Sources and Control of Contamination

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Chapter: Pharmaceutical Microbiology : Microbial Spoilage, Infection Risk And Contamination Control

Regardless of whether manufacture takes place in industry or on a smaller scale in the hospital pharmacy, the microbiological quality of the finished product will be determined by the formulation components used, the environment in which they are manufactured and the manufacturing process itself.



A)  In Manufacture


Regardless of whether manufacture takes place in industry or on a smaller scale in the hospital pharmacy, the microbiological quality of the finished product will be determined by the formulation components used, the environment in which they are manufactured and the manufacturing process itself. Quality must be built into the product at all stages of the process and not simply inspected at the end of manufacture:


• Raw materials, particularly water and those of natural origin, must be of a high microbiological standard.

• All processing equipment should be subject to planned preventive maintenance and should be properly cleaned after use to prevent cross-contamination between batches.

• Cleaning equipment should be appropriate for the task in hand and should be thoroughly cleaned and properly maintained.

• Manufacture should take place in suitable premises, supplied with filtered air, for which the environmental requirements vary according to the type of product being made.

• Staff involved in manufacture should not only have good health but also a sound knowledge of the importance of personal and production hygiene.

• The end-product requires suitable packaging which will protect it from contamination during its shelf-life and is itself free from contamination.


a)   Hospital Manufacture


Manufacture in hospital premises raises certain additional problems with regard to contamination control.


i)     Water

Mains water in hospitals is frequently stored in large roof tanks, some of which may be relatively inaccessible and poorly maintained. Water for pharmaceutical manufacture requires some further treatment, usually by distillation, reverse osmosis or deionization or a combination of these, depending on the intended use of water. Such processes need careful monitoring, as does the microbiological quality of the water after treatment. Storage of water requires particular care, as some Gram-negative opportunist pathogens can survive on traces of organic matter present in treated water and will readily multiply to high numbers at room temperature. Water should therefore be stored at a temperature in excess of 80 °C and circulated in the distribution system at a flow rate of 1–2 m/s to prevent the build-up of bacterial biofilms in the piping.


ii)                 Environment


The microbial flora of the hospital pharmacy environment is a reflection of the general hospital environment and the activities undertaken there. Free-living opportunist pathogens, such as Ps. aeruginosa, can normally be found in wet sites, such as drains, sinks and taps. Cleaning equipment, such as mops, buckets, cloths and scrubbing machines, may be responsible for distributing these organisms around the pharmacy; if stored wet they provide a convenient niche for microbial growth, resulting in heavy contamination of equipment. Contamination levels in the production environment may, however, be minimized by observing good manufacturing practices (GMP), by installing heating traps in sink U-bends, thus destroying one of the main reservoirs of contaminants, and by proper maintenance and storage of equipment, including cleaning equipment. Additionally, cleaning of production units by contractors should be carried out to a pharmaceutical specification.


iii)              Packaging


Sacking, cardboard, card liners, corks and paper are unsuitable for packaging pharmaceuticals, as they are heavily contaminated, for example with bacterial or fungal spores. These have now been replaced by nonbiodegradable plastic materials. In the past, packaging in hospitals was frequently reused for economic reasons. Large numbers of containers may be returned to the pharmacy, bringing with them microbial contaminants introduced during use in the wards. Particular problems have been encountered with disinfectant solutions where residues of old stock have been ‘topped up’ with fresh supplies, resulting in the issue of contaminated solutions to wards. Reusable containers must therefore be thoroughly washed and dried, and never refilled directly.


Another common practice in hospitals is the repackaging of products purchased in bulk into smaller containers. Increased handling of the product inevitably increases the risk of contamination, as shown by one survey when hospital-repacked items were found to be contaminated twice as often as those in the original pack (Public Health Laboratory Service Report, 1971).


B)   In Use


Pharmaceutical manufacturers may justly argue that their responsibility ends with the supply of a well-preserved product of high microbiological standard in a suitable pack and that the subsequent use, or indeed abuse, of the product is of little concern to them. Although much less is known about how products become contaminated during use, their continued use in a contaminated state is clearly undesirable, particularly in hospitals where it could result in the spread of cross-infection. All multidose products are vulnerable to contamination during use. Regardless of whether products are used in hospital or in the community environment, the sources of contamination are the same, but opportunities for observing it are greater in the former. Although the risk of contamination during product use has been much reduced in recent years, primarily through improvements in packaging and changes in nursing practices, it is nevertheless salutary to reflect upon past reported case histories.


b)     Human Sources


During normal usage, patients may contaminate their medicine with their own microbial flora; subsequent use of such products may or may not result in self-infection (Figure 17.3).


