New USP Revisions to Proposed Rapid Microbiological Methods Chapters

Image created by Dr. Michael J. Miller

The new year brings some substantial revisions to prior drafts of USP chapters focused on the use of rapid methods for short-life products. Specifically, chapters <72>, Respiration-Based Microbiological Methods for the Detection of Contamination in Short-Life Products, and <73>, ATP Bioluminescence-Based Microbiological Methods for the Detection of Contamination in Short-Life Products, which were initially released for public comment in 2022, have had significant revisions which appear to address serious technical concerns with the previous versions. The revisions can be viewed online in the Pharmacopeial Forum (PF), issue 50(1), Jan-Feb 2024. The PF is a free bimonthly online journal in which USP publishes proposed revisions to USP–NF for public review and comment. Anyone can access the PF after a one-time registration is completed. The link to the OF login portal is: https://online.usppf.com/usppf.

A revision to chapter <1071>, Rapid Microbial Tests for Release of Sterile Short-Life Products: A Risk-Based Approach, has also been published for public comment. Additionally, chapter <86>, Bacterial Endotoxins Test Using Recombinant Reagents, can also be reviewed and commented on.

All chapters are currently open for public comment through March 31, 2024.

A summary of each chapter is provided below.

<72> Respiration-Based Microbiological Methods for the Detection of Contamination in Short-Life Products. 

This new chapter proposal is based on the version published in PF 46(6) as "Respiration-Based Rapid Microbial Methods for the Release of Short Shelf Life Products". The previous proposal has been canceled and is being replaced by this updated version, which includes the following revisions by the Microbiology Expert Committee:

• Change the title to "Respiration-Based Microbiological Methods for the Detection of Contamination in Short-Life Products."
• Change the requirements of the selection of culture media and incubation temperature to align with existing USP chapters.
• Add more requirements in the Method Suitability Test to include the following:
• Inoculation of test microorganisms at not more than 10 CFU.
• Specification that the list of microorganisms in Table 1 is the minimal requirement. Inclusion of product- and processing-relevant strains and local isolates should be considered with appropriate risk-based justification.
• Specification that positive control and negative controls should be included in the suitability test.
• Introduction of a safety margin concept to determine the longest time to detection.

<73> ATP Bioluminescence-Based Microbiological Methods for the Detection of Contamination in Short-Life Products. 

This new chapter proposal is based on the version published in PF 46(6) as "ATP Bioluminescence-Based Rapid Microbial Methods for the Release of Short Shelf Life Products". The previous proposal has been canceled and is being replaced by this updated version, which includes the following revisions by the Microbiology Expert Committee:

• Change the title to "ATP Bioluminescence-Based Microbiological Methods for the Detection of Contamination in Short-Life Products".
• Change the requirements of the selection of culture media and incubation temperature to align with existing USP chapters.
• Add more requirements in the Method Suitability Test to include the following:
• Inoculation of test microorganisms at not more than 10 CFU.
• Specification that the list of microorganisms in Table 1 is the minimal requirement. Inclusion of product- and processing-relevant strains and local isolates should be considered with appropriate risk-based justification.
• Specification that positive control and negative controls should be included in the suitability test.
• Guidance for the direct inoculation of the culture medium and membrane filtration when testing for the microbial detection in the product to be examined.
• Introduction of a safety margin concept to determine the longest time to detection.

<1071> Rapid Microbial Tests for Release of Sterile Short-Life Products: A Risk-Based Approach. 

This proposal is based on the version of the chapter official as of December 1, 2019. The Microbiology Expert Committee proposes the following revisions:

• Change the title to “Rapid Microbiological Methods for the Detection of Contamination in Short-Life Products—A Risk-Based Approach”.
• Redefine the application of rapid microbiological methods to short-life products.
• Introduce a calculation to evaluate the probability of contamination and define an adequate sample volume.
• Remove the limit of detection as the critical operation parameter to be used in determining a risk-based microbiological method.
• Provide more guidance on the validation and suitability testing of the rapid microbiological method.
• Update the example technologies to align with the USP Microbiology Expert Committee evaluation: ATP bioluminescence, nucleic acid amplification, respiration, and solid phase cytometry.

<86> Bacterial Endotoxins Test Using Recombinant Reagents. 

This proposed new test chapter provides additional techniques using non-animal derived reagents to the Bacterial Endotoxins Test <85>.

This general chapter is not currently being introduced into a specific monograph or listed in General Notices. It is the responsibility of the user to review the supplier's primary validation package and to verify product suitability for use in testing specific products or materials. This verification must include specific experiments to confirm that the method is suitable for its intended purpose under the conditions of use for the material, drug substance, and/or drug product. The selected verification experiments should be based on an assessment of the complexity of the material to which the method is being applied. The user should refer to Verification of Compendial Procedures <1226>. Regulatory authorities may require supplemental data prior to acceptance. An example of supplemental data may include a comparative study of the material tested by techniques described in this chapter and those in <85>.

Remember: the USP must receive comments no later than March 31, 2024 to be considered. You may submit comments by clicking on the "Submit Comment" button found in each proposed chapter.