Safety assessment biopharmaceutical products

The impact of the drug attributes of biopharmaceuticals on preclinical safety assessment programs for oncology products is not unique to this therapeutic area. As is true for all biopharmaceuticals, species cross-reactivity must be determined prior to selection of an appropriate animal model for safety evaluation. The nature of cross-reactivity can be based on a combination of phar-... 

Preclinical development activities assess biological activity and the safety of the potential biopharmaceutical product through laboratory testing and nonclinical studies in experimental animals. In general ... 

The pharmacokinetic evaluation of biopharmaceuticals is generally simplified by the usual metabolism of products to small peptides and to amino acids, and thus classical biotransformation and metabolism studies are rarely necessary. Routine studies to assess mass balance are not useful. However, both single- and multiple-dose toxicokinetic data are essential in safety pharmacology asessments, and these can be complicated by two factors (1) biphasic clearance with a saturable, initial, receptor-dependent clearance phase, which may cause nonlinearity in dose-exposure relationships and doseresponses [14] and (2) antibody production against an antigenic biopharmaceutical that can alter clearance or activity in more chronic repeat-dose safety studies in the preclinical model. 

Cells by themselves or by secreting pharmacologically active substances may have effects on the CNS, cardiac, respiratory, renal, or GI systems. Safety pharmacology should therefore be considered on a case-by-case basis depending on the specific characteristics of the cell-based product [52], In general, specific assessments are made as part of the toxicology assessments rather than as stand-alone studies consistent with the assessments made with protein-based biopharmaceuticals [50]. The fundamental physiological differences (e.g., total blood volume,pulmonary capillary surface area, and volume) should... 

As is true for all biopharmaceuticals, toxicity studies should be performed in relevant animal models. For cellular therapies these models are often in animal models intended to mimic the human disease. When possible the intended human cells are utilized for assessments with or without low-dose immunosuppressants (e.g., lOmg/kg, i.p. dose of cyclosporine A in rats). The immunosuppressive drug is generally administered prior to the cell dose and extended for a specified period after the transplant. In cases where it is not feasible to use the intended clinical material, largely due to the inability of the cells to engraft sufficiently into the host, analogous cells can be used to assess preclinical safety and activity. In such cases it is important to understand the potential impact of any differences between the analogous product and the clinical product in order to improve extrapolation of safe and active cell doses to humans. 

For products that are prepared extemporaneously at a regular basis or even for a limited stock, a product specific documentation (product file) is needed. This will include specifications, instructions, and records but also a pharmaceutical assessment of safety data, toxicity, biopharmaceutical aspects, stability, and product design. The product file should also include a product review as soon as a product is used repeatedly or over longer periods. 

GPP touches upon the processes assessment of the physician s prescription or formulation design in the Documentation paragraph a pharmaceutical assessment of therapeutic rationale, safety data, toxicity, biopharmaceutical aspects, stability and product design should be carried out, before preparation takes place. No further details are established however. 

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