This paper discusses the rationale for and some aspects of the substance of consulting services that can be provided to firms in the pharmaceutical and related industries in the broad area of GMP compliance.
Firms in the industries regulated by the FDA have special requirements for assistance with compliance. The language of the principle articles of 21CFR is crafted in very generalterms. It needs experienced and careful interpretation to avoid excessive and cumbersome application. This applies to matters of plant operations, facility design and construction projects, and product quality assurance activities in addition to the complex issues of drug discovery, development, and marketing approval. The ovearching criterion provided in the code is the requirement for cGMP, however the determination of what is compliant (or not) is not explicitly stated. The codes are in effect a "performance specification" i.e. they define the result that is needed without stating the specific method to achieve that result.
The language of the codes is structured this way purposefully. It provides a fairly wide latitude of interpretation to the industry so that a single rigid requirement for all companies is avoided. Such a single requirement would certainly stifle innovation. In fact it would be completely impractical given the diversity of manufacturing cultures, products, facilities, and financial strengths of the several hundred large and small companies that make up the industry. The broad language also provides the FDA with latitude to administer the compliance with judgement rather than literal fact, a factor that is sometimes frustrating to the industry, but also at times provides a practical approach to handling a complex issue.
Given the varied interpretation, and the fact that individual FDA inspector judgement influences what is perceived to be GMP compliant or not, what should a plant operator in the FDA regulated industries do to minimize the cost of GMP compliance. In the area of plant operations and facilities, there are three critical things:
As in every dimension of business management, proper organizational structure is needed to ensure that the business process can go forward expeditiously and without waste. No CEO or CFO would question the need for manager of production, or a manager of accounting services. It is equally essential that there be a person charged with the responsibility to manage the firms activities in the area of GMP compliance as it relates to plant operations and facilities. Given the dire critical impact on business for a determination by FDA that a firm is non-compliant, the position must be centered at the highest possible level in the organization where authoritative decisions can be taken. It must also be structured with complete independence from any stake-holder whose responsibilities foster the likelihood that engaging in non-compliant activities might be seen as an expedient or a personal benefit of some kind.
The classical position in large-pharma companies that fills this requirement is often the Director of Regulatory Affairs reporting directly to the CEO. However, within the office of this director it is not uniform that a single individual is designated to manage the GMP compliance issues related to plant operations and facilities. Regulatory affairs are often seen to be issues relating directly to product registration and product quality. For matters relating to plant and equipment, responsibility is often assigned to line production supervisors, for the plant operational issues, and the facilities engineering manager for physical plant. While these functional personnel have obligations to obtain prior-approval of regulatory affairs before taking action, there is no direct reporting relationship. Such organization violates the principles of checks and balances needed to implement an effective auditing procedure.
While it is not practical to have universal industry standards on a detail level, it is entirely appropriate, and practical to have detailed GMP standards within a single firm. Such standards provide the procedures, document formats, equipment and facility design criteria, and governing rules on all matters whereby the employees can perform in ways that ensure compliance. These standards, which are frequently called "SOPs" (Standard Operating Procedures) are critical to operation in a GMP environment. They define in detail the "who", "what", "where", and "how" applicable to every operation in the plant. A well developed set of SOPs will constitute a manual of procedure through which the firm's quality management and regulatory compliance is implemented. To cover the full range of topics, the indexed set of SOPs includes upwards of fifty titles. The subject matter ranges from how to prepare an SOP, ("SOP on SOPs") to how often to wash the building floors. ("SOP on Facility Housekeeping").
SOPs provide detailed instructions in all three of the key elements needed to establish an effective and high quality manufacturing operation in FDA regulated industry. These are:
The SOPs also are the documents which govern the preparation, use, and filing of the full array of documentation required to adequately support the record keeping and chain of custody FDA expects to see in a pharmaceutical manufacturing operation. Such documents, which are not SOPs in themselves, are an integral part of the internal standards for compliance.
These include, among others, such items as:
Collectively the documents comprising these internal standards make up a substantial library of technical and operational information. For a moderate size pharmaceutical plant operation the library will fill several shelves of a typical bookcase. For a new entrant to pharmaceutical manufacturing, creating this library from bare shelves is a daunting task that requires significant dollar investment and time to completion. For smaller firms it is an impossible task without outside help.
It is well known that GMP compliance, from the aspect of successful completion of an FDA inspection is a moving target. There is a fundamental shortcoming in the practice of working with internal standards as described in the section above. Namely, the individual firms in the industry are inspected by an agency that has detailed visibility of a large number of firms in the industry. As the FDA inspects from one plant to another there is a growing body of information that natural evolves to an ever higher expectation for quality of facility or quality of performance as the higher quality plants are inspected. A firm that operates totally without exposure to practices of other firms in the industry will eventually be seen as non-complying in some aspect of its operation. What can the firm do to counter this situation? There is only one answer, it must look outside of itself.
There are a variety of sources and manners whereby members of an individual firm can gain visibility to practices in the industry at large. Professional and trade associations provide opportunities to exchange information. Trade publications present articles on latest echnologies. FDA publishes guidelines that incorporate new insights. Formal programs of "benchmarking" are conducted between groups of firms. These are good sources, but they may give limited results. Typically these sources are encumbered by concerns of secrecy, and sometimes fears of collusion in matters that may have anti-trust implications. The depth of information that is shared may be limited to protect the proprietary business interests of presenter firm. For example, information may be readily shared on matters of health and safety, but any discussion of a best practice for cleaning a process vessel may be a taboo. It is quite universal that most of the documents enumerated in the section above are considered company confidential. Giving a copy of one of these things to another firm is strictly prohibited except under the most tightly controlled conditions, i.e. secrecy agreement and a need to know.
In this environment substantial benefit can be gained when the firm engages a qualified and active industry consultant to provide advice on a current issue of interest. Such consultants acquire a broad view of industry practices through their client contact. Although working under secrecy to each client, and reputable professional consultants will not divulge confidential information, there is an integration of technology in their recommendations or their design solutions. They typically offer best practice answers to the specific assignment for which they are engaged. These best practice answers are constructed from direct observations, prior analytical exercises, previous successes, and failed trial solutions that were tested in previous assignments. Sometimes knowing what not to do is as important as knowing what to do.
It is in the consultant's interest to suggest solutions that have a good chance of solving the client's problem. Their good reputation, opportunity for repeat assignments, and professional integrity demand that they provide their very best knowledge about the item and their best effort. If they have appropriate experience, they are the best source for introducing state-of-art practice to a firm.
Services or assignments appropriate for execution through engagement of a GMP compliance consultant include:
Selective Problem Solving/Incident Investigation/Failure Analysis, New Operation Introductions/Defective Operations
In Materials and In Process
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