Bioavailability of Therapeutic Proteins by Inhalation—Worker Safety Aspects

Abstract

A literature review and analysis of inhalation bioavailability data for large therapeutic proteins was conducted in order to develop a practical estimate of the inhalation bioavailability of these drugs. This value is incorporated into equations used to derive occupational exposure limits(OELs) to protect biopharmaceutical manufacturing workers from systemic effects. Descriptive statistics implies that a value of 0.05, or 5% is an accurate estimate for large therapeutic proteins (molecular weight ≥ 40kDa). This estimate is confirmed by pharmacokinetic modeling of data from a human daily repeat-dose inhalation study of immunoglobulin G. In conclusion, we recommend using 5% bioavailability by inhalation when developing OELs for large therapeutic proteins.

Closed-system transfer device use with oncology biologics: A survey of Canadian healthcare practitioners

“…HCPs who have graduated more recently may therefore have a greater understanding of the inherent properties of these large molecules, which in general are minimally hazardous through routine occupational exposures due to negligible bioavailability through oral inhalation or dermal absorption. 24 , 25 This may also be why they are less likely to use CSTDs with all oncology biologics than their counterparts with more than 15 years of experience.…”

Considerations for setting occupational exposure limits for novel pharmaceutical modalities

“…Due to the general instability of biologic therapeutics, differences in their manufacturing (generally closed processes to protect sterility) and their potential limited bioavailability (BA) via the inhalation, oral and dermal routes ( Gould et al, 2018 ; Pfister et al, 2014a ; Bos and Meinardi, 2000 ; Krause and Sahin, 2019 ), it can be argued that a different set of exposure controls can be utilized to protect employees when working with biologics as compared to small molecules. Based on this information as well as extensive industrial hygiene monitoring conducted by BMS showing that airborne concentrations of biologics are most often <1 μg/m 3 (data not shown), a simplified two-band system was developed for biologics for use when there is insufficient information available to calculate an OEL.…”

“…For peptides where there is no target in the lung, the inhalation route would be less of a concern, although inhalation BA would still need to be considered. An evaluation of inhalation studies with peptides conducted by Pfister et al (2014) reported BAs of up to 100%, with most being <50% ( Pfister et al, 2014a ).…”

“…Compounds >500 Da are not expected to be bioavailable via dermal exposure ( Bos and Meinardi, 2000 ). Low systemic exposure potential is generally expected via the inhalation route of exposure (BA<1%) in the occupational setting for biologics with a MW > 10 kDa ( Gould et al, 2018 ; Pfister et al, 2014b ). Limited studies conducted on the inhalation BA of Fc-fusion proteins, have shown BAs of 20–50%, which is substantially higher than the BA observed with mAbs, emphasizing the importance of considering the binding component when estimating the inhalation BA of fusion proteins ( Gould et al, 2018 ; Dumont et al, 2005 ; Pfister et al, 2014b ).…”