PHARMACEUTICAL PRODUCT MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 288

been used to control and indicate the microbiological quality of nonsterile man-
ufacturing. However, as a result of a lack of set standards, the application
of environmental control and monitoring of nonsterile processes ranges from
nonexistent to programs parallel to aseptic processing. In some cases, the type
and frequency of data generated from some programs may be of little value in
determining the microbiological quality of environments in which the product
is manufactured. In addition, uncertainties exist on how the data will be used
and interpreted and its significance regarding product quality and safety to the
patient.
The use of environmental control and monitoring data has often been misap-
plied as a means of microbial and process control. Hence, the question is how
microbial control can be applied effectively in the manufacture of nonsterile
products? The answer lies in the use of a risk-based approach to understand the
manufacturing process, in defining where microbial contamination could occur
and in effectively determining the best level of control and applying monitoring
methods to minimize microbial contamination of the final product.
Does the microbial count in the air provide meaningful information for deter-
mining the state of control of a nonsterile manufacturing process or will the
critical manufacturing control points provide more protection from microbial
contamination?
In this case, where the risk factors are microbial in nature, the critical manu-
facturing control points provide more protection. The reason is that the microbial
quality of the air would be more indicative of the level of general cleanliness pro-
vided by routine surface cleaning and the efficiency of the air filtration systems
rather than the level of microbial contamination control in the manufacturing
process. Samples for microbial counts of the air are only taken typically at des-
ignated times (e.g., quarterly) and at designated locations (e.g., taken in two to
three locations). This information is limited. It reflects only the snap shot in time
when the samples are taken. Therefore, it is not relevant to the immediate activity
happening on a daily basis. Further, samples may require incubation for several
days to enumerate microbes on growth media. Results are not known until days
later and this prevents immediate correction of an uncovered problem. For these
reasons, there is greater value in determining the critical manufacturing control
points to protect the product against microbial contamination.
The process steps where microbial contamination is likely to be introduced
or occur are determined. Controls are put in place during the process steps to
eliminate or reduce the likelihood of contamination. The controls provide a means
for real-time or near-time performance feedback, so corrections or adjustments
can be made if needed in a timely manner.
To minimize the risk of microbial contamination, the application of techni-
cal and scientific principles for control of the microbial hazards because of the
facility, equipment, and production process needs to occur. One risk management
tool for assessing microbial hazards is hazard analysis and critical control points
[21-34].