For decades, drug companies have depended on a component in the blood of the horseshoe crab to test injectable medicines, including vaccines, for dangerous bacterial contaminants called endotoxins.
Conservationists and some businesses have pushed for wide acceptance of an alternative test, to protect the horseshoe crabs and birds that feed on their eggs. Earlier this year, these people seemed to be on the brink of success as the nongovernmental group that issues quality standards for such tests moved toward putting the alternative test on the same footing.
But on Friday, that organization, the U.S. Pharmacopeia, announced that the alternative test known as rFC (recombinant factor C) requires significantly more study.
Pharmacopeia representatives said they have 30 years of data on the current test and only two years on the new test so they needed more information.
Internationally, the European Pharmacopeia has approved widespread use of the alternative test.
The debate has been widely monitored as demand has grown for testing new vaccines against the coronavirus. Billions of vaccine doses would eventually require endotoxin testing.
Endotoxins are molecules in the cell walls of many common bacteria. E. coli is one, salmonella another. The toxins can cause fever and death in humans even if the bacteria that produced them have been killed. Toxic shock syndrome is caused by endotoxins.
Pharmaceutical companies must make sure the toxins are not present in any injectable drugs they make. Ingredients, like water, must be tested at each step of the manufacturing process, as well as in the final product.
“It is crazy making that we are going to rely on a wild animal extract during a global pandemic,” Ryan Phelan, the head of the nonprofit Revive and Restore, said before the recent decision. Her group supports technological solutions to conservation problems, including replacing the test that uses a component of horseshoe crab blood, called LAL, with a test that uses rFC. It is the synthetic equivalent of a chemical in the crab blood, produced by inserting genes for its creation into microorganisms grown in the lab.
The billions of doses of candidate vaccines, and many of the ingredients at many steps in the production process will all have to undergo endotoxin testing. But companies that produce LAL from horseshoe crab blood say that the supply is adequate.
Lonza AG, a multinational biotechnology company, sells both tests. Also, Lonza recently struck a deal with Moderna to produce a much publicized vaccine candidate for Covid-19. Lonza said in a statement that five billion doses of vaccine would require “less than a day’s combined production for all three LAL manufacturers in the United States.” The three manufacturers are Lonza, Charles River and Associates of Cape Cod. They all argue that the supply of crabs is more than adequate and current production could handle the vaccine surge without difficulty.
Ms. Phelan said this calculation “boggles the mind” because, “for every dose going out the door — each manufacturer will use 10 times the amount of LAL to test every step along the way in the process.” That includes vials, stoppers and other ingredients in the vaccines. In addition, Ms. Phelan said there are likely to be numerous companies producing vaccines in the test phase and along the way.
The rFC test is allowed by the Food and Drug Administration, which is the governmental agency that rules on the safety of drugs, but companies must do more work for their F.D.A. submissions than if they were to use the standard test.
The F.D.A. relies both on work done by manufacturers and on the standards set by the U. S. Pharmacopeia. If a company uses rFC, it must demonstrate to the F.D.A. that, for each new drug, rFC is as effective as the standard LAL test.
The U.S. Pharmacopeia also announced that it would provide some additional information for any vaccine makers to assist them in doing the tests to validate rFC. Revive and Restore had been asking for some form of emergency authorization for use of rFC, given the stress of potential vaccine production.
One company that is turning to the new test in a big way is Eli Lilly, which also pushed for broader approval of the new test.
Jay Bolden, a biologist with Eli Lilly, said the company had been looking at rFC testing since 2015 for several reasons, including a consistent quality of a lab product, a supply that doesn’t depend on an animal population, a company commitment to replace animal use when possible and a reduction in costs.
“In 2016,” he said, “we kind of drew a line in the sand.” The company decided to use rFC for new injectable products even if additional work is required. It has since had one new product, a migraine medicine, approved in the United States by the F.D.A.
On Monday, Mr. Bolden expressed disappointment with the Pharmacopeia decision. “It probably looks like a three-to-four year delay with no guarantee,” he said, that rFC would be considered equivalent to the LAL test.
Rob Anderson, the vice president of global communications at the U. S. Pharmacopeia, said that more evidence is needed to show the equivalence between the two tests because of the many years of data on LAL and a lack of data on rFC.
Fouad Atouf, the vice president of global biologics for the rFC, said the reason for caution was that “we are dealing with a safety test.” And more evidence was needed on rFC.
“We’re working to build that evidence base and data,” Mr. Anderson said, “But we can’t put a time on that.”
Dr. Bolden, at Eli Lilly, said that given the delays his company will continue using rFC but follow a different path in submissions to the F.D.A.
“We’ll just start using the European test chapter,” he said, referring to the European pharmacopeia’s inclusion of rFC, which “goes live July 1.” He said the company had reason to believe the F.D.A. would accept the information from the European group, which would, essentially, put the alternative test and the traditional one “on an even playing field.”
nytimes.com, 3 June 2020