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Biocontamination Control In Pharmaceutical Production: An EMD Millipore White Paper


Biocontamination refers to biological contamination of products by bacteria and/or fungi, as well as the toxic by-products of these microorganisms, such as endotoxin and mycotoxins from Gram-negative bacteria and fungi, respectively. When designing a biocontamination control strategy, which is based on the manufacturing process, there are three components to take into consideration, each of which requires risk assessment: designing process systems to avoid contamination,  monitoring process systems to detect contamination and  reacting to contamination events and putting proactive measures in place. The design of process systems is where maximal effort should be placed.

Although often overlooked by some laboratories, the international standard on biocontamination control, ISO 14698, is an important resource for the development of a biocontamination strategy. There are two parts to this standard: Part 1 covers general principles and methods of biocontamination control; Part 2 covers the evaluation and interpretation of biocontamination data. Both parts of ISO 14698 are currently undergoing revision. It is important to clarify the distinction between the cleanroom standard ISO 14644 from ISO 14698. ISO 14644 is a 12-part cleanroom certificate standard that is focused on airborne particulates.

This standard covers cleanroom design, HEPA filter specification, pressures, and how to monitor a cleanroom in order to assess the cleanroom class. ISO 14698 focuses on the ongoing assessment of cleanrooms for viable contamination.


Despite good design and the available guidance, cleanrooms are at risk for several sources of contamination, of which people are the greatest source. Some studies estimate that people can contribute up to 70% of microorganisms found within a standard cleanroom. Second to people, water is a key source of contamination. The challenge with water is that it not only allows contamination to spread, but it also helps microorganisms to grow.

Microorganisms are carried in air streams until they are deposited on a surface. Unless they have recently been disinfected, most surfaces will have contamination on them. The risk arises when the contamination moves from a less critical to a critical location, so it follows that using clean utensils and having clean gloves is very important to minimize contamination transfer.
To minimize contamination from people, proper gowning is essential to curtail the amount of shedding of skin matter and microorganisms that a person can deposit within a cleanroom. Localized protection, such as isolators and unidirectional airflow cabinets, should also be established around the product to minimize contact with people. Good cleanroom design includes high-efficiency particulate air filters (HEPA), pressure cascade, and air distribution. Cleanrooms must also be cleaned and disinfected regularly, and transfer of items in and out of the cleanroom must be controlled.

Once good design principles are in place, an environmental monitoring program should be designed in order to provide information about the state of control of the facility. It is important to note that environmental monitoring does not replace good environmental control (the design of cleanrooms and operational practices); environmental monitoring only provides a ‘snapshot’ of time. Individually counts are rarely significant, but it is the trends emerging over time that are important: as counts, as frequency of incidents, and as microflora. The presence of microflora, such as waterborne bacteria or organisms that are hard to kill with disinfectants, may indicate the breakdown of control.

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