GENERAL GUIDANCE
International regulations governing drugs require that components of the drugs be manufactured, processed, packed, and held in accordance with good manufacturing practices. Unlike other pharmaceutical products and components, until now there was no guidance that specifically addressed the manufacture of bulk pharmaceutical excipients.
Excipients are substances, other than the active drug substance or finished dosage form, that have been appropriately evaluated for safety and are included in drug delivery systems 1) to aid in the processing of the drug delivery system during its manufacture; 2) to protect, support, or enhance stability, bioavailability, or patient acceptability; 3) to assist in product identification; or 4) to enhance any other attribute of the overall safety, effectiveness, or delivery of the drug during storage or use.
The application of good manufacturing practices to excipients is relevant when it is determined that a chemical is intended for use as a component of a drug product. Excipient manufacture should be carried out in accordance with the manufacturing practice concepts consistent with the information in this chapter. The objective of excipient good manufacturing practices is to ensure that excipients are manufactured with the appropriate quality characteristics.
Excipients generally are manufactured on a large scale, which means that the use of automated process controls and continuous stream processing are more likely to be utilized. Production equipment and operations will vary depending on the type of excipient being produced, the scale of production, and the type of operation (e.g., lot or batch versus continuous). The use of automated equipment is appropriate when adequate inspection is conducted and calibration and maintenance procedures are followed.
Manufacturing practice requirements increase as the process progresses. At some logical processing step, usually well before the final finishing operation, appropriate manufacturing practices should be imposed and maintained throughout the remainder of the process. To determine the processing step at which these manufacturing practices should be implemented, good judgment and a thorough knowledge of the process are required. A detailed process flow should identify the unit operations, equipment used, stages at which various substances are added, key steps in the process, critical parameters (time, temperature, pressure, etc.), and monitoring points.
ISO 9000 series is a quality system standard of general application that can be applied to cover every aspect of manufacturing to the benefit of both the manufacturer and customer. It has taken several years since its introduction in 1987 for the ISO 9000 series to be utilized worldwide. There is no current regulatory requirement in Europe, Japan, or the United States for third party certification. A manufacturer may apply the standard with or without certification. However, certification has the benefit of providing assurance to customers that conformance to this quality system has been independently confirmed. Incorporation of GMP requirements into the ISO 9000 quality system enhances not only the quality system, but a company's operational procedures as well. Final dosage formulators worldwide increasingly regard compliance with ISO 9002 as an essential qualification for their suppliers. Obtaining certification is a business decision and is not discussed in this general information chapter.
Excipient Purity
The processes used for the production of bulk pharmaceutical excipients and those used for the production of bulk pharmaceutical chemicals are similar. Both can be manufactured by chemical synthesis, recombinant DNA technology, fermentation, enzymatic reactions, recovery from natural materials, or any combination of these processes. Impurities, contaminants, carriers, vehicles, inert ingredients, diluents, or unwanted crystalline or molecular forms may be present in the raw materials. Therefore, the starting materials for excipients may not be required to be manufactured in accordance with the manufacturing practices specified in this chapter because often the starting materials (or their derivatives) undergo significant chemical change and physical modification or blending, with the result that many of the impurities present in the starting materials are removed. The ultimate manufacturing objective is purification and physical or chemical alteration, which is accomplished by various chemical, physical, or biological processing steps. The effectiveness of these steps is confirmed by chemical, biological, and physical testing of the excipient. Excipients, once synthesized or isolated, normally undergo additional, extensive purification during manufacture.
Many excipients have applications other than for pharmaceutical uses and are used in food, cosmetics, or industrial products. Thus, environmental conditions, equipment, and operational techniques employed in excipient manufacture often reflect the chemical industry rather than the pharmaceutical industry. Many chemical processes have the potential to produce toxic impurities from side reactions. Therefore, careful process control may be essential. Also, the manufacturing environments may contain deleterious substances. However, chemical processes used to manufacture excipients are either performed in closed systems that afford protection against such contamination—even when the reaction vessels are not enclosed in buildings—or else these processes are in environments that must be controlled.
It is important that manufacturers identify and set appropriate limits for impurities. These limits should be based upon appropriate toxicological data, or limits described in national compendia as requirements, as well as sound manufacturing practice considerations. Manufacturing processes should be adequately controlled so that the impurities do not exceed such established specifications.
Excipients in Finished Dosage Forms
The formulator of finished dosage forms is highly dependent on the excipient manufacturer to provide bulk pharmaceutical excipients that are uniform in chemical and physical characteristics. This is particularly important in the context of the product approval process where bioequivalency comparisons are made between pivotal clinical biobatch production and commercial scale-up lots or batches. To provide adequate assurance of drug product performance, the excipient used to manufacture commercial lots or batches should not significantly differ from those used in biobatches. Where significant differences do occur, additional testing by the manufacturer of finished dosage forms may be required to establish the bioequivalence of the finished product. It remains equally important to ensure that the bioequivalence of subsequent, post-approval commercial lots or batches of drug product is not adversely affected over time.
In general, excipients are used as purchased. Consequently, impurities present in the excipient will be present in the finished dosage form. While manufacturers of dosage forms may have limited control over excipient quality through specifications, the excipient manufacturer has greater control over physical characteristics, quality, and the presence of impurities in the excipient.
Excipients are used in different types of dosage forms where physical characteristics, such as particle size, may be important. While it is primarily the responsibility of the manufacturer of finished dosage forms to identify the particular physical characteristics needed, it is the responsibility of the excipient manufacturer to adequately control processes to ensure the excipient's consistent conformance to specifications. The excipient's end use should be identified and considered during inspection of excipient manufacturers' facilities.
Particularly important is whether the excipient is a direct component of a drug dosage form, whether the excipient will be used in the preparation of a sterile dosage form, or whether the excipient is represented as pyrogen free. The excipient manufacturer is responsible for ensuring that excipients are pyrogen free if the manufacturer makes such a representation in specifications, labeling, contractual agreement, or a Drug Master File (DMF).
