Managing emissions of active pharmaceutical ingredients from manufacturing facilities: An environmental quality standard approach

Abstract

Active pharmaceutical ingredient (API) residues have been found to be widespread in the aquatic environment, albeit in most cases at trace levels, with the route to the environment predominantly being via therapeutic use and subsequent excretion to sewer. Although manufacturing discharges may be a low overall contributor to environmental concentrations, they need to be managed effectively so that they do not adversely affect the local receiving environment. In order to achieve this, a risk-based approach is proposed that identifies the long-term and short-term concentrations, referred to as environmental reference concentrations (ERCs) and maximum tolerable concentrations (MTCs), respectively, of an API which should not be exceeded in the aquatic environment receiving effluent from pharmaceutical manufacturing sites. The ERC approach is based on established environmental quality standard concepts currently used in much national and international legislation. Building on these concepts, the approach takes into account indirect exposure of potential consumers such as fish-eating mammals and humans, as well as primary producers (e.g., algae) and primary and secondary consumers (e.g., invertebrates and fish). Although chronic toxicity data are preferred for ERC derivation, acute data, with appropriate considerations of uncertainty, may be used when chronic data are not available. This approach takes all available information into account, particularly for older established medicines that may predate current regulatory requirements for environmental data, and consequently helps prioritize resources for environmental testing. The ERC approach has been applied to 30 of AstraZeneca's APIs. Merits of the approach are discussed together with opportunities for potential future refinement.

Combined environmental risk assessment for the antiviral pharmaceuticals ganciclovir and valganciclovir in Europe

“…Then, for the case of an otter as a top predator with a default body mass of 10 kg, an intake of 1 kg fish and 0.79 L of water per day is assumed; the concentration of the substance in fish is based on the surface water PEC and the bioaccumulation factor. The combined daily intake of an otter from fish and water is then compared with the MTDI [22].…”

“…Lastly, a potential surface water risk from indirect exposure of human consumers from drinking water, approximately 40% of which is produced from surface water in Europe [24], and from fish, which may bioaccumulate substances, is derived following Murray-Smith et al [22]. Briefly, assuming as a worst case that GCV is not removed during drinking water production, the surface water PEC is taken as the drinking water PEC, and a default volume of 2 L drinking water consumption per day is assumed.…”

“…Briefly, assuming as a worst case that GCV is not removed during drinking water production, the surface water PEC is taken as the drinking water PEC, and a default volume of 2 L drinking water consumption per day is assumed. For fish consumption, bioaccumulation from surface water into fish is considered (PEC Â BCF fish [with BCF being the bioconcentration factor]), and a default amount of fish of 0.115 kg/d is assumed [22]. The combined resulting daily uptake of GCV from drinking water and fish consumption is compared with the acceptable daily oral intake for GCV [4].…”

“…An MTDI for GCV for (semi)aquatic top predators is derived [22] based on available acute and (sub)chronic mammalian toxicity data [4]; although acute tests were performed with oral dosing, most of the (sub)chronic assays were performed with intravenous administration in view of the low oral biovavilability of GCV. Specifically, the acute median lethal doses (LC50s) were higher than the highest dose of 2000 mg/kg body weight in mice and of 1000 mg/kg body weight in dogs.…”

“…In the (sub)chronic tests, the lowest no-observed-adverse-effect levels for GCV were 1) a daily intravenous dose of 6 mg/kg body weight in a developmental toxicity and teratogenicity study in the rabbit; 2) a daily intravenous dose of 0.4 mg/kg body weight in a fertility and reproductive performance study in mice, where the adverse effect at higher doses was testicular toxicity; 3) a daily oral dose of 1 mg/kg body weight in an 18-mo carcinogenicity study in mice; and 4) a daily intravenous dose of 0.06 mg/kg body weight in a 12-mo chronic toxicity study in dogs, where the only effect was sebaceous gland atrophy [4]. Dividing the lowest LC50 of >1000 mg/kg by an assessment factor of 100 [22] results in an acute-based MTDI of >10 mg/kg body weight/d, whereas dividing the lowest chronic or reprotoxicity no-observed-adverse-effect level of 0.06 mg/kg body weight/d by an assessment factor of 30 [22] gives a chronic-based MTDI of 0.002 mg/kg body weight/d. The latter, lower MTDI was selected for top predator risk assessment.…”