These guidelines supplement the general GMP guidelines for pharmaceutical products published by WHO. They also incorporate some of the concepts for quality management systems determined by the International Organization for Standardization (ISO).

Excipients significantly affect the finished product quality, in some cases making up almost the entire formulation. 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 bioe-quivalence 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.

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.

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.

-- World Health Organisation