The manufacture of sterile excipients for use in aseptic/sterile processing presents technical challenges. It is essential that adequately qualified and trained personnel be used to supervise and perform procedures associated with the manufacture of sterile excipients. The environment in which procedures are conducted, and the operators themselves, are significant potential sources of contamination in aseptic operations. Processes should be designed to minimize contact between excipient and the environment and operators. Those aseptic excipient operations which require considerable operator involvement must have adequate controls. Major potential problem areas include aseptic removal of the excipient from centrifuges, manual transfer to drying trays and mills, and the inability to sterilize the drier. Not all equipment currently in use can be sterilized.

The excipient manufacturer must document the cleaning of critical processing equipment such as centrifuges and driers. Any manipulation of sterile excipients after sterilization must be performed as a validated aseptic process. This is particularly important for those excipients which are not further sterilized prior to packaging into final containers. In some instances, the compendial monographs may specify that an excipient which does not meet parenteral grade standards must be labelled as not suitable for use in the preparation of injectable products.

Some manufacturers of non-sterile excipients use heat, gamma radiation and other methods to reduce the microbial burden. These methods are acceptable provided the manufacturer has shown that the product meets microbial requirements and that the process is under control within the manufacturer's specifications. Any procedure should be validated in accordance with recognized international standards to demonstrate that the process will produce the intended result. Post-production treatment of excipients should not be used as a substitute for attention to microbiological control during production.

A protected environment may be necessary to avoid microbial contamination or degradation caused by exposure to heat, air or light. The degree of protection required may vary depending on the stage of the process. Often, direct operator contact is involved in the unloading of centrifuge bags, transfer hoses (particularly those used to transfer powders), drying equipment and pumps, and equipment should be designed to minimize the possibility of contamination. The sanitary design of transfer and processing equipment should be evaluated. Those with moving parts should be assessed for the integrity of seals and other packing materials to avoid product contamination.

Special environments required by some processes must be monitored at all times to ensure product quality (e.g. inert atmosphere, protection from light). If interruptions in the special environment occur, adequate evidence must be provided that they have not compromised the quality of the excipient. Such environmental concerns become increasingly important after purification of the excipient has been completed.

The environment to which the excipient may be exposed should be similar to that used in the manufacture of the final dosage form. This is especially true in the case of excipients intended for parenteral dosage forms. For example, controlled areas may need to be established along with appropriate air quality classifications. Such areas should be serviced by suitable air handling systems and there should be adequate environmental monitoring programmes. Any manipulation of sterile excipient after sterilization must be performed as an aseptic process, using Class 100 air¹ and other aseptic controls.

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, Section 17.3 (WHO Technical Report Series, No. 823).