Get your Sterile Device to Market with Ease: Understanding Five Key Endotoxin Testing Requirements

By: Laura Lakemeyer, Senior Microbiology and Quality Consultant

Important ST72:2019 updates can help ensure successful 510(k) submissions or avoid non-conformances

The American National Standards Institute (ANSI) and the Advancement of Medical Instrumentation (AAMI) recently released substantial revisions to the updated standard ANSI/AAMI ST72:2019, Bacterial endotoxins – Test methods, routine monitoring, and alternatives to batch testing. An understanding of the key updates can help ensure that your 510(k) submissions pass successfully or prevent non-conformance setbacks.

Changes Leading to the ST72 Update
In 2016, the FDA clarified their expectations for bacterial endotoxin testing of sterile devices in a new Guidance for Industry, expanding on the requirements for implantable devices. One of the most impactful changes of this guidance was the inclusion of “implants” on the list of device categories that should meet pyrogen limit specifications. For devices that had been historically excluded from the testing requirement, this presented a new challenge for manufacturers with little to no endotoxin testing experience. Further, committing to batch release bacterial endotoxin testing proved to be challenging, especially for devices produced in small batches. While ANSI/AAMI ST72 (2011), provided guidance on this topic, the need for a more instructional guidance to speak to the now broader audience was evident.

Key Updates
While the revised ST72:2019 standard includes many new and updated definitions for terms used throughout the document, including acceptance of a new ambeocyte lysate reagent, (Tachypleus tridentatus, (TAL) and clarification on test methods, we will focus on five of the key updates that make this revision so important.

  1. Reduction of minimum batch requirement for qualification/ suitability studies –  The minimum requirement of three batches per product or product family for qualification studies has been reduced to a minimum of one batch per product or product family to demonstrate method suitability. While the minimum requirement has been simplified in ST72:2019, it should be noted that the clause also states that the number of batches chosen for the suitability study must be justified and reflect the level of process control.
  1. Product required to be non-pyrogenic – Applicability of the non-pyrogenic requirement has been substantially expanded to include implantable medical devices for bacterial endotoxin evaluation. This discussion includes specific guidance on how to determine if certain device components may be excluded, in particular multi-component kits. Implantable medical devices that only make contact with intact tissue during use may be excluded.
  1. Annex B, Guidance on test methods, routine monitoring, and alternatives to batch testing – Annex B is not a new annex, but now includes examples of an alternative to a batch testing sampling plan, a risk assessment flow diagram and worked examples for Maximum Valid Dilution for both an extract solution and using extraction volume.
  1. Annex D, Guidance on in-process monitoring of manufacturing processes or component testing – Annex D is a new addition to ANSI/AAMI ST72, providing specific guidance on selection of a sampling plan. A sampling plan of 3% of a given batch, with a minimum of 3 samples and maximum of 10 samples taken at random is generally recommended, however, the standard acknowledges that based upon a risk assessment, a smaller sampling or sample pooling may also be appropriate. This annex includes examples of criteria to consider when performing the endotoxin risk assessment for in-process and end-product testing.
  1. Annex E, Guidance on conducting a risk assessment to support alternatives to batch testing – One of the most important updates to ANSI/AAMI ST72 is the expanded guidance on how to evaluate and justify alternatives to batch testing. Annex E provides the framework for conducting a risk assessment and real-world examples to assist in ranking severity, probability and the overall assessment of risk. Worked examples help demonstrate why it would be expected to implement additional control measures to mitigate identified risks despite an overall risk rating in the acceptable range. This annex also demonstrates how to use the risk assessment to define and justify sample size and testing frequency.

If you are a manufacturer of a sterile device with bacterial endotoxin testing questions or are interested in other ways QA Consulting can support your medical device business, please call 512-328-9404 or email at info@qaconsultinginc.com.

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