Biopharmaceuticals genotoxicity

In vitro Studies Table 5.3 shows the in vitro preclinical studies conducted for the 34 biopharmaceuticals. Most were in vitro genotoxicity studies that are not required by the ICH S6 guideline. This is not the case of poor understanding of the ICH S6. In vitro genotoxicity studies are usually conducted at the early stage of development. Almost all the in vitro genotoxicity studies examined by the JPMA survey in 2001 were conducted before the ICH S6 notification. The cross-reactivity studies were used to understand interspecies reactivity to a biopharmaceutical, especially in case of antibodies. 

It is generally accepted now that genotoxicity studies are not applicable for biopharmaceuticals, unless there is a chemical linker or toxic conjugate to... 

In general, genotoxicity standard assays (e.g., bacterial reverse mutation assay [Ames test], in vitro chromosomal aberration assay, mouse lymphoma gene mutation assay, and rodent micronucleus assay) may not be suitable assays because the test cells do not contain the appropriate receptors to transport the product (i.e.,not a relevant species) or because the biopharmaceutical... 

Twenty-seven out of 44 FDA-approved biopharmaceuticals have been tested in a battery of genotoxicity assays. Eighty-five different assays performed yielded negative results. The most commonly performed assays were the Ames test, the chromosomal aberration assay in human lymphocytes, the mouse lymphoma gene mutation assay, and the mammalian in vivo erythrocyte micronucleus test. Examples of the range of biopharmaceutical products tested include, domase alfa (deoxyribonuclease I-DNAse), trastuzumab (mAb to human epidermal growth factor receptor 2), alteplase (tissue plasminogen activator), infliximab (mAb to the human tumor necrosis factor a). 

A pivotal publication of 78 biopharmaceuticals provides data supporting the lack of positive genotoxicity with peptides. The publication concluded, geno-toxicity testing is generally inappropriate and unnecessary [5], Additional support for this position comes from the regulatory agencies in a 2004 review... 

Similar to protein-based biopharmaceuticals, the standard battery of genotox-icity studies is not considered to be relevant for cell-based therapies unless there is a specific cause for concern regarding the nature of any expressed products that would indicate a potential interaction directly with DNA or other chromosomal material [50,52], The conduct of genotoxicity studies for assessing the genotoxic potential of process related contaminants is also not considered to be appropriate [50],... 

Note 3 With some biopharmaceuticals there is a potential concern about accumulation of spontaneously mutated cells (e.g., via facilitating a selective advantage of proliferation) leading to carcinogenicity. The standard battery of genotoxicity tests is not designed to detect these conditions. Alternative in vitro or in vivo models to address such concerns may have to be developed and evaluated. 

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