The Role of Bioburden in the Contamination-Control Plan

A company’s contamination-control plan is an important document designed to formalize the rationale, methods, and validation of contamination-control procedures in a manufacturing facility. The plan is a valuable tool for pharmaceutical, medical device, and personal product manufacturers and should be written to address all phases of the facility’s life cycle. Specifically, the contamination-control plan should achieve the following goals:

• Minimizing the bioburden throughout the manufacturing processes. This step is important for reducing the challenge posed to the sterilization process (i.e., in sterile manufacturing) or to the finished-product bioburden (i.e., in nonsterile production).

• Minimizing the level of batch residual cross-over contamination. This step reduces the chance that chemical contaminants from previous batches will come into contact with a product manufactured on the same piece of equipment.

• Minimizing the level of cleaning-material residual contamination. This step reduces the chance that chemical contaminants from cleaning agents will come into contact with a product manufactured on a given piece of equipment.

This article will describe the role of bioburden in the contamination-control plan. The control of bioburden in modern pharmaceutical manufacturing relies on several mutually supporting activities. Accurate information about the type and number of microorganisms in a facility is the basis for controlling bioburden, therefore personnel must use validated sampling and testing methods for bioburden. In practice, this requirement means that personnel must develop a validated sampling plan that identifies sample sites, establishes a predetermined frequency of sampling, and mandates the regular evaluation of data generated by the environmental-monitoring program. Valid methods for testing utilities (e.g., water, process gas, and air) and surfaces also are required.

In addition to measuring bioburden in the facility, personnel should take steps to minimize and monitor bioburden in the manufacturing process. A validated cleaning and sanitization program for the equipment and facility is crucial to success in this regard. The contamination-control plan should describe how the cleaning and sanitization program will be validated and monitored for continuing effectiveness. The contamination-control plan should include consideration of incoming raw materials, the validation of the cleaning and sanitation programs, the control of personnel, in-process bioburden and control, and environmental monitoring.

Controlling the bioburden that enters the facility is another necessary step. For example, personnel should accept raw materials (e.g., excipients, water, and active pharmaceutical ingredients [APIs]) and components only after they are certain that these materials meet bioburden requirements and all other incoming-material specifications. A certificate of analysis generally is sufficient evidence of adequacy.

Because personnel are the greatest source of contamination in a facility, plant managers should exercise due care to protect the process from the operator. Appropriate gowning requirements should be in place, but they vary depending on the process, product, and manufacturing site.

Ambient and process conditions can affect the characteristics of APIs and other materials, thus environmental control and monitoring are two crucial elements of the contamination-control plan for sterile and nonsterile production facilities. All manufacturing facilities should restrict access to crucial areas (i.e., generally areas of product exposure to the environment) and should establish and justify relevant control over these areas in terms of background bioburden contamination levels. The adequacy of this control is demonstrated through passive and active viable microbial monitoring of the air, and through monitoring the relevant surfaces with contact plates or swabs.

In addition, well-defined standard operating procedures (SOPs) are necessary for training and procedural consistency. No supervisor can be present at all locations at all times. Thus, each operator must be aware of his or her role in contamination control and know how to minimize the overall risk to batch integrity. The contamination-control plan should cite the need for clear SOPs on all aspects of manufacturing, monitoring, and control.

Bioburden control is simplified when a manufacturing process is well-defined and understood. As part of the process-validation procedures, the manufacturing process should be evaluated for its potential to limit or eliminate bioburden through bioburden-reduction steps. This evaluation can be performed using hazard analysis and critical control point analysis or the failure modes and effects analysis approach. Organic solvents, heat, and other elements can greatly reduce the bioburden of a process. Other factors, such as compression and associated shear, for example, should be evaluated for their ability to reduce the risk of excessive microbial contamination. The finished product’s water activity also should be analyzed for its ability to limit the growth of potential bioburden present in the product.

The requirements for bioburden control and monitoring are described in the pharmaceutical good manufacturing practices in sections 21 CFR 211.46(b), 21 CFR 211.84(c)(5), 21 CFR 211.110(a)(6), CFR 211.113(a–b), and 21 CFR 211.165(b). The “Orange Guide” of the European Union provides detailed guidance on aspects of this program, and additional guidance may be found in USP <1117> and the Parenteral Drug Association’s technical report #13, “Fundamentals of an Environmental Monitoring Program.”

Developing a contamination-control plan is a proven method to document a comprehensive system for minimizing or eliminating product contamination. This control plan should describe all aspects of the production process and environment and provide the rationale for the control measures taken. The plan also should describe minimal requirements for those measures and provide guidance on the system in place to monitor that state of control.

Scott Sutton, PhD, is the principal at The Microbiology Network, 150 Parkway, N. Chili, New York 14514, tel. 585.594.8273, [email protected]. He also is a member of Pharmaceutical Technology’s editorial advisory board.