(1999; 168 pages) [Spanish]
1. General considerations
These guidelines, which focus on aspects of good manufacturing practices (GMP) specific for pharmaceutical excipients, supplement the general GMP guidelines for pharmaceutical products published by WHO.1 They also incorporate some of the concepts for quality management systems determined by the International Organization for Standardization (ISO).
1 Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-second report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical Report Series, No. 823).
Excipients significantly affect the finished product quality, in some cases making up almost the entire formulation. Many pharmaceutical excipients are used in much greater quantities in other industries, such as the food, cosmetic or industrial chemical industry. Consistency and rigour of product specifications may not be as critical in these industries as they are for pharmaceuticals, and many of the excipients used are highly variable. Therefore, a programme must be in place which will monitor these excipients and provide the necessary assurance that they meet the quality parameters for pharmaceutical manufacturing processes. The purpose of this document is to lay out some criteria which may be used to achieve this level of assurance.
The formulator of the finished dosage form is highly dependent on the excipient manufacturer to provide bulk substances that are uniform in chemical and physical characteristics. This is particularly important in the product approval process, where bioequivalence comparisons are made between clinical bioequivalence ("biobatch") production and commercial scale-up batches. To provide adequate assurance of drug product performance in vivo, the excipient used to manufacture commercial batches should not differ significantly from that used in biobatches. Where significant differences may be expected, additional testing by the finished dosage manufacturer 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 batches of drug products is not adversely affected over time.
In general, excipients are used as purchased, with no further refinement or purification. Consequently, impurities present in the excipient will be carried over to the finished dosage form. While dosage form manufacturers may have a limited control over excipient quality (i.e. by obtaining certificates of analysis and testing representative samples), the excipient manufacturer has greater control over physical characteristics, quality, and the presence of trace-level impurities in the excipient. The excipient manufacturer should perform periodic performance trend analyses of processes, and the purchaser of the material should also maintain a trend analysis of all testing done on the excipient upon receipt.
In the manufacture of excipients, the environmental conditions, equipment and operational techniques employed reflect the chemical industry rather than the finished drug manufacturing industry. In some processes chemical and biochemical mechanisms have not been fully characterized; therefore, the methods and procedures for materials accountability will often differ from those applicable to the manufacture of finished dosage forms. Many chemical processes are performed in closed systems that tend to provide protection against contamination, even when the reaction vessels are not enclosed in buildings. However, this does not preclude the introduction of contaminants from equipment, materials used to protect equipment, corrosion, cleaning and personnel.
Some excipient manufacturing processes may require observance of GMP applicable to finished drug products or bulk active ingredients because of the excipient's intended use. However, such observance is neither feasible nor necessary in many processes, particularly during the early processing steps. The requirements increase as the process progresses. At some logical processing step, usually well before the final finishing operation, appropriate GMP should be imposed and maintained throughout the remainder of the process. To determine the processing step at which these GMP should be implemented, good judgement 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.
An excipient manufacturer should be able to identify critical or key points in the process where selective intermediate sampling and testing is necessary in order to monitor process performance. Towards the end of the process, the records should be increasingly thorough.
Significant processing steps, required to produce an excipient that meets the established physical and chemical criteria, should be identified by the excipient manufacturer. These steps can involve a number of unit operations or unit processes. Unit operations include physical processing steps involving energy transfer where there is no chemical change of the molecule. Unit processes are those processing steps where the molecule undergoes a chemical change.
Significant processing steps include but are not limited to the following:
• Phase changes involving either the desired molecule, a solvent, inert carrier or vehicle (e.g. dissolution, crystallization, evaporation, drying, sublimation, distillation or absorption).
• Phase separation (e.g. filtration or centrifugation).
• Chemical changes involving the desired molecule (e.g. removal or addition of water of hydration, acetylation, formation of a salt).
• Adjustments of the solution containing the molecule (e.g. adjustment of pH).
• Precision measurement of added excipient components, in-process solutions, recycled materials (e.g. weighing, volumetric measuring).
• Mixing of multiple components.
• Changes that occur in surface area, particle size or batch uniformity (e.g. milling, agglomeration, blending).
Automated process controls and processing equipment are more likely to be used in an excipient plant than in a plant manufacturing finished dosage forms. Use of automated equipment is appropriate when adequate inspection, calibration, and maintenance procedures are performed. Production equipment and operations will vary depending on the type of excipient being produced, the scale of production, and the type of operation (i.e. batch versus continuous).
ISO "certification" for excipient manufacture is increasingly being required by final dosage formulators in the USA, Europe and Japan. Compliance to the International Standards of ISO 9000 series, in particular to ISO 9002, can confer greater acceptability of a supplier's excipients in world markets. There is additional value to applying the principles of ISO 9000 to excipient manufacture, since quality system measures enhance GMP. Such ISO considerations as conformance to specific customer requirements, purchase of raw materials and statistical techniques benefit both the excipient customer and the manufacturer, and strengthen the relationship between the two.
It is therefore recommended that excipient manufacturers establish and implement a formal company-wide quality policy. Management should be committed to this policy and should appoint appropriate company personnel to be responsible for coordination and implementation of the quality system. Management should participate in the development of the company's quality policy and provide the resources necessary for development, maintenance and periodic review of such a policy and quality system. Any significant changes in the processes should be validated with respect to excipient performance. It is recommended that all pharmaceutical manufacturers and also local agents should be informed of these changes. Ideally, excipient manufacturers should not subcontract any part of their process without the explicit knowledge of the pharmaceutical manufacturer.
Safe handling instructions should be provided by the excipient manufacturer to ensure that the purchaser is adequately equipped to handle the material. This should include information on the material's toxicity and the measures to be taken upon accidental exposure. The equipment requirements for proper handling of the material should also be established.