WHO Expert Committee on Specifications for Pharmaceutical Preparations - WHO Technical Report Series, No. 885 - Thirty-fifth Report
(1999; 168 pages) [Spanish] View the PDF document
Table of Contents
View the documentWHO Expert Committee on Specifications for Pharmaceutical Preparations
View the document1. Introduction
Open this folder and view contents2. The international pharmacopoeia and related issues
Open this folder and view contents3. International Chemical Reference Substances and Infrared Reference Spectra
Open this folder and view contents4. Quality control - national laboratories
Open this folder and view contents5. Good manufacturing practices
Open this folder and view contents6. Quality systems and inspection
Open this folder and view contents7. Other quality assurance topics
Open this folder and view contents8. Nomenclature and terminology
Open this folder and view contents9. Legal aspects of pharmaceuticals
Open this folder and view contents10. Regulatory issues
Open this folder and view contents11. Training activities
View the document12. Pharmaceuticals contaminated with diethylene glycol
View the documentAcknowledgements
View the documentReferences
View the documentAnnex 1. List of available International Chemical Reference Substances1
View the documentAnnex 2. List of available International Infrared Reference Spectra1
Open this folder and view contentsAnnex 3. General guidelines for the establishment, maintenance and distribution of chemical reference substances
Open this folder and view contentsAnnex 4. Good manufacturing practices: authorized person - role, functions and training
Close this folderAnnex 5. Good manufacturing practices: supplementary guidelines for the manufacture of pharmaceutical excipients
View the document1. General considerations
View the document2. Glossary
View the document3. Self-inspection and quality audits
Open this folder and view contents4. Equipment
Open this folder and view contents5. Materials
Open this folder and view contents6. Documentation
Close this folder7. Good practices in production and quality control
View the document7.1 Change control and process validation
Close this folder7.2 Good practices in production
View the document7.2.1 Prevention of cross-contamination
View the document7.2.2 In-process blending/mixing
View the document7.2.3 Control of microbial contamination
View the document7.2.4 Water systems/water quality
View the document7.2.5 Packaging operations
View the document7.2.6 Delivery
Open this folder and view contents7.3 Good practices in quality control
Open this folder and view contentsAnnex 6. Guidelines for inspection of drug distribution channels
View the documentAnnex 7. Good pharmacy practice in community and hospital pharmacy settings
Open this folder and view contentsAnnex 8. National drug regulatory legislation: guiding principles for small drug regulatory authorities
Open this folder and view contentsAnnex 9. Provisional guidelines for developing training programmes: inspection and examination of counterfeit pharmaceuticals
View the documentWorld Health Organization Technical Report Series
View the documentSelected WHO Publications of Related Interest
View the documentBack Cover
7.2.3 Control of microbial contamination

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).


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