Mutagenicity, carcinogenicity and other tests

Mutagenicity tests are usually carried out in vitro and in vivo, often using both prokaryotic and eukaryotic organisms. A well-known example is the Ames test, which assesses the ability of a drug to induce mutation reversions in E. coli and Salmonella typhimurium. 

Longer-term carcinogenicity tests are undertaken, particularly if (a) the product s likely therapeutic indication will necessitate its administration over prolonged periods (a few weeks or more) or (b) if there is any reason to suspect that the active ingredient or other constituents could be carcinogenic. These tests normally entail ongoing administration of the product to rodents at various dosage levels for periods of up to (or above) 2 years. 

Many drugs, including many biopharmaceuticals, are administered to localized areas within the body by, for example, s.c. or i.m. injection. Local toxicity tests appraise whether there is any associated toxicity at/surrounding the site of injection. Predictably, these are generally carried out by s.c. or i.m. injection of product to test animals, followed by observation of the site of injection. The exact cause of any adverse response noted (i.e. active ingredient or excipient) is usually determined by their separate subsequent administration. 

The indicator molecule serves to assess the state of health of the cultured cells. The dye neutral red is often used (healthy cells assimilate the dye, dead cells do not). The major drawback to such systems is that they do not reflect the complexities of living animals and, hence, may not accurately reflect likely results of whole-body toxicity studies. Regulatory authorities are (rightly) slow to allow replacement of animal-based test protocols until the replacement system is proven to be reliable and is fully validated. 

In addition, tests for mutagenicity and carcinogenicity are not likely required for most biopharma-ceutical substances. The regulatory guidelines and industrial practices relating to biopharmaceuti-cal preclinical trials thus remain in an evolutionary mode, and each product is taken on a case-by-case basis. An overview of the main preclinical tests undertaken for a sample biopharmaceutical 

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