Preclinical safety testing of biotechnology-derived pharmaceuticals

Brennan, Frank R.; Shaw, Leigh; Wing, Mark; Robinson, Christine

doi:10.1385/mb:27:1:59

Cited by 61 publications

(25 citation statements)

References 82 publications

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“…E.g. BP are more complex molecules with special production and limited predictability of clinical outcomes [16,41,42]. These and other peculiarities may lead to the increase in uncertainty in terms of safety profile of biological pharmaceuticals at the moment of registrations; this has been confirmed by a range of studies.…”

Section: Discussionmentioning

confidence: 94%

Safety of Biological Preparations and Small Molecules. Are There Any Differences?

Колбин¹,

Харчев²

2013

Pediatr. farmakol.

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Section: Discussionmentioning

confidence: 94%

Safety of Biological Preparations and Small Molecules. Are There Any Differences?

Колбин¹,

Харчев²

2013

Pediatr. farmakol.

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“…ICH S6 and the addendum ICH S6(R1) step 2 provide the framework for a flexible approach to nonclinical safety evaluation of biologics. In addition, numerous publications have detailed several aspects of what constitutes an appropriate toxicology assessment for such molecules (Serabian and Pilaro, 1999;Gocke et al, 1999;Brennan et al, 2004;Nakazawa et al, 2004;Snodin and Ryle, 2006;Tabrizi and Roskos, 2007;Cavagnaro, 2008a, b;International Conference on Harmonization, 2008). Table 2 summarizes key considerations for the different types of nonclinical safety studies currently conducted for biologics under consideration in this Review.…”

Section: Nonclinical Toxicology Studies Conducted For Biopharmaceuticalsmentioning

confidence: 99%

Overview of the nonclinical quality and toxicology testing for recombinant biopharmaceuticals produced in mammalian cells

Lebrec

Narayanan

Nims

2010

J of Applied Toxicology

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Biopharmaceuticals represent significant advances in therapeutic approaches for unmet medical needs, and increasingly, traditional pharmaceutical firms have been incorporating biotechnology capabilities into their product portfolios. There are some differences in the overall safety testing paradigms for small molecules and biopharmaceuticals, this safety testing including both quality and toxicology aspects. These differences are associated with both the manufacturing processes involved and the molecules themselves. For example, for biopharmaceuticals, living cells represent the factories for synthesizing complex molecular entities. As a result of this, safety testing for this class of drugs includes adventitious agent testing (e.g. viral, mycoplasma, transmissible spongiform encephalopathy agents) not normally needed for small molecules. Also, strategies for nonclinical toxicology testing of biopharmaceuticals differ from the paradigms used for small molecules and often need to be defined on a case-by-case basis, primarily taking into consideration species cross-reactivity attributes of the molecule of interest. Certain studies required for small molecules are not applicable to most biopharmaceuticals (i.e. genotoxicity testing, testing for interactions with the hERG channel). This manuscript provides an overview of both the quality and nonclinical toxicology testing for these mammalian-cell-derived products, two elements pivotal to the overall nonclinical assessment of the safety of these biopharmaceutical products.

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“…The purpose of immunotoxicity studies is to determine the adverse effects of therapeutic mAbs on the immune system. 44,45 Stimulation and expansion of immune cells leading to an autoimmune disease, immune suppression resulting in decreased host resistance to infectious agents or tumor cells are considered as main adverse events affecting the immune system. In standard toxicity studies, evaluation of total leukocyte counts, absolute differential leukocyte counts, lymphoid tissues at necropsy, and histopathology of the spleen and thymus may indicate toxicity to the immune response.…”

Section: Guidance Documents By Regulatory Agenciesmentioning

confidence: 99%

Practical considerations for nonclinical safety evaluation of therapeutic monoclonal antibodies

Lynch

Hart

Grewal

2009

mAbs

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Monoclonal antibodies (mAbs) are a well established class of therapeutics as evidenced by a large number of FDA approved mAbs for the treatment of cancers and autoimmune diseases. Monoclonal antibodies that are molecularly engineered for enhanced functions and pharmacokinetic properties are routinely being considered for development by many biotechnology companies. Safety evaluation of current generation of mAbs poses new challenges due to the highly complex nature of engineering aspects and variability induced by the diverse recombinant cell systems to generate them. This review provides a basic outline for nonclinical safety evaluation of therapeutic antibodies. Important considerations for planning a preclinical program, the types of nonclinical safety studies, and a general timeline for their conduct in relation to clinical trials are described. A list of relevant regulatory documents issued by government agencies is also provided. Adoption of these principles will greatly enhance the quality and relevance of the nonclinical safety data generated and will facilitate future development of mAb therapeutics.

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Preclinical safety testing of biotechnology-derived pharmaceuticals

Cited by 61 publications

References 82 publications

Safety of Biological Preparations and Small Molecules. Are There Any Differences?

Safety of Biological Preparations and Small Molecules. Are There Any Differences?

Overview of the nonclinical quality and toxicology testing for recombinant biopharmaceuticals produced in mammalian cells

Practical considerations for nonclinical safety evaluation of therapeutic monoclonal antibodies

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