Whilst product contamination during use is largely outside the manufacturer’s control, there are many steps that can be taken to minimize contamination while the product is made, both by restricting the entry of new organisms into it and by limiting the opportunities for growth of organisms that are unavoidably present at the start, such as those from water or raw materials.
Many of these procedures and precautions are described in Rules and Guidance for Pharmaceutical Manufacturers and Distributors
(known as the ‘Orange Guide’; Medicines and Healthcare products Regulatory Agency, 2017).
That publication and other regulatory and pharmacopoeial requirements make it clear that use of good manufacturing practices to limit microbial contamination in the first place is the preferred strategy, rather than,
for example, permitting contaminants to enter and proliferate in the product and then attempting to kill them by physical or chemical means.
The factors impacting on the hygienic manufacture of medicines are shown in Fig. 1 above.
Much of this is self-explanatory, although certain aspects merit more attention. Standards for atmospheric cleanliness in the manufacturing area apply not just for the production of sterile products but also for the production of nonsterile medicines. Thus the air supply is invariably high-efficiency particulate air (HEPA) filtered, and as air-conditioning plants often act as a breeding ground for microorganisms, filters need to be installed downstream of such equipment.
The factors to be considered in the design of premises and equipment are detailed in the Orange Guide, as are the procedures for cleaning and disinfection.
There is evidence that persistent use of a single disinfectant might predispose to the development of bacterial resistance to it, although this evidence is far less strong than that concerning antibiotics.
Nevertheless, there is a requirement that disinfectants be used on a rotational basis to minimize this risk, and in asepticnareas where sterile products are manufactured, the disinfectant solutions are filter-sterilized because they may, themselves, be a source of contamination with resistant organisms.
Because humans are frequently the principal source of microbial contamination in the manufacturing
environment, their health, hygiene, clothing and training may all have an impact on product contamination. The design of clothing for use in different areas is described in detail in the Orange Guide.
Whilst it is an unacceptable practice to use heat, radiation or antimicrobial chemicals to ‘clean up’ a product
which has been allowed to acquire a high level of contaminants that could have been avoided, it is acceptable to use these methods to reduce high bioburdens that are unavoidable (e.g. in raw materials of natural origin).
Thus raw materials may be exposed to radiation or ethylene oxide for this purpose, and filtration units or ultraviolet (UV) light sources may be used to reduce the bioburden in water.
If the water is to be used as an ingredient of an injectable product, filtration is preferable to exposure to UV light because it physically removes the contaminating Gram-negative bacteria that may act as a source of endotoxins, which could cause fever on injection.
Although UV light kills the bacteria, the endotoxins remain because the lipopolysaccharide component of the bacterial outer membrane from which they are derived is not destroyed.
Because of the ability of Gram-negative bacteria to grow readily in stored
purified water, it is also common for the water to be maintained at a high temperature, typically 80°C, whenever possible during the manufacturing process so as to prevent such growth.
The final factor shown in Fig. 1 to impact on hygienic manufacture is that of preservative availability.
Whilst the inclusion of a preservative to protect the product from spoilage sounds simple in principle, there are several ways in which the preservative
activity may be diminished or virtually abolished as a result of interaction with other components of the formulation or the container. These are considered.