In August 2023, the US Pharmacopeia announced that there was going to be an addition to the endotoxin testing information.
This new addition included official instructions for using recombinant factors for endotoxin testing in new chapter <86>. The current official procedure is based on the reagent LAL, derived from bleeding horseshoe crabs in chapter <85>.
Horseshoe crabs currently play a critical role in ensuring the health of the Atlantic States’ coastal ecosystem and populations are currently suffering from this use.
These recombinant factors have been around for a while and remove the need for animal products, and thus have obvious environmental and ethical benefits.
The comments and FAQs unveiled some interesting questions and hinted at the direction of the USP in the future
Despite these benefits, there has been hesitancy in adopting the recombinant factor approach. This has been attributed to concerns about validation and accuracy, as well as the lack of compendial status with the USP and global standards harmonisation.
In November 2024, the USP published the comments the organisation received in response to this announcement, as well as an FAQ page on the issue.
The comments and FAQs unveiled some interesting questions and hinted at the direction of the USP in the future.
Alternative?
Among the reagent manufacturer commenters were bioMérieux, Charles River, Lonza, and Associates of Cape Cod.
Generally, all of the manufacturers received the news positively, with Charles River saying it was "pleased to see the inclusion of commercially available recombinant Factor C and recombinant Cascade Reagents in draft Chapter <86>", and bioMérieux saying is "strongly believe[s] that this is the right way to innovate in pharmaceutical microbiology labs."
Both Lonza and bioMérieux were in favour of the addition, but believed that the terminology of "alternative" was confusing.
Lonza: "This document states that the recombinant products are Alternate Tests. Therefore the document should be numbered above 1000, which is for alternative tests that are guidelines and not regulatorily enforceable. If this is not an alternative test, please state such by removing the word “alternative”.
bioMérieux: "Alternative in this context can be misleading."
Future innovation and harmonisation
Looking at the future of this change, there are a few factors that commenters considered.
The European Federation of Pharmaceutical Industries and Associations (EFPIA) expressed concern that the tests identified in the new chapter were limiting to new agents.
EFPIA: "The acceptance should not be restricted to rFC (recombinant Factor C) and rCR (recombinant Cascade Reagent) only, but potentially to new recombinant agents, after adequate validation"
Further, many commenters examined the decision to make <86> separate to <85>.
Anthony Cundell said: "If the USP believes the reagents are comparable I recommend that <86> be folded into <85> as a local option until it becomes part of a harmonised test."
This was such a common question, and USP included it in its FAQs, stating: "<85> is a harmonised chapter with corresponding chapters in Europe, India, and Japan. These chapters are part of ICH Q4B, which implies that they are considered interchangeable within the regulators in the ICH regions. Therefore, it is more difficult to make changes in a timely manner. Harmonising current and future rBET chapters is desired."
For USP standards, cross-pharmacopoeia harmonisation occurs through the Pharmaceutical Discussion Group (PDG). The USP further stated in the FAQs that "harmonisation via PDG is achievable and desired; efforts are underway to open the discussion for future harmonisation with PDG," stated USP.
The environmental sector's reaction
The announcement was welcomed by many environmental organisations such as Friends of Animals and PETA.
The USP was also inundated with encouragement for the change, seemingly from supporters of these charitable organisations. Evidenced by a pre-written comment being sent into the USP hundreds of times.
Friends of Animals as an example, said: "Friends of Animals commends USP’s efforts to switch to animal-free methods and materials."
However, a push for more came from Jeffrey Brown, Senior Scientist, Pharmaceuticals and Medical Devices PETA Science Consortium International. Brown said: "Additional language would be beneficial to communicate the key aspects of product specific validation, as new products in development should not be expected to be evaluated using the BET before being evaluated using rFC.
