BET
collection methods have matured, and consistent with the basic tenants of Good Manufacturing Practice, more reagent is currently used to monitor water systems, raw materials and processes than is used to test finished product. Today, we realize the benefits of thinking about product lifecycles so that we can identify critical control points for endotoxin in raw materials, equipment, and process during the development phase, well before the product goes commercial. We understand that we can’t test quality into the product, but we can monitor quality of the product throughout the process.
This test has served patients remarkably well for the last 40 years, and we (including countless numbers of New Zealand White rabbits) are in debt to the scientists in FDA and industry who researched, realized, regulated and commercialized BET assays. Over the years, we have made the assay convenient for people to use so that we can continue to ensure patient safety. In spite of the many changes in the value of testing, the BET community is still faced with some challenges going forward.
“Food for Thought” – The Next 15 Years
With the advent of more complex drug product formulations, particularly in biologics, and with the increasing number of therapeutic and administration options (time release, nanoparticles, combination drugs), the BET community will be faced with new challenges to testing. We will likely find more formulations that interfere with the BET assay, meaning that we will have to not only understand the product formulation, but the science of the LAL reaction to determine the cause of the interference and the appropriate mitigations.
We know that the variability in microbiological assays is significantly higher than for standard analytical assays. Is the BET assay an analytical assay because it has a computer, a standard curve, and a result that reports out to 4-5 significant figures or is it a biological assay with a considerable error? We need to understand the scientific and mathematical limitations of the assay to understand the sources and implications of variability.
Until recently, the focus of the BET assay has been endotoxin as a Pyrogen (fever causing agent).
The underlying studies to support the current
threshold pyrogenic dose were conducted by looking at temperature rise after injection of metered levels of an endotoxin standard. We know, however, that endotoxin can result in a variety of clinical manifestations,
not the least of which is inflammation. Should we be concerned about threshold inflammatory dose? If so, how does that impact on different routes of administration including inhalation, intraocular, intraperitoneal or topical application?
The use of an endotoxin standard has served us well for the last 40 years, yet endotoxin standards do not exist in nature.
The endotoxin
that contaminates our product is different than the Reference Standard Endotoxin (the primary standard, or RSE) or the Control Standard Endotoxin (secondary standard, or CSE) that we use to prepare positive product controls and standard curves. We know that the product matrix can affect endotoxin aggregation and recovery of purified endotoxin, so when is it appropriate to use a natural endotoxin in recovery studies? How do we justify such use, and how do we prepare those “natural” standards? Is an endotoxin standard necessarily the best to use for depyrogenation studies? Is the current requirement for a 3 log reduction of purified endotoxin standard the best indicator of depyrogenation, or is it more practical to validate the reduction of naturally occurring levels of endotoxin to levels that are safe for patients?
With endotoxin, as with all tests, we are challenged to make the best use of the data. Because of variability, the accuracy of and information provided by any single test result is not as great as the trend drawn from a series of data points. Process control is all about trends and connections to other systems or actions taken by the company. With the implementation of more formal process control programs in our industry, we need to continue to explore benefits of trends and assure that we use this valuable tool to our best advantage.
Indeed, we have come a long way technically, but the more difficult tasks of understanding the information that we get from assays and acting on it will continue to confront us. As an industry, we will meet the challenge to make the best of the tools that have been provided to assure process control and patient safety.
Congratulations and thank you to American Pharmaceutical Review for fifteen years of providing those of us who manufacture and test pharmaceutical products with information on the latest in technological innovation and compliance.
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