Alternatives to the LD50 assay for botulinum toxin potency testing: Strategies and progress towards refinement, reduction and replacement
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چکیده
Therapeutic preparations of botulinum toxin products are calibrated by a mouse LD50 assay, and the labelled unit of activity is expressed in mouse LD50 units, defined as the median lethal intraperitoneal dose at a defined time-point. Potency and stability testing are required at several stages of the production process. Testing at the final lot stage requires high precision, so a large number of animals are used. LD50 assays are severe, and are at the front line for replacement on humane grounds. The Humane Society of the United States submitted a Test Method Nomination for "Alternative Methods to Replace the Mouse LD50 Assay for Botulinum Toxin Potency Testing" to ICCVAM, and a workshop organized by ICCVAM/NICEATM/ECVAM was held in Washington DC, USA, in November 2006. Several alternative methods, developed and validated at NIBSC over the past 15 years, were reviewed at that workshop. The workshop participants concluded that the validation of a refined in vivo local paralysis assay could provide a realistic short-term strategy for replacing the LD50 assay. Transferability studies with a UK testing laboratory are in progress. It was further anticipated that one or more of the in vitro methods, such as an enzyme cleavage assay, could be validated for particular applications, and then used to confirm consistency of production. The approach adopted at NIBSC has led to the elimination of the LD50 assay during independent confirmatory testing of the final lot product, and refined and alternative methods are included in the European Pharmacopoeia monograph, for use, subject to validation.
منابع مشابه
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تاریخ انتشار 2006