Manufacturing, pharmaceutical sterile products

Areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate level of microbial and particulate cleanliness four grades (Table 22.1) are specified in the Rules and Guidance for Pharmaceutical Manufacturers and Distributors (1997), defined by measures of airborne contamination (Table 22.2). Environmental quality is substantially influenced by the air supplied to the manufacturing environment. 

It is quite rare that the composition or the packaging of an ophthalmic pharmaceutical will lend itself to terminal sterilization, the simplest form of manufacture of sterile products. Only a few ophthalmic drugs formulated in simple aqueous vehicles are stable to normal autoclaving temperatures and times (121°C for 20-30 min). Such heat-resistant drugs may be packaged in glass or other heat-de-formation-resistant packaging and thus can be sterilized in this manner. The convenience of plastic... 

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. 

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. ... 

There are several sources of standards and limits that may be applied to the manufacture of sterile products. They can be divided into sector-specific standards which are focused specifically on the manufacture of sterile pharmaceuticals and generic standards that are focused on particular technologies, irrespective of how the technologies are to be applied. 

The UK Orange Guide (Rules and Guidance for Pharmaceutical Manufacturers and Distributors, 2002) emphasizes the fundamental point that the manufacture of sterile products ... 

Guidelines for the manufacture of sterile products, annex to the basic standards of good manufec-turing practice for pharmaceutical products (1973) Report PHI/73, EFTA Secretariat, Geneva Guide to good pharmaceutical manufecturing practice (1977) Department of Health and Social Security (HMSO), London... 

For the manufacture of sterile products please refer to Part Three, section 17. For the manufacture of active pharmaceutical ingredients (bulk drug substances) please refer to Part Three, section 18. 

The guidelines given here describe the measures and provisions which are considered to be the minimum necessary to obtain pharmaceutical products of specified and constant quality, in view of the special measures which are required in the manufacture of sterile products, supplementary guidelines are provided for this purpose. 

For the chapter on the manufacture of sterile products, the Pharmaceutical inspection Convention s Guidelines for the Manufacture of Sterile Products, PH 5/81 (Convention for the Mutual Recognition of Inspections in respect of the Manufacture of Pharmaceutical Products). 

Pharmaceutical products are used in a variety of ways in the prevention, treatment and diagnosis of disease, hi recent years, manufacturers of pharmaceuticals have improved the quality of non-sterile products such that today the majority contain only a minimal microbial population. Nevertheless, a few rogue products with an unacceptable level and type of contamination will occasionally escape the quality control net and when used may, ironically, contribute to the spread of disease in patients. 

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. 

EC (2003), Guide to Good Manufacturing Practice Manufacture of Sterile Medicinal Products, Revision to Annex 1, Brussels. Available at http //europa.eu.int/comm/ enterprise/pharmaceuticals/eudralex/vol-4/pdfs-en/revanl vol4 3.pdf (accessed October 2006). 

Agalloco, J., and Akers, J. (2006), Aseptic processing for dosage form manufacture Organization validation, in Carleton, F. J., and Agalloco, J. P, Eds., Validation of Pharmaceutical Processes Sterile Products, Marcel Dekker, New York. 

Sharp, J. Manufacture of sterile pharmaceutical products using blow-fill-seal technology. The Pharm. J. 1987, 259(106), 22. 

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. 

Preprocessed closures, commonly referred to as RtS or Ready for Sterilization and RtU or Ready for Use, are an unstoppable trend in pharmaceutical packaging. Information on the manufacturing of these products was described previously in this review. The purpose of preprocessed closures is to reduce total processing costs and improve closure characteristics. Typical RtS closure characteristics are as follows ... 

Injectable products, ophthalmic products, and inhalation solutions Pharmaceutical ingredients Purified water Manufacturing environment Products As above Loop and taps daily Every shift in critical aseptic processing areas Every batch with the exception of terminally sterilized products approved for parametric release... 

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