EMA: 3 new Q&As on EU GMP Annex 1
The EMA has published 3 new or updated questions and answers on Annex 1 of the EU GMP Guide. They deal with bioburden levels and sampling, and open versus closed isolators. The answers are summarised below:
What is the maximum acceptable bioburden level?
The specification limits for bioburden should be NMT 10 CFU/100 ml, in line with the guideline “sterilisation-medicinal-product and active-substance ref EMA/CHMP/CVMP/QWP/850374/2015)". This applies also when a prefilter is installed. Exceptions may be considered with appropriate justification, such as processes involving fermentation or specific components, where a higher bioburden limit before prefiltration might be acceptable. In such cases, it is crucial to demonstrate that the first filter can achieve a bioburden limit before the last filtration of NMT 10 CFUs/100 ml, aligning with notes for guidance on manufacture of the finished dosage form (CPMP/QWP/486/95 and EMEA/CVMP/126/95).
Is rapid method valid for the detection of microorganism within grade A and B?
Rapid method is one of the alternative monitoring systems that may expedite the detection of microorganisms pending that the requirements of annex 1 points 9.28, 9.30 and 9.31) are fulfilled.
Is an isolator considered as a „closed isolator“ if the semi-continuous ingress and/or egress of materials during operations isconducted via reproducible biodecontamination steps?
The answer discusses the distinction between two types of isolators outlined in Annex 1. Closed isolator systems prevent external contamination by using aseptic connections to auxiliary equipment, remaining sealed throughout operations. Open isolator systems, on the other hand, allow continuous material transfer through engineered openings, maintaining isolation through measures like continuous overpressure.
An isolator interfacing with a material transfer airlock that uses a reproducible bio-decontamination steps (active vapor-phase hydrogen peroxide (VPHP) decontamination) may be considered a closed isolator if it effectively prevents external contamination, supported by qualification/validation studies and monitoring data. Specific considerations include the validation of VPHP cycles and protection of the filling chamber environment by a sealed door during loading and decontamination. However, it is important to discuss these elements with the competent authority.
What are the requirements for the bioburden sampling to support parametric release?
Annex 1 and Annex 17 emphasise the need for a pre-sterilisation bioburden monitoring program to support parametric release of products. Both documents stress the importance of developing such a program, performing bioburden assays for each batch (or sub-batch), and selecting sampling locations based on worst-case scenarios representative of the batch. Identification of any organisms found during testing is crucial.
Companies are advised to consider the bioburden on a batch or sub-batch level, with careful consideration of the time between sampling, sterilisation, and testing. Any alternative approaches should be thoroughly justified, taking into account materials involved, homogeneity of bioburden within sub-batches, presence of organisms, and the time elapsed between sampling and sterilisation.
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