The Extent of Microbial Contamination

THE EXTENT OF MICROBIAL CONTAMINATION

Most reports of medicament-borne contamination in the literature tend to be anecdotal in nature, referring to a specific product and isolated incident. Little information is available on the overall risk of products becoming contaminated and causing patient infections when subsequently used. Such information is considered invaluable not only because it may indicate the effectiveness of existing practices and standards, but also because the value of potential improvements in patient quality can be balanced against the inevitable cost of such processes.

A)  In Manufacture

Investigations carried out by the Swedish National Board of Health in 1965 revealed some startling findings on the overall microbiological quality of non-sterile products immediately after manufacture. A wide range of products was routinely found to be contaminated with Bacillus subtilis, Staph. albus, yeasts and moulds, and in addition large numbers of coliforms were found in a variety of tablets. Furthermore, two nationwide outbreaks of infection in Sweden were subsequently traced to the inadvertent use of contaminated products. Two hundred patients were involved in an outbreak of salmonellosis, caused by thyroid tablets contaminated with Salmonella bareilly and Sal. muenchen (now known as Salmonella enterica subsp. enterica serovar Bareilly and Sal. enterica serovar Muenchen respectively); and eight patients had severe eye infections following the use of a hydrocortisone eye ointment contaminated with Ps. aeruginosa. The results of this investigation had a profound effect on the manufacture of all medicines; not only were they then used as a yardstick to compare the microbiological quality of nonsterile products made in other countries, but also as a baseline upon which international standards could be founded.

Under the UK Medicines Act 1968, pharmaceutical products made in industry were expected to conform to microbiological and chemical quality specifications. The majority of products have since been shown to conform to a high standard, although spot checks have occasionally revealed medicines of unacceptable quality and so necessitated product recall. By contrast, pharmaceutical products made in hospitals were much less rigorously controlled, as shown by several surveys in the 1970s in which significant numbers of preparations were found to be contaminated with Ps. aeruginosa. In 1974, however, hospital manufacture also came under the terms of the Medicines Act and, as a consequence, considerable improvements were subsequently seen not only in the conditions and standard of manufacture, but also in the chemical and microbiological quality of finished products. Hospital manufacturing operations were later rationalized. Economic constraints caused a critical evaluation of the true cost of these activities. Competitive purchasing from industry in many cases produced cheaper alternatives, and small-scale manufacturing was largely discouraged. Where licensed products were available, NHS policy dictated that these were to be purchased from a commercial source and not made locally.

Removal of Crown immunity from the NHS in 1991 meant that manufacturing operations in hospitals were then subject to the full licensing provisions of the Medicines Act 1968, i.e. hospital pharmacies intending to manufacture were required to obtain a manufacturing licence and to comply fully with the EC Guide to Good Pharmaceutical Manufacturing Practice (Anon, 1992, revised in 1997, 2002 and 2007). Among other requirements, this included the provision of appropriate environmental manufacturing conditions and associated environmental monitoring. Subsequently, the Medicines Control Agency (MCA) issued guidance in 1992 on certain manufacturing exemptions, by virtue of the product batch size or frequency of manufacture. The need for extemporaneous dispensing of  ‘one-off ’ special formulae continued in hospital pharmacies, although this work was largely transferred from the dispensing bench to dedicated preparative facilities with appropriate environmental control. Today hospital manufacturing is concentrated on the supply of bespoke products from a regional centre or small-scale specialist manufacture of those items currently unobtainable from industry. Repacking of commercial products into more convenient pack sizes is, however, still common practice.

B)  In Use

Higher rates of contamination are invariably seen in products after opening and use and, among these, medicines used in hospitals are more likely to be contaminated than those used in the general community. The Public Health Laboratory Service Report of 1971 expressed concern at the overall incidence of contamination in non-sterile products used on hospital wards (327 of 1220 samples) and the proportion of samples found to be heavily contaminated (18% > 10⁴ CFU/g or CFU/ml).

Notably, the presence of Ps. aeruginosa in 2.7% of samples (mainly oral alkaline mixtures) was considered to be highly undesirable.

By contrast, medicines used in the home are not only less often contaminated but also contain lower levels of contaminants and fewer pathogenic organisms. Generally, there are fewer opportunities for contamination here because individual patients use smaller quantities. Medicines in the home may, however, be hoarded and used for extended periods of time. Additionally, storage conditions may be unsuitable and expiry dates ignored; thus problems other than those of microbial contamination may be seen in the home.