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Alternative method to animal experiments used for testing Botulinum Neurotoxin-containing medical products

39/2015, 17.12.2015

Working group headed by the German Federal Institute for Risk Assessment (BfR) advises on the development and validation of alternative methods to replace animal experiments

Botulinum Neurotoxin-containing medical products are used for many different purposes. Among them are, for example, the treatment of eyelid spasms, torticollis and post-stroke spasticity, and also reduction of facial wrinkles in aesthetic medicine. Up until recently, the activity of Botulinum Neurotoxin products (BoNT-products) was determined with a lethalitiy test (LD50 activity test) using mice, which is required by the regulatory authorities. In December 2015, the Federal Institute for Drugs and Medical Devices (BfArM) approved a cell-based assay to replace the LD50 activity test on mice for certain products containing the active agent Botulinum Toxin Type A. "The approval of this alternative method is a major success for the work of the BoNT Expert Working Group of the BfR and a good example of the work of the BfR as the German Centre for the Protection of Laboratory Animals", says BfR President Professor Dr. Dr. Andreas Hensel. "It is our goal to restrict animal experiments to the indispensable amount and to ensure the best possible protection of laboratory animals." This new alternative method to animal experiments for testing Botulinum Neurotoxin-containing products is approved throughout the EU.

BoNT stands for Botulinum Neurotoxin, a metabolite of the bacterium Clostridium Botulinum. BoNT-containing products are used for many purposes. Before these products may be used on patients, the efficacy of the products must be verified. Botulinum Neurotoxin is the strongest known neurotoxin. Following injection, it leads to paralysis by inhibiting neurotransmission from nerve cells to muscles. This is precisely the effect which is used for therapeutic purposes. It is important to ensure, however, that BoNT products are safe for patients.

Due to the high toxicity of BoNT products, regulatory authorities worldwide demand precise activity measurement for each production unit launched on the market. As part of this requirement, each batch of a product must be tested before it is approved for patient use. Tests must also be conducted to ensure the stability and hence the consistent quality of the products.

Until recently, the LD50 activity test was the standard test for BoNT products. As part of this test, mice are injected with different concentrations of BoNT. Thereafter the BoNT concentration is determined at which 50 % of the mice die. Since this test causes severe suffering to the animals, alternative methods to replace it are now being developed worldwide.

In 2009, the internationally composed BoNT Expert Working Group (BoNT EWG) was established at the BfR in close cooperation with the Federal Institute for Drugs and Medical Devices (BfArM). This group is composed of representatives from regulatory authorities and validation centres as well as manufacturers and scientists. The BoNT EWG is mandated to develop recommendations on the validation and acceptance by regulatory authorities of alternative methods to the mouse LD50 activity test for the purpose of approval and batch-based release of BoNT products.

About the BfR

The German Federal Institute for Risk Assessment (BfR) is a scientific institution within the portfolio of the Federal Ministry of Food and Agriculture (BMEL) in Germany. It advises the Federal Government and Federal Laender on questions of food, chemical and product safety. The BfR conducts its own research on topics that are closely linked to its assessment tasks.

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