SUMMARY
In the current regulatory climate, large corporations in general have fully integrated their internal R&D groups into the traditional drug/device development process, implementing documentation procedures and controls early in research and development to facilitate tech transfer, when and if it occurs. However, as always, many important new technologies continue to be developed by small, "start-up" firms and university researchers, who develop their product to a certain point, then transfer further development and marketing to established corporations.Because these innovation sources fall outside of the traditional industrial structure, they may be less likely to adopt a methodical approach to documentation and quality control during R&D. This is partly because they may be unfamiliar with the regulatory requirements that will affect their product if it proceeds down the pipeline, and partly because as research groups or small, privately-held companies, they most likely have established no standard operating procedures requiring these controls.
Regardless of who develops a new medical product, several problems can surface at any point in the subsequent transfer of novel technologies if R&D has functioned without the benefit of an informal but regulatorily-informed "compliance program" during research and development. These problems include generation of data which are unsuitable for regulatory purposes, or unsuccessful scale-up of the production process due to a number of factors. As many large corporations have already recognized, the key to preventing these clogs in the pipeline is to acknowledge the critical role of Good Practices during the early stages of new product development. Strategic implementation of "Good Development Practices (GDPs)" can prevent potential problems and offer a competitive edge by saving valuable time in reaching development milestones. Considering the significant stakes riding on a successful, expeditious product approval for researchers, manufacturers and investors alike, small wonder that reasonably-structured R&D documentation and controls are looking more like friend than foe for developers, large and small, of novel biotech products.
BACKGROUND
Good Manufacturing Practice regulations (GMPs) were promulgated by FDA in 1978 (1,2) to establish minimum controls for the manufacture of drugs, biologics and medical devices. Also in 1978, the agency established Good Laboratory Practice regulations (GLPs) for the conduct of laboratory studies (3). Rules pertaining to the conduct of clinical research (4,5,6) - and colloquially known as Good Clinical Practices (GCPs) - govern sponsors, investigators and institutional review boards. FDA instituted the Good Practice systems to minimize the occurrence of quality problems in these regulated healthcare industries. In today's regulatory environment, systemic or repeated non-compliance with Good Practice regulations is grounds for FDA to take serious enforcement action against a firm, even without proof that a defective product exists.Although Good Practice systems are not required by FDA for most research efforts, GLPs are applicable to toxicology and biosafety studies, GMPs are applicable to drugs and biologics produced for clinical trials, and GCPs are applicable to clinical studies. During product development, many established pharmaceutical and medical device firms institute Good Practice systems beyond the mandatory boundaries. For example, batches for toxicology or stability studies are often manufactured under controlled conditions similar to GMPs, and the majority of pre-clinical testing is frequently conducted in conformance with most or all GLP requirements. To be valuable, these activities cannot be haphazard or randomly applied. Planning of the overall product development process should involve established timetables for initiating conformance and a determination of how extensive these initial compliance efforts should be.
While the Good Practice regulations share a number of general concepts, their most consistent requirement is the establishment of documented systems for assuring control over relevant activities to minimize the occurrence of defects or other problems. Clearly, start-ups and research groups whose primary focus is the development of "fast-track," novel technologies will benefit from informally adopting these controls early in the research and development process, not only to prevent delays during technology transfer, but also to help assure the regulatory acceptability of data intended for submissions such as a product's first Investigational New Drug Application (IND) or Investigational Device Exemption (IDE). After all, for developers who intend to license their technologies, a promising product is only as valuable as its ability to successfully reach the marketplace.
GDPs During pharmaceutical manufacturing, GMPs require documented adherence to established procedures and (written) descriptions of personnel, facilities and equipment, as well as component, production, packaging and laboratory controls. Similarly, for laboratory studies, GLPs require documented descriptions of personnel, facilities and equipment, facility operations, test articles, and study operations.
Good Development Practices (GDPs) can be defined as the requirement to describe facilities and equipment; to document established procedures (including changes to those procedures and investigations of deviations); and to maintain method development data at the research and development stage. To counter the most common problems that arise during tech transfer and the most prevalent deficiencies in data intended for regulatory submissions, GDPs should include the following areas:
Documentation Systems. A documentation system must be implemented as soon as product is used to generate data intended for regulatory submissions. This includes product intended to determine stability or to support pre-clinical or clinical testing. Whether the system is composed of a limited number of Standard Operating Procedures (SOPs), product records (such as batch records), or a combination of both, can be left to the discretion of each firm, since the product and processes are not yet fully defined. It is critical, however, that the chosen documentation system effectively describes and records the details of the manufacturing processes - especially the direct steps in the manufacture of the product. Additionally, the product's developer can significantly reduce a number of very controllable variables by establishing and documenting routine processes (such as autoclaving, sterility testing, material control, and diluent or media preparation) as well.
