Microbial contamination of pharmaceutical products

Baird, R. M. (1985) Microbial contamination of pharmaceutical products made in a hospital pharmacy. Pharm J, 234, 54-55. 

Microbial contamination of pharmaceutical products may result in deterioration of the product or direct hazard to the patient. 

During development of the manufacturing process, an experienced microbiologist should be consulted as to the potential for microbial contamination of the product. Issues may include the selection of appropriate pharmaceutical ingredients, the ability of the manufacturing steps to control microbial contamination, the validation of sterilization processes, the cleaning and sanitization of process equipment, the adequacy of... 

It has been known for many years that microbial contaminants may effect the spoilage of pharmaceutical products through chemical, ply sical or aesthetic changes in the nature of the product, thereby rendering it unfit for use (see Chapter 18). Active drug constituents may be metabolized to less potent or chemically inactive forms. Physical changes commonly seen are the breakdown of emulsions, visible surface growth on solids and the formahon of slimes, pellicles or sediments in hquids, sometimes... 

Ringertz O. Ringertz S.H. (1982) The clinical significance of microbial contamination in pharmaceutical and allied products. Sci, 5, 201-226. 

The tests for microbial limits and recommendations for microbial quality criteria of raw materials, excipients, drug substances, and pharmaceutical products have been established in pharmacopoeial compendia for over 30 years. These tests are listed in the USP 24 Chapter (61) Microbial Limits Tests and in the Ph. Eur. 3rd ed.. Biological Tests 2.6.12 and 2.6.13, Microbial Contamination of Products Not Required to Comply with the Test for Sterility (total viable count, tests for specified microorganisms) and the JP XIII 30 Microbial Limit Test. 

Monitoring pharmaceutical ingredients, water for pharmaceuhcal purposes, the manufacturing environment, and finished products submitted to the laboratory to demonstrate control of microbial contamination of the pharmaceutical products manufactured... 

In the general chapter on microbial attributes of nonsterile pharmaceutical products, the guidance suggests that the presence of microbial contaminants in nonsterile products [25] can reduce or inactivate the therapeutic activity of the product and has the potential to adversely effect the health of the patients and recommends manufacturers to ensure that contamination levels are as low as possible for finished dosage forms. Microbial enumeration limits for raw materials (total aerobic microbial count and total combined yeasts and molds count) and finished dosage forms are described. For inhalation, nasal, and topical routes of administration, tests for total aerobic microbial count and total combined and yeast and mold count,... 

The average number of recalls per annum for microbial contamination of non-sterile pharmaceutical and OTC drug products is six (Table 4). The emphasis on waterborne Gram-negative bacteria of the species Bulkholderia (Pseudomonas) cepacia (nine recalls), P. putida (three recalls), P. aeruginosa (three recalls). Pseudomonas spp. (two recalls), and Ralstonia (P.) pickettii (one recall) is notable and reflects the concern for bacteria capable of growth in liquid oral dosage forms that overwhelm the preservative system. 

Preservatives. These are included in pharmaceutical preparations to prevent microbial spoilage of the product and to minimize the risk of the consumer acquiring an infection when the preparation is administered. Preservatives must be able to limit proliferation of microorganisms that may be introduced unavoidably into non-sterile products such as oral and topical medications during their manufacture and use. In sterile products such as eye-drops and multi-dose injections preservatives should kill any microbial contaminants introduced inadvertently during use. It is essential that a preservative is not toxic in relation to the intended route of administration of the preserved preparation. 

Attention should be paid to classification of clean area requirements taking into account the possible high degree of initial microbial contamination of herbal materials. Classification of premises as applied to sites for the production of other pharmaceutical substances may not be applicable to processing of herbal materials. Specific and detailed requirements should be developed to cover microbial contamination of equipment, air, surfaces and personnel, and also for rest rooms, utilities, ancillary and supporting systems (e.g. water and compressed air). 

Packaging Similarly, information on the closure/packaging systems must be provided in terms of material specification, suitability/compatibility with the pharmaceutical product, dimensional specifications, water impermeability, and so on. Defence against microbial contamination should be discussed in the context of either packaging of sterile product or use of preservatives as appropriate. 

The first chapter in this section provides a unique account of the ecology, i.e. distribution, survival and life-style, of microorganisms in the factory environment, and should enable process designers, controllers and quality control personnel to comprehend, trace and eradicate the sources of failure due to extraneous microbial contaminants in the finished product. Much of the information given here is applicable to hospital manufacture also, and this is extended in a contribution (Chapter 19) dealing with contamination in hospital pharmaceutical products and in the home. 

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. 

---