Topical products are considered to be most at risk, as the product will probably be applied by hand, thus introducing contaminants from the resident skin flora of staphylococci, Micrococcus spp. and diphtheroids but also perhaps transient contaminants, such as Pseudomonas or coliforms, which would normally be removed with effective hand-washing. Opportunities for contamination may be reduced by using disposable applicators for topical products or by giving oral products by disposable spoon.


In hospitals, multidose products, once contaminated, may serve as a vehicle of cross-contamination or cross-infection between patients. Zinc-based products packed in large stockpots and used in the treatment and prevention of bedsores in long-stay and geriatric patients were reportedly contaminated during use with Ps. aeruginosa and Staphylococcus aureus. If unpreserved, these products permit multiplication of contaminants, especially if water is present either as part of the formulation, for example in oil/water (o/w) emulsions, or as a film in w/o emulsions which have undergone local cracking, or as a condensed film from atmospheric water. Appreciable numbers of contaminants may then be transferred to other patients when the product is reused. Clearly the economics and convenience of using stockpots need to be balanced against the risk of spreading cross-infection between patients and the inevitable increase in length of the patients’ stay in hospital. The use of stockpots in hospitals has noticeably declined over the past two decades or so.


A further potential source of contamination in hospitals is the nursing staff responsible for medicament administration. During the course of their work, nurses’ hands become contaminated with opportunist pathogens which are not part of the normal skin flora but which are easily removed by thorough hand-washing and drying. In busy wards, hand-washing between attending to patients may be overlooked and contaminants may subsequently be transferred to medicaments during administration. Hand lotions and creams used to prevent chapping of nurses’ hands may similarly become contaminated, especially when packaged in multidose containers and left at the side of the hand-basin, frequently without lids. Hand lotions and creams should be well preserved and, ideally, packaged in disposable dispensers. Other effective control methods include the supply of products in individual patient’s packs and the use of non-touch techniques for medicament administration. The importance of thorough hand-washing in the control of hospital cross-infection cannot be overemphasized. In recent years hospitals have successfully raised the level of awareness on this topic among staff and the general public through widespread publicity and the provision of easily accessible hand disinfection stations on the wards.


c)  Environmental Sources


Small numbers of airborne contaminants may settle in products left open to the atmosphere. Some of these will die during storage, with the rest probably remaining at a static level of about 102–103 colony forming units (CFU) per gram or per millilitre. Larger numbers of waterborne contaminants may be accidentally introduced into topical products by wet hands or by a ‘splash-back mechanism’ if left at the side of a basin. Such contaminants generally have simple nutritional requirements and, following multiplication, levels of contamination may often exceed 106 CFU/g. In the past this problem has been encountered particularly when the product was stored in warm hospital wards or in hot steamy bathroom cupboards at home. Products used in hospitals as soap substitutes for bathing patients are particularly at risk and soon not only become contaminated with opportunist pathogens such as Pseudomonas spp., but also provide conditions conducive to their multiplication. The problem is compounded by stocks kept in multidose pots for use by several patients in the same ward over an extended period of time.


The indigenous microbial population is quite different in the home and in hospitals. Pathogenic organisms are found much more frequently in the latter and consequently are isolated more often from medicines used in hospital. Usually, there are fewer opportunities for contamination in the home, as patients are generally issued with individual supplies in small quantities.


d)   Equipment Sources


Patients and nursing staff may use a range of applicators (pads, sponges, brushes and spatulas) during medicament administration, particularly for topical products. If reused, these easily become contaminated and may be responsible for perpetuating contamination between fresh stocks of product, as has indeed been shown in studies of cosmetic products. Disposable applicators or swabs should therefore always be used.


In hospitals today a wide variety of complex equipment is used in the course of patient treatment. Humidifiers, incubators, ventilators, resuscitators and other apparatus require proper maintenance and decontamination after use. Chemical disinfectants used for this purpose have in the past, through misuse, become contaminated with opportunist pathogens, such as Ps. aeruginosa, and ironically have contributed to, rather than reduced, the spread of cross-infection in hospital patients. Disinfectants should only be used for their intended purpose and directions for use must be followed at all times.

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