New Method for Botox Analysis Involves No Lab Animals
In October of 2010, Botox (onabotulinumtoxinA) was approved by the FDA for the treatment of chronic Migraine. This prompted many discussions of its use for Migraine prevention. Among those discussions, I remember at least one in which some people decided they would not use Botox because it was tested on lab animals.
Allergan, the manufacturer of Botox, recently announced FDA approval of a new analysis method that replaces animal testing. To share this good news with you, here's the press release regarding this new method of testing:
Allergan, Inc. today announced the United States Food and Drug Administration (FDA) has approved a fully in vitro (outside the body in an artificial environment), cell-based assay for use in the stability and potency testing of BOTOX® (onabotulinumtoxinA) and BOTOX® Cosmetic. The newly approved assay will be implemented immediately for release of product for sale in the United States. Allergan estimates that use of the new assay will reduce the use of animal-based assay testing for BOTOX® and BOTOX® Cosmetic by up to 95 percent or more over the next three years, as other regulatory agencies around the world approve this new assay. The new assay is the first to be developed and approved for any botulinum neurotoxin currently available worldwide, and is specifically applicable to Allergan’s botulinum toxin type A product.
“We are proud to have achieved this major scientific milestone in the development of a safe and effective alternative test capable of eliminating the need for an animal-based assay for BOTOX®,” said Scott Whitcup, M.D., Allergan’s Executive Vice President, Research and Development and Chief Scientific Officer. “Following the FDA approval, we will work hard to secure approval of the new assay to replace the current animal testing requirements for the release and stability testing of BOTOX® and BOTOX® Cosmetic in countries in which we market and distribute the product.”
The FDA approval follows more than a decade of Allergan research and development and an approximately $65 million investment directed toward minimizing to the greatest degree possible the need for animal-based assays in the manufacture of BOTOX® and BOTOX® Cosmetic. The mouse LD50 potency assay is required by the FDA, the Medicines and Healthcare products Regulatory Agency (MHRA) in Europe and regulatory agencies around the world for testing final product for release to assure its safety and efficacy. Limitations associated with the current mouse LD50 assay, which has been the standard for potency and stability testing of BOTOX® and BOTOX® Cosmetic and other botulinum neurotoxin type A products, include the necessary involvement of animals due to the current structure of the assay, the complexity of the procedures involved, lack of specificity, as well as variability between assays and laboratories.
“The new cell-based potency assay we have developed for BOTOX® and BOTOX® Cosmetic has many advantages over current methods including the potential for greater precision and consistency in stability and potency testing, making this a significant breakthrough in both the science and manufacturing of neurotoxins,” said Timothy Terrell, DVM, Ph.D, DACVP, Allergan’s Senior Vice President, Drug Safety Evaluation.
Currently all pharmaceutical manufacturers are required by the FDA and by other worldwide health regulatory agencies to protect patients and consumers by assuring product safety and efficacy through animal testing and other methods. BOTOX® is a unique and complex biological product with 21 different approved medical uses, and is derived from natural sources – in this case from the bacterium C. botulinum. When manufacturing biological products, testing is particularly critical to ensuring the consistent safety and efficacy of each batch of product. BOTOX® and BOTOX® Cosmetic are the same product, manufactured in exactly the same way, and therefore the potency and stability of each batch must be determined before release, regardless of whether the batch is intended for medical or aesthetic use. BOTOX® is Allergan’s only product that has required use of an animal-based assay for stability and potency testing, as mandated by global regulatory authorities to ensure safe product use in humans.
About the BOTOX® Cell-Based Potency Assay (CBPA)
Over the years a number of attempts have been made to find strategies to replace the animal-based LD50 assay for testing of botulinum neurotoxins but have fallen short for a variety of reasons. Botulinum neurotoxin is one of the most potent naturally occurring substances and has a complex multi-stage mechanism of action. Purified botulinum neurotoxin type A is the active ingredient in BOTOX® and blocks the release of neurotransmitters from nerves, resulting in a localized and temporary reduction in the overacting muscle or gland. The amount of neurotoxin in BOTOX® is extremely small; in fact, less than one gram per year is required to supply the entire world.
A suitable replacement potency assay to the LD50 assay must therefore be sensitive enough to measure the complex mode of action of extremely small amount of the neurotoxin used in BOTOX® in the cellular level. Established performance criteria against which the new cell-based potency assay needed to be validated included the ability to assess all primary modes of action of the neurotoxin. In addition, the new assay format had to be suitable for use in an intensely quality-controlled environment and at the high capacity needed to support commercial production.
“This significant achievement was made possible by Allergan scientists’ long-standing leadership and deep expertise in neurotoxin research and development, and by our corporate commitment to the “3R” principles of refinement, reduction and eventual replacement of laboratory animals in the final manufacturing stages of BOTOX®,” said Dr. Terrell.
The new cell-based potency assay for BOTOX® and BOTOX® Cosmetic is specific to Allergan’s formulation of botulinum neurotoxin type A. Allergan is discussing how to license the technology to other parties that share its commitment to implementing non-animal alternatives to animal-based assays in the manufacture of their medical products.
Kudos to Allergan for developing this new method of testing without lab animals. It will be interesting to see how many other companies follow their lead.
Press Release. "Allergan Received FDA Approval for First-of-Its-Kind, fully in Vitro, Cell-Based Assay for Botox® and Botox® Cosmetic (onabotulinumtoxinA)." Irvine, California. June 24, 2011.