3.2.P.2.5 Microbial Attributes

Biological drug products are composed of heat sensitive active substances for which terminal sterilization is not a suitable unit operation for obtaining a sterile product. Instead, sterility of the product is ensured through aseptic validation and control of several microbial attributes. The single most critical aspect is proper training and qualification of staff in the aseptic procedures. Equally important is the prior knowledge from the cGMP manufacturing site in terms of facility design, cleaning and environmental monitoring.  Apart from this, several elements are required to ensure a proper control strategy for sterility throughout the entire supply chain.  

The following items are key elements in the aseptic control strategy; 

• Bacterial endotoxin and bioburden monitoring before sterile filtration 

• Filter validation of the sterile filter 
  a) Filter Integrity testing

b) Compatibility 

c) Bacterial retention challenge

• Media fill validation 

• Closure integrity of the primary packaging.  

For multiple use drug products which contain preservatives the same as above applies including preservative efficacy testing according to compendial requirements. However, once the drug container has been breached the product cannot per definition be considered as sterile unless the repeated dose preparation and storage has been under aseptically validated conditions.  

Background and requirements 

The ICH M4Q provides limited guidance on microbial attributes for injectable products. More product specific requirements for aseptic drug products can be found in ICH Q4B-Annex 8 and EudraLex-Annex 1.

What type of information should be presented in CTD section 3.2.P.2.5? 

The results and conclusions on the validation studies mentioned above should be presented and reflect the expected commercial manufacturing process.  

Bioburden data from representative batches should be presented based on routine sampling of the bulk formulation prior to end of filtration. Appropriate bioburden limits must be in place at this step.

Container closure integrity testing (CCIT) has been gaining much attention the recent years. The test methods and understanding of the closure process and primary packaging properties have advanced significantly which makes this variable statistically more tangible to monitor and control as part of the aseptic fill & finish process. The CCIT serves as a verification of the barrier properties and demonstrates that the primary packaging is capable of withstanding ingression of contaminants from external sources. This must be confirmed for release of drug product but also end of shelf-life data should be available on representative batches.

Attributes that need to be controlled in order to ensure drug product sterility. For each variable a validation study or monitoring with well defined acceptance criteria should be in place.