The goal of the documentation system is not only to provide an accurate, step-by-step "recipe" for manufacturing the product, but also to provide a historical perspective of what was manufactured, how it was manufactured, and which controls were in place. Control over the quality of the documentation is especially critical: R&D personnel typically are talented individuals with a wealth of knowledge about the product that often is not captured by research documentation. During the tech transfer phase, product will likely be manufactured by individuals who are highly proficient in manufacturing techniques, but lack the "intuitive" knowledge enjoyed by research personnel, who may have worked on the product for years. Hence, the extra effort by researchers to record even obvious details about the technology may alleviate much guesswork and gnashing of teeth - and save hundreds of labor hours downstream of the product's development. This may be especially valuable when technology is transferred from a start-up firm or research group to a larger corporation, and researchers are not readily available to fill in "knowledge gaps" upon request.
Deviations and Change Control. A system of change control is important during product development - not to force a rigid system of documentation, but simply to record the changes that will, by necessity, take place as the production process is refined. For example, with biological products, even small changes sometimes have major repercussions and can change the quality of the finished product. What happens if after manufacturing five consecutive pre-clinical batches using the same process, the researcher discovers that the next batch is "different"? All further development may stall until the "which" hunt - to locate which variable(s) caused the aberrant batch - is satisfactorily concluded. When these circumstances arise, the accuracy and reliability of manufacturing documentation will be instrumental to quickly identifying critical process parameters.
Not surprisingly, the most common (and often, most serious) problems usually occur due to lack of detailed documentation of "minor" process changes. In fact, it is relatively rare for firms to be able to accurately trace the development of a product from initial research through commercial scale-up. Inevitably, there are gaps; most often, at the early research stage or at the technology transfer stage. These lapses can be particularly costly if the manufacturer discovers a problem with the scaled-up product, then finds that the manufacturing method used at commercial scale neglected to include several unrecorded "process improvements" developed at the bench or pilot scale. Such events are not uncommon, and if atypical product is used in toxicological or clinical trials, years and hundreds of thousands of dollars can be lost.
Therefore, it is important during product development to utilize some type of systematic investigation process for unexpected results, and ensure that the findings from these investigations are incorporated into the development plan. Relatedly, a process for recording changes in methods and procedures as they occur is also needed.
Facilities and Equipment. Although it generally is not necessary to fully qualify all equipment and validate all processes used in the manufacture of a product during its early development stages, it is important to document which equipment was utilized, why it was selected, and how it was used, cleaned, etc. If calibration of the equipment used to manufacture the product would typically be required in a GMP environment, a similar system is highly desirable at the research and development stage. In short, an intelligent evaluation of which pieces of equipment are critical to the operation should be made as soon as possible, and those critical pieces of equipment should be targeted to achieve compliance with "GMP-like" requirements by the time clinical-grade material is produced. Analogously, if the manufacturing process requires microbiologically-controlled facilities, it is prudent to measure and document the environmental control of these facilities to maintain product integrity and comparability.
Setting priorities for reaching compliance with GMP requirements is an integral part of product development planning. Once critical facilities and equipment have been identified, it is time to establish a schedule for generating compliance documentation. During product development, the move toward full compliance with Good Practice regulations is best regarded as a continuum, rather than a "now nothing, now everything" approach.
Quality Assurance. It is helpful to establish a system of checks and balances between R&D personnel and individuals who are less closely responsible for research, by creating a Research Quality Assurance Unit. (This is analogous to the check-and-balance relationship between Production and Quality Assurance established by the GMP regulations.) Portentous as the Research QA Unit may sound, in a typical start-up firm or research group, it may actually be a single research individual who, through education, past industry experience, or a combination thereof, has also developed a QA perspective, a foundation of basic regulatory knowledge, and an appreciation for the value of reasonably-structured quality systems. The Research Quality Assurance Unit can assist with training and implementation of GDP concepts, independently investigate deviations and anomalies, review completed documentation for accuracy, and in general, ease the transition for other personnel toward GDPs.
Analytical Assays. The two questions most frequently asked by R&D personnel are: 1) "When do we start validating our assay?" and 2) "Which ones should we do first?" Generally, those methods that assess the potency and safety of the product should be developed and at least qualified as early in the development process as possible. It simply is not a good "risk" to proceed with product development and testing unless the potency and safety of a product can be reliably assessed. At a minimum, the precision and accuracy of the methods must be established to ensure that a reasonable scientific basis exists for relying on results generated by the chosen potency and safety assays. Eventually, all methods used to assess the potency, purity, identify, quality, safety and stability of the drug will require validation prior to filing the marketing application. Clearly, analytical method development and validation are ongoing processes in parallel with product development. It is important that method development data, including documentation of any changes and the comparability of products tested with the evolving methods, be maintained. By the time the method is finalized and ready for validation, there should be a wealth of assay development data from early qualification studies to facilitate a straightforward validation.
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