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Final Revision to Annex 1 Published - Rapid Methods Highlighted

Image created by Dr. Michael J. Miller

After many years, the final revision to Annex 1 "Manufacture of Sterile Medicinal Products," under the The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, was published today, and will go into effect August 25, 2023.

The revision may be downloaded here:

Of note, the use of rapid and alternative microbiological methods is encouraged. Specifically:

"The use of appropriate technologies (e.g. Restricted Access Barriers Systems (RABS), isolators, robotic systems, rapid/alternative methods and continuous monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of endotoxin/pyrogen, particulate and microbial contamination such as personnel, materials and the surrounding environment, and assist in the rapid detection of potential contaminants in the environment and the product."

"The adoption of suitable alternative monitoring systems such as rapid methods should be considered by manufacturers in order to expedite the detection of microbiological contamination issues and to reduce the risk to product. These rapid and automated microbial monitoring methods may be adopted after validation has demonstrated their equivalency or superiority to the established methods."

"For products with short shelf life, the environmental data for the time of manufacture may not be available; in these cases, the compliance should include a review of the most recent available data. Manufacturers of these products should consider the use of rapid/alternative methods."

Some of the most encouraging changes are associated with the use of rapid methods instead of the standard methods for environmental monitoring. For example, one of the notes in Table 2, which discusses the maximum permitted microbial contamination level during qualification of a cleanroom, states, "Limits are applied using CFU throughout the document. If different or new technologies are used that present results in a manner different from CFU, the manufacturer should scientifically justify the limits applied and where possible correlate them to CFU." Therefore, the EU allows us to revise the numerical values for the CFU-based maximum permitted microbial contamination level to new numerical values based on a rapid method's alternative microbial detection signal. One example of a new rapid signal is an intrinsic fluorescent count which can be derived in real-time and does not require growth on conventional microbiological media. 

Similar guidance on the use of alternative limits is provided in the footnotes for Table 6, which discusses the maximum action limits for viable particle contamination during routine manufacturing. Additionally, although the table provides CFU-based limits for active air samples, settle plates, contact plates and glove prints, one footnote allows for the use of methods other than those specified in the table. Specifically, "[I]t should be noted that the types of monitoring methods listed in the table above are examples and other methods can be used provided they meet the intent of providing information across the whole of the critical process where product may be contaminated (e.g. aseptic line set-up, aseptic processing, filling and lyophilizer loading)." 

The finalization of this long-awaited revision is welcomed and demonstrates  the EU's commitment to advancing the detection of microorganisms during sterile drug manufacturing by encouraging and implementing 21st Century rapid microbiological methods.

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