This informal CPD article ‘Cleanroom Design and Validation: The Foundation of Contamination Control’, was provided by Pharmalliance Consulting, who offer specialist support to pharmaceutical companies to maintain and increase quality compliance levels.
Introduction
Pharmaceutical manufacturing requires tightly controlled environments to ensure product safety and efficacy. One critical aspect is the use of cleanrooms – specially designed spaces that limit contamination through rigorous controls on particles, air quality, and microbial levels.
Understanding Cleanroom Classifications
Cleanrooms are classified based on their cleanliness levels, measured in particles per cubic meter (PDA). In pharmaceuticals, different cleanliness grades align with specific stages of manufacturing, as outlined by standards like EU GMP and ISO 14644, which have equivalency. These standards establish classifications from ISO 5 (Grade A) to ISO 8 (Grade D), each suited to various contamination risks:
- Grade A (ISO 5) is the highest cleanliness level, used for critical processes like aseptic filling. Clean airflow and rigorous contamination controls are essential, achieved through laminar airflow cabinets that maintain low particle levels.
- Grade B (ISO 7 in operation) typically serves as a background environment for Grade A areas, where stringent particle and microbial limits are monitored.
- Grades C and D (ISO 7 and ISO 8) are applied to less critical processes, such as the initial stages of component preparation or equipment assembly.
The classification ensures that each manufacturing step occurs under conditions appropriate to its contamination risk level, which minimises the chances of microbial growth and particulate contamination.
Closed vs. Open Systems: Protecting Processes from Environmental Exposure
One important aspect of cleanroom design is the distinction between open and closed systems. In a closed system, all operations occur within sealed equipment, significantly reducing the risk of contamination from the environment. In contrast, open systems expose the product or process to the surrounding air, necessitating a higher cleanroom classification to control potential contamination.
For example, open bioprocesses, where product solutions are directly exposed, require cleanroom environments with strict contamination limits to keep microbial and particulate levels low. On the other hand, closed systems can operate in lower-grade environments as they inherently protect the product, reducing contamination risks and the need for high classification requirements.
Key Elements of Cleanroom Design for Contamination Control
The design of a cleanroom is vital in maintaining consistent cleanliness levels. The most important components of an effective cleanroom are:
- Properly designed airflow is essential to direct particles away from critical zones. In ISO 5 environments, unidirectional airflow keeps contaminants suspended, while lower-grade cleanrooms may use non-unidirectional patterns. Computational Fluid Dynamics (CFD) simulations help optimise airflow designs by predicting particle behaviour.
- Pressure differentials can be used to create barriers against contaminants, with cleaner areas kept at higher pressures to resist external air infiltration. This method is particularly effective when combined with airlocks, which reduce particle migration between spaces of varying cleanliness.
- Temperature control reduces human particle generation from perspiration, while humidity control prevents microbial growth.
Validation and Monitoring for Cleanroom Maintenance
Regular validation and monitoring are essential to confirm that cleanrooms continue to meet contamination control standards. Cleaning validation ensures that surfaces and equipment remain free from harmful residues and bioburden between uses. Clean hold studies, for example, test how long equipment can remain clean before requiring re-cleaning. Environmental monitoring helps detect any deviation from established cleanliness standards. Monitoring programs ensure that contamination is quickly identified and corrected, maintaining the cleanroom’s integrity and product quality.
Conclusion
Cleanrooms are the backbone of contamination control in pharmaceutical manufacturing, from their initial design to ongoing validation and maintenance. By applying appropriate cleanliness grades, designing for optimal airflow and pressure, and implementing robust monitoring protocols, pharmaceutical companies can protect their processes and ensure product safety. As technology advances, cleanroom design and validation will continue to be essential in maintaining the highest standards of cleanliness and quality control.
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References
PDA (Parenteral Drug Association), 2012. Points to Consider for Cleaning Validation, Bethesda, MD.
PDA (Parenteral Drug Association), 2021. Cleanroom Contamination Prevention & Control, Bethesda, MD.
