The FDA mandates the adoption and use of Current Good Manufacturing Practices (cGMPs) by the pharmaceutical industry (FDA, 1996). GMP manufacture applies to the following: APIs (bulk drug substances), pharmaceutical excipients (substances other than the API that are used in the finished dosage form), sterile pharmaceutical products, biological products, investigational pharmaceutical products for humans, herbal medicinal products, radiopharmaceutical products, and medical devices (FDA, 2004a).
cGMP regulations describe the methods, equipment, facilities, and controls required for producing human and veterinary products, medical devices, and processed food (FDA, 1996). cGMPs are built around safety, identity, strength, purity, and quality of the pharmaceutical product. The FDA developed GMP regulations over time in response to various public health crises caused by unsafe or ineffective medical products. FDA's charge, and the purpose of cGMPs, is to ensure that medical products are safe and have the
"identity and strength and meet the quality and purity characteristics" that they are purported or represented to possess. The cGMPs are a quality assurance system that requires control of the drug (or device) production process from the time materials (excipients, actives, and packaging and labeling materials) are received at the plant, through production and testing, and shipment into the commercial marketplace. The requirements of the cGMPs, published in the Federal Register, are general and represent the minimum requirements around which a company should construct its own specific quality program. The FDA has certain expectations as to what must be covered and how matters must be handled to meet the requirements of GMP, depending on the type of product manufactured and the current state of the art in a particular industry. The FDA expects manufacturers to remain current in the state of the art of manufacture, testing, and packaging of their products, hence the name cGMP.
As noted above, the manufacture of most medicines involves many steps, which lead ultimately to the API. cGMP regulations apply to API and its final dosage form, and not necessarily to steps before the API, as explained earlier. This is the case with a non-cGMP contract manufacturer. However, most non-cGMP manufacturers comply with the International Organization for Standardization's (ISO) 9000 standards (International Organization for Standardization, 2005) or some such system in which quality of the chemical intermediates produced is subject to close monitoring and control, and the manufacturer must adhere to internationally accepted benchmarks for quality. We now present a brief description of ISO 9000 quality management.
The ISO 9000 family is primarily concerned with "quality management,'' which covers what the organization does to fulfill the customer's quality requirements and applicable regulatory requirements, while aiming to enhance customer satisfaction and achieve continual improvement of its performance in pursuit of these objectives. In practical terms, it means the manufacturer strives to reduce variation in the product to as close to zero as possible.
The cGMPs require thorough documentation. In FDA's eyes, if it is not documented, it did not happen or does not exist. Every procedure must be committed to writing and reflect the actual operating practices at the company, and all critical steps in the process must be controlled and recorded in a detailed manner. The FDA requires that critical processes, such as manufacturing, cleaning, and analytical testing be validated with documented evidence that they consistently perform their intended function this regulation assures that the result of the process meets predetermined quality attributes.
The FDA focuses on the company responsible for producing and packaging the drug; however, many manufacturers outsource manufacturing of several intermediates to other firms. The FDA does not oversee the manufacture of all intermediate compounds and does not regulate facilities that are not subject to its current cGMP regulations (see below). However, the final manufacturing stage, which results in API synthesis, is always subject to rigorous FDA control. Hence non-cGMP manufacturers, who synthesize intermediates and supply them to the drug maker, for the final stage, must also meticulously control their manufacturing processes. If they do not, they risk the introduction of impurities or contaminants into the pharmaceutical, which can lead to adverse effects in patients consuming the drugs.
The FDA conducts inspections of medical product manufacturers to determine if the company is operating in a state of compliance with cGMP requirements. Failure to comply with cGMP regulations results in range of consequences, from a listing of observations on an FDA form 483 and a possible warning letter, to injunction and seizure or to criminal indictment if repeated warnings are not heeded.
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