Answers by EMA on the Topic Bioburden

Recommendation

18/19 June 2024
Copenhagen, Denmark

Environmental Monitoring
Compliant and Reasonable

EMA (European Medicines Agency) answers at random intervals questions arising from the EC GMP Guideline and its Annexes. Actually, two questions on the topic bioburden from Annex 1 "Manufacture of Sterile Medicinal Products" are answered:

Where should bioburden monitoring take place for an aseptically produced product?

Annex 1 describes that the bioburden should be monitored before each sterilisation and testing should be performed on each batch. For routine commercial manufacturing, bioburden testing should be performed on the bulk solution, immediately before its sterile filtration. If a prefilter is additionally installed, then sampling for bioburden testing should be performed prior to the prefiltration, provided that the actual filtration is carried out immediately afterwards!

What is the maximum accepted bioburden level?

With reference to the EMA Human and Veterinary Notes for Guidance on Manufacture of the Finished Dosage Form (CPMP/QWP/486/95 and EMEA/CVMP/126/95) a bioburden limit of no more than 10 CFU/100 ml is specified. When a prefilter is installed, this value should also be achieved prior to the prefilter. Higher bioburden limits should not be justified by the higher capacity of two consecutive bacteria retaining filters.

Exceptions can be made in the areas of  fermentation or biological or herbal components, or if purified water is used for ophthalmic preparations. But, in such cases, it should be demonstrated that the prefilter has the capability to achieve a bioburden prior to the last filtration of no more than 10 CFUs/100 ml.

Sources:
CPMP/QWP/486/95 - Committee for proprietary medicinal products - Note for Guidance on Manufacture of the Finished Dosage Form

EMEA/CVMP/126/95: Committee for veterinary medicinal products - Note for Guidance: Manufacture of the Finished Dosage Form

EMA Questions & Answers