Pharmaceutical Cleanroom Design: Key Points in Process Planning

The safe and high-quality drug production process is largely achieved through pharmaceutical cleanrooms. To meet stringent regulatory requirements, these meticulously designed and managed clean environments maintain low levels of pollutants such as dust, microorganisms, and airborne particles. The primary goal of cleanrooms is to prevent contamination and cross-contamination, thereby protecting drugs from impurities that could compromise their safety or efficacy.

I. Pressure Control Requirements

Pressure gradients must be established between rooms of different cleanliness classes to prevent cross-contamination. According to EU GMP Annex 1, the pressure differential between two areas of different cleanliness levels should be at least 10 Pa.

Pressure levels are typically controlled by maintaining a constant supply airflow while regulating exhaust airflow through volume flow controllers to sustain the required pressure differentials. In sterile drug production areas, pressure differences must be continuously monitored and recorded. Alarms must be triggered in case of pressure drops. This requirement also applies to airlocks.

II. Types of Pressure Control

Generally, two different types of pressure cascade systems can be distinguished: the "bubble type" (positive pressure system) and the "sink type" (negative pressure system).

1.       The bubble system focuses on protecting the product from contamination from adjacent less clean areas and personnel. This is achieved by maintaining a higher static pressure in the cleanroom or cleanroom area compared to adjacent areas, ensuring that airflow moves from cleaner to less clean zones. This prevents airborne contaminants from entering from lower-classification areas. Bubble systems are commonly used in the manufacture of liquid products, which are generally more susceptible to microbial contamination.

2.       The sink system is used in situations where, in addition to product protection, the safety of personnel and the environment is also critical. Examples include handling highly active pharmaceutical ingredients or radioactive substances. To prevent contaminated air from reaching adjacent areas, a negative pressure is maintained in the hazardous area relative to the surroundings/adjacent zones. This system is typically employed in areas where dusty materials or products are processed. To select the appropriate pressure system for the intended production, the following steps are necessary:

● Analyze the entire production process and document all process steps required to determine the cleanroom classification.

● Conduct a risk analysis: What is the primary protection requirement (product, personnel, environment)?

● What are the contamination risks (particles, microorganisms, endotoxins/pyrogens, chemicals)?

● What are the potential sources of product contamination?

● Where does the greatest contamination risk lie?

III. Key Planning and Design Considerations

Planning and designing a clean zone is a challenging task. To avoid errors, the following aspects should be particularly considered:

● Where there is a risk of recontamination, separate airlocks should be provided for the entry and exit of materials, waste, and/or products.

● Sufficient space should be allocated for material transfer.

● Adequate storage space should be available even within classified areas—airlocks are not storage areas.

● Materials in different states should be separated within storage areas.

● Washing and processing rooms should be separated—through-type washers and sterilizers are ideal.

● Decontamination procedures must be followed when materials enter.

● Access to all areas should be controlled.

A well-managed cleanroom continuously dilutes or displaces contaminants generated during the drug production process, creating the necessary background environment for the process. It positions equipment or processes in a manner suitable for their intended use and controls and manages the flow of people and materials through effective planning and operation to prevent contamination and cross-contamination.