Guidance for the manufacturing of sterile medicinal products

This standard applies to sterile medicinal products and active substances, and focuses on preventing contamination of products by particulates, microbes and endotoxins (a fever-causing pyrogen). Some guidance may also be used to support the manufacture of non-sterile products (e.g., liquids, creams and ointments) where contamination control is important to control bioburden levels and ensure efficacy of final terminal sterilization steps. 

Specific guidance for cleanrooms used in the manufacturing of sterile medicinal products includes 4 grades:  

  • Grade A: Local zones for high-risk operations (e.g. a sterile filling zone).
  • Grade B: For aseptic preparation (i.e., a background environment for grade A zones where barrier technology is not used to protect the Grade A zone).
  • Grade C/D: Clean areas for performing less-critical manufacturing steps. 

Cleanrooms and clean air devices should be classified in accordance with ISO 14644-1:2015 and should be routinely monitored based on a formal risk analysis. Note: it is not considered acceptable to use the method in ISO 14644-1:2015 for routine environmental monitoring programs. Users must carry out a risk assessment to determine where their product/process is most at risk and define a routine environmental monitoring program to ensure they routinely sample in those locations.

Manufacturers should perform continuous air particle monitoring for all critical processing steps in grade A zones, unless potential contaminants would damage particle counters or present a hazard (e.g., live organisms and radiological materials). In such cases, monitoring during routine equipment set up operations should be done prior to risk exposure. 

Manufacturers should also perform air particle monitoring during simulated operations. 

Monitoring frequency

Manufacturers should monitor grade A zones at such a frequency—with suitable sample sizes—to ensure all interventions, transient events, and potential system deterioration are captured, and alarms triggered if alert limits are exceeded.  

They should use a similar monitoring system for grade B zones, although sampling frequency may be decreased.