Manufacturing, pharmaceutical sterility assurance

This procedure provides the information required to support the sterility assurance of the drug product (product name), USP, manufactured by ABC Pharmaceutical Industries. It references the FDA Guidance titled Guidance for Industry for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Dmg Products prepared by the Sterility Technical Committee of the Chemistry Manufacturing Controls Coordinating Committee of the Center for Dmg Evaluation and Research (CDER) and the Center for Veterinary Medicine (CVM) in November of 1994. 

The manufacture of sterile products is universally acknowledged to be the most difficult of all pharmaceutical production activities to execute. When these products are manufactured using aseptic processing, poorly controlled processes can expose the patient to an unacceptable level of contamination. In rare instances contaminated products can lead to microbial infection resulting from products intended to hasten the patient s recovery. The production of sterile products requires fastidious design, operation, and maintenance of facilities and equipment. It also requires attention to detail in process development and validation to ensure success. This chapter will review the salient elements of sterile manufacturing necessary to provide acceptable levels of risk regarding sterility assurance. 

Aseptic pharmaceutical BFS technology for the manufacture of sterile liquid products demonstrates high levels of sterility assurance when correctly operated and configured. The technology is continually improving as more expertise is developed. 

At present, the pharmaceutical industry regulatory requirements refer to isolators specifically in the context of the manufacture of sterile products. There is no reference to their role in broader areas of crosscontamination and operator safety control. Within Europe, the current EU GMP clearly states that isolators might produce improvements in sterility assurance of sterile products, and that aseptic processing manufacturing isolators should be placed in at least a Grade D surrounding environment. The Food and Drug Administration (FDA) requirements are less well defined, but it is likely that in equivalent circumstances, they would like to see an isolator located in a class 100,000 or M6.5 environment In Operation. ... 

In making this proposal, the FDA recognizes that a dual standard of sterility a iunmee has been in operation. Terminal sterilization processes for parenteral pharmaceutical products are currently required to be validated to sterility assurance levels of 10 aseptic processes can only be demonstrated to achieve sterility assurance levels of 10. This is clearly an example of dual standards. Fuithefmore, to the FDA it appears to be fundamentally wrong for products that are quite capable of tolerating terminal sterilization to be manufactured asepti-cally. 

Rules and Guidance for Pharmaceutical Manufacturers and Distributors (1997) London HMSO. Spooner D.F. (1996) Hazards associated with the microbiological contamination of cosmetics, toiletries andnon-sterile pharmaceuticals. Iw.Microhial Quality Assurance in Cosmetics, Toiletries andNon-sterile Pharmaceuticals, 2nd edn (eds R.M. Baird S.F. Bloomfield), pp. 9-27. London Taylor Francis. 

ABC Pharmaceutical Industries routinely monitors the microbial content of the air, inanimate surfaces, personnel, water systems, and product component bioburden. Microbiological monitoring of these areas generally reflects on the efficiency of cleaning and sanitization procedures and employee practices. Continuous environmental monitoring provides the assurance that product is produced by a controlled process that will maximize the sterility and quality of the manufactured sterile product. 

None of the testing done by the manufacturers of filters can guarantee that unacceptable substances or biologically active substances are not going to be extracted into a particular pharmaceutical formulation. It is therefore incumbent upon all users of sterilizing filters to perform validation trials particular to their own applications. This usually means nonvolatile extraciables and LAL testing, but it may include other methods if these do not give adequate assurance. 

Aseptic manufacture is one of the most technically demanding operations in the pharmaceutical industry. To provide adequate assurance of sterility it is necessary to demonstrate that every critical mechanism and protective system consis-... 

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