The biomanufacturing industry and BioPhorum are on a journey to build more sustainability into processes and analytical methods. Sustainability takes many paths, but one of them is to reduce the use of animals and animal-derived products.
Testing for bacterial endotoxins is mandatory for all parenteral products and is traditionally done using the blood of the Atlantic horseshoe crab, using the Limulus Amebocyte Lysate (LAL) test that has been used since the 1970s.
An alternative test method – the recombinant Factor C (rFC) method – has been available for many years, using only synthetic components and is typically more sensitive and specific than the LAL test. This has been recognized by many compendial standard organizations that include the alternative method in their pharmacopeias – except the USP.
Because of the non-inclusion of the rFC method in the USP, take-up has been slow as it has been seen as unacceptable in the US market. However, this does not reflect the FDA position, i.e., that the rFC method is acceptable if appropriate validation is provided.
FDA expectations for validation were presented at the 2021 PDA Endotoxins Workshop through a session entitled FDA perspective on recombinant endotoxin detection systems. The presentation recognized that the validation package provided by rFC method suppliers can be a major contributor to FDA expectations, thereby drastically simplifying implementation by biomanufacturers.
Several BioPhorum members have taken the opportunities presented by FDA to implement the rFC method. However, questions are still being asked regarding the US review of submissions, including rFC methods for testing bacterial endotoxins or US inspection of manufacturing sites using rFC methods. Within BioPhorum organizations, internal questions also arise around the justification for implementing the alternative method.
This is why the Regulatory Governance team has published presentation slides on Introduction to Recombinant Factor C Endotoxin Testing to be used as a response to these questions.
The presentation introduces the rFC method and its suitability as an alternative to a compendial LAL test in the US. It compares LAL and rFC testing methods and briefly discusses the similarities (e.g., principle, sample preparation and calibration) and the differences (e.g., origin and purity of the reagent, and the detection method for activity).
It also talks about the added benefits of the rFC testing method, such as compliance with the 3R principles of animal testing that our members all support (Replacement, Reduction, and Refinement), higher specificity, and better lot-to-lot reproducibility. The slides also consider the current regulatory landscape.
Importantly, our slides summarize a validation approach for rFC as an alternative to a compendial method. This covers:
- Performance qualification
- Method suitability at the testing site
- Method suitability for the product – definition of the non-interfering concentration
- Method suitability for the product – test for interfering factors.
Our Regulatory Governance team is also exploring the opportunity to share the slide pack with FDA reviewers and inspectors to proactively preempt and address future questions.
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