review process for warning let-ters before any sanctions are imposed on a company, the nondisclosure provisions of the Federal Food, Drug, and Cosmetic Act prevent industry representatives from participating in such a process. Nevertheless, the working group encouraged FDA to establish an advance review of this type, and to make its results available to industry as appropriate.
Moderate Overzealous Investigators. FDA should discourage the activities of overzealous investigators and should assist industry in understand-ing how to deal with such investigators. FDA has already undertaken activities designed to discourage overzealous investigators. But it is equally important for the agency to provide guidance on the proper management of inspections, particularly to small companies that may lack other good sources of information. Such guidance should include the proper way for companies to deal with investigators whose demeanor or observations they consider inappropriate. The working group is willing to help develop this guidance document.
Support Joint Activities. FDA should continue to support joint activi-ties involving industry and agency representatives, and should encourage the formation of such groups where they do not currently exist. The Baltimore IVD Roundtable is serving a useful purpose in bringing together the regulators and the regulated community. The time that roundtable members spend working together offers them an opportunity to understand one another's perspectives and to establish common goals. This is a most effective means of ensuring regulatory compliance and of striving toward the ideal level playing field desired by both FDA and industry.
Conclusion
The recommendations of the Baltimore working group provide an agenda that will be a challenge to both FDA and industry. To make progress toward eliminating inspectional inconsistency, this agenda will require them to overcome resistance to change, set aside their differences, and work as partners. In an area of enforcement that can be highly charged with emotions this may be lot to ask, but the benefits of doing so will be felt throughout all sectors of the medical device and diagnostics industry.
