This article presents a control strategy for maintaining a low level of particulates, thereby a low bioburden in cleanrooms,
and for conducting environmental monitoring to demonstrate the ongoing state of control. Consideration will be given to current
and proposed regulatory guidance and other cleanroom standards and monographs. In particular, the revised United States Pharmacopeia
(USP) general chapter <1116> on microbiological control of cleanrooms and other controlled environments will be discussed.
Changes to the ISO standard 14644 for cleanroom commissioning and qualification are also underway and will be addressed. Finally,
some pointers for good practices in contamination control will be presented.
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In 2012, mold contamination was found in supposedly sterile vials recalled from the marketplace after hundreds of people were
infected with fungal meningitis; the compounding pharmacy responsible for manufacture of the product had clear warning signals.
According to one newspaper report, their environmental monitoring program showed extensive contamination by mold and bacteria
throughout the production area but they failed to implement effective corrective actions (1).
In environmental control, it is essential to keep microbes out of a cleanroom environment. Escherichia coli (E. coli) has a doubling time of 20 minutes and one E. coli in a facility at 08:00 in the morning, means 8 by 09:00, and 16 million
by 16:00 under ideal conditions. Therefore, to keep the environment clean, microbes must be excluded from the environment.
To exclude microbes from the cleanroom, a control strategy is needed. A control strategy is defined as “a planned set of
controls, derived from … process understanding, that assures process performance and product quality” (2), or in other words,
risk mitigation. Having identified the risk as one of contamination, the source being microbes that are carried on particulates,
a whole host of measures is implemented to avoid contamination, starting with facility and equipment and primarily designed,
wherever feasible, to separate the operator from exposed product.
Where complete separation is not possible, another set of measures is implemented with the intent of containing as much as
possible of the particulate contamination that is shed by humans. Low levels of particulates (i.e., viable and total counts—the
latter includes viable and non-viable but we cannot distinguish) are designed into the facility by having a sealed building
shell with flush fittings and no gaps or cracks. High efficiency particulate air (HEPA) filters remove not less than 99.97%
of particles greater than or equal to 0.3-micron diameter, which in the absence of humans in the area, gives a sterile environment
with respect to microbes. Very high volumes of air are pushed through the clean area every hour ensuring many (usually more
than 100) air changes per hour in the aseptic core. Cleaning and disinfection procedures are carefully designed and applied
to remove any contamination that does find its way into the area, before it can multiply or settle. Operators undergo scrupulous
gowning procedures to contain their bodies such that any particles shed are caught inside the cleanroom apparel and only removed
outside the aseptic core. Operators are trained and qualified to perform operations in a cleanroom in a manner that does not
disturb air currents and that minimizes shedding. Each of the individual measures that are part of the microbial control strategy
is potentially crucial to the sterility of finished product especially where such product is aseptically filled (i.e., undergoes
no terminal sterilization process in its final container).
Breach of any measure can potentially result in contaminated product, although this is not by any means a one-to-one relationship.
Nevertheless, it is a risk that needs to be monitored, which is where environmental monitoring enters the picture. Environmental
monitoring is like an intelligence service. It is a risk-monitoring tool that allows us to collect useful data, analyze the
data, and feedback the information into our environmental monitoring program. The Central Intelligence Agency (CIA) defines
their mission as:
- Collecting intelligence through … appropriate means
- Correlating and evaluating intelligence related to (national security) and providing appropriate dissemination of such intelligence
- Providing overall direction for and coordination of the collection of national intelligence
- Creating special, multidisciplinary centers to address high priority issues.
Shouldn’t every pharmaceutical company have a director of environmental monitoring responsible for assuring the existence
of an appropriate cleanroom environment by collecting and evaluating data related to the state of control of the environment
and providing overall direction (based on analysis of the data collected) regarding the continued collection (e.g., when special
sampling and/or corrective actions might be needed)? Most importantly, such a director could create special, multidisciplinary
task forces that can get into action fast when high priority issues are identified.