Many of the principles in this general information chapter are derived from an international guidance on the extent and point of application of appropriate good manufacturing practice principles. It is intended to assist excipient manufacturers in determining whether the methods used in, and the facilities and manufacturing controls used for, production adequately ensure that an excipient possesses the quality, purity, safety, and suitability for use that it purports to possess.
The principles and information in this chapter can be applied to the manufacture of all bulk pharmaceutical excipients (referred to throughout this document as “excipient(s)”) intended for use in human drugs, veterinary drugs, and biologics. It covers the quality systems and the extent of good manufacturing practices necessary throughout the chain of production up to and including delivery to customers. As an international guidance document, it does not provide information for all national legal requirements nor cover in detail the particular characteristics of every excipient. The quality system standard used as a framework for this chapter is ISO 9002, which is appropriate to manufacturing. Information specific to excipients has been added. Because of the diversity of excipients, some principles in this information chapter may not be applicable to certain products and processes.
This information chapter combines existing governmental regulatory good manufacturing practices principles and international quality management system requirements as developed by The International Organization for Standardization (ISO). In view of the increasing globalization of the pharmaceutical industry and the harmonization of pharmaceutical registration requirements, deference to both schemes is becoming necessary. Therefore, relevant portions of both manufacturing concepts are employed throughout this chapter.
The General Guidance section provides an overview of the appropriate manufacturing practices criteria applicable to excipient manufacture and the point of application of excipient good manufacturing practices and quality systems. This section also recommends measures to limit contamination of an excipient and provides the relationship of excipients to finished dosage forms. For a list of terms and their definitions used in this information chapter, see Appendix 1. The section Excipient Quality Systems provides information on the requirements necessary for compliance with relevant good manufacturing practice principles and implementation of an excipient quality system. Information for production facility requirements are included under Process Control. No attempt has been made to include details specific to particular excipients. The information under Appendix 2, General Auditing Considerations, sets forth key criteria to aid in the audit of an excipient manufacturing facility.
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.
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.
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).
The information described below can be used as the basis for a quality system in the manufacture of excipients. Procedures that are utilized in the manufacture and control of excipients should be written. Conformance to those procedures should be documented. A quality manual is a documented base and is intended to describe the quality policy and the commitment of the supplier to quality. The procedural system should have adequate formal controls related to procedure approval, revision, and distribution. These controls should provide assurance that the proper version of a procedure is being utilized throughout the operation.
Management should demonstrate commitment to a quality policy that should be implemented within the operational unit. Management should participate in the development of the company's quality policy and provide the resources necessary for development, maintenance, and review of such policy and quality system at least annually. Management should be committed to this policy and should appoint appropriate company personnel to be responsible for coordination and implementation of the quality system.
There should be a quality unit, independent of production, that has the responsibility and authority to approve or reject all components, in-process materials, packaging materials, and finished excipients. The quality unit should have the authority to review production records to ensure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality unit should be responsible for approving or rejecting excipients manufactured, processed, packaged, or held under contract by another company. The quality unit can delegate these responsibilities if proper controls, such as periodic audits and documentation of training, are in place. Adequate laboratory facilities for the testing and approval or rejection of raw materials, packaging materials, in-process materials, and finished excipients should be available to the quality control unit.
It is the responsibility of an independent unit, usually the quality assurance group, which is independent of production, to participate in issuing procedures, authorizing changes to processes, specifications, procedures, and test methods and in investigating failure and complaints.
An organization chart by function should be available showing interdepartmental relationships as well as relationships to the management of the company. As a minimum, all quality assurance, quality control, production maintenance, and engineering functions should have clear job descriptions.
Employees engaged in the manufacture, processing, packaging, or holding of an excipient should wear clean clothing appropriate for the duties they perform. Protective apparel, such as head, face, hand, and arm coverings, should be worn as necessary to protect excipients from contamination. Only employees authorized by supervisory personne
