Considerations for setting occupational exposure limits for novel pharmaceutical modalities

Abstract

In order to develop new and effective medicines, pharmaceutical companies must be modality agnostic. As science reveals an enhanced understanding of biological processes, new therapeutic modalities are becoming important in developing breakthrough therapies to treat both rare and common diseases. As these new modalities progress, concern and uncertainty arise regarding their safe handling by the researchers developing them, employees manufacturing them and nurses administering them. This manuscript reviews the available literature for emerging modalities (including oligonucleotides, monoclonal antibodies, fusion proteins and bispecific antibodies, antibody-drug conjugates, peptides, vaccines, genetically modified organisms, and several others) and provides considerations for occupational health and safety-oriented hazard identification and risk assessments to enable timely, consistent and well-informed hazard identification, hazard communication and risk-management decisions. This manuscript also points out instances where historical exposure control banding systems may not be applicable (e.g. oncolytic viruses, biologics) and where other occupational exposure limit systems are more applicable (e.g. Biosafety Levels, Biologic Control Categories).

Identifying nonhazardous substances in pharmaceutical manufacturing and setting default health‐based exposure limits (HBELs)

“…The same principles apply for the OEL calculation in Table 3 An OEL is expected to represent a safe level of exposure to prevent both biologically significant pharmacological and toxicological effects in healthy workers. OELs are established based on the potency (activity) and critical hazard effects of the substance (Dankovic et al, 2015;Graham et al, 2020;Ku, 2000). OEL is defined as the TWA for 8-h exposure over five times per week, during the working lifetime via inhalation.…”

Approaches for setting occupational exposure limits in the pharmaceutical industry

“…Recently, Graham and coworkers have described the exposure control bands (ECBs) for various novel therapeutic modalities including small molecules, peptides, oligonucleotides and antibody‐drug conjugates based on the dose at which pharmacological or clinically relevant biological effect occurs in vivo. They proposed ECB of 1–10 μg/m 3 for substances having potency >5 mg (100 μg/kg × 50 kg body weight) and an ECB of 0.1 to <1 μg/m 3 for substances having potency of 0.5–5 mg (Graham et al, 2020). Table 3 presents the scheme for occupational exposure banding, also known as health hazard banding (ABPI, 1995; ECETOC, 2006; Graham et al, 2020; Lentz et al, 2019; Naumann et al, 1996).…”

“…They proposed ECB of 1–10 μg/m 3 for substances having potency >5 mg (100 μg/kg × 50 kg body weight) and an ECB of 0.1 to <1 μg/m 3 for substances having potency of 0.5–5 mg (Graham et al, 2020). Table 3 presents the scheme for occupational exposure banding, also known as health hazard banding (ABPI, 1995; ECETOC, 2006; Graham et al, 2020; Lentz et al, 2019; Naumann et al, 1996). As more data become available later, assessment may be reviewed to provide an updated OEL value.…”

Nickel-Catalyzed Antibody Bioconjugation

“…Seminal work by Buchwald and Pentelute detailed the use of preformed palladium oxidative addition complexes to achieve interchain cysteine arylation of an antibody, creating a stable S- aryl linkage (Figure , top) . The requirement for the synthesis of these metal complexes in a glovebox and their isolation prior to use, however, imparts practicality and safety issues for the construction of oncology ADCs given the payload exposure control band is the highest possible (<0.1 μg/m 3 ) . We hypothesized that an aqueous system capable of in situ generation of reactive aryl-metal species from the corresponding ubiquitous aryl bromides in the presence of an antibody would allow for the expedient synthesis of conjugates from diverse areas of chemical space previously unavailable for biologic drug discovery efforts (Figure , bottom).…”