Anaphylaxis and the inclusion of polysorbates in biotherapeutics
The formulation and manufacturing of parenteral biotherapeutic products occur at the interface of science and regulatory concerns. Science dictates the formulation composition, often including the addition of certain excipients in order to stabilize the biotherapeutic protein, ameliorate undesirable properties such as aggregation or short shelf life, or allow for increased concentration permitting smaller administration volumes, thus placing the final product in a condition better suitable for administration to patients. Biotherapeutic formulations are significantly more complicated to formulate than small molecule drug formulations, often requiring the inclusion of a host of functional excipients. Since no biotherapeutic formulation can be perfect in all respects, regulatory concerns are intended to balance the risks of life-saving technological enhancements against the known limitations or deficiencies associated with commercial biotherapeutic products with the aim of achieving an acceptable compromise with respect to product safety. The rapidly growing use of monoclonal antibodies (mAbs) in the treatment of neoplastic, autoimmune, and inflammatory diseases is an exciting development, but one that has led to a significant increase in hypersensitivity reactions worldwide, complicating their use as first-line therapies and limiting patient survival and quality of life. Anaphylaxis is often attributed to some undefined intrinsic property of the protein biotherapeutic, often ignoring potential contributions from other formulation components. In particular, polysorbates PS-20 or PS-80 (Tween 20 and Tween 80, respectively) are incorporated in approximately 70% of all mAb formulations in order to prevent aggregation. They are highly effective in this role. However, polysorbates contain ether linkages (within polyoxyethylene moieties) and unsaturated alkyl chains that spontaneously self-oxidize in aqueous solutions form immunogenic (neoantigenic) and anaphylactogenic (anaphylaxis stimulating) chemical species, including hydro- and alkyl peroxides, epoxy acids, and reactive aldehydes such as formaldehyde and acetaldehyde.