With the implementation of the European Medicines Agency’s (EMA’s), ‘Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (EMA/CHMP/CVMP/SWP/169430/2012)’, the importance of Health-based Exposure Limits (HBEL) through scientific toxicological risk assessment has increased in the pharmaceutical industry.
Permitted Daily Exposure (PDE) / Acceptable Daily Exposure (ADE) Calculations
The EMA guideline insists on establishing HBELs which will be used while evaluating the risks of possible carryover contamination of residual active substances through medicinal product. Thus, for pharmaceutical manufacturing facilities or Contract Manufacturing Organization (CMO), derivation and establishment of Permitted Daily Exposure (PDE) also known as Acceptable Daily Exposure (ADE) has become an integral part of cleaning validation program to comply with various Regulatory or cGMP requirements.
The potential risk of cross-contamination can be controlled or restricted by the use of PDE/ADE values derived by a scientific and toxicological risk assessment of clinical and non-clinical data. The PDE calculation involves steps like hazard identification through structured and strategized literature search, identification of critical effects, establishment of NOEL/NOAEL for critical effects and application of adjustment factors including bioavailability correction factors for a route to route extrapolation as per the EMA, 2014, ICH Q3C, ISPE and VICH GL18. The PDE/ADE values are used in cleaning validation in manufacturing facilities to further determine the maximum acceptable carryover (MACO values). The PDE/ADE values of most hazardous substances like cytotoxic drugs, hormones and steroids etc., also help in determination of dedicated and separate equipment and facilities.
Occupational Exposure Limit (OEL) Calculations and OEL Banding
Occupational Exposure Limit (OEL) refers to the maximum airborne concentration of a chemical to which most workers could be exposed, without consequent adverse health effects or impacts. Exposure limits are typically expressed as milligrams of contaminant per cubic meter of air (mg/m3). Additionally, skin notation is also used to indicate the possibility of skin absorption and the contribution of skin absorption in the overall exposure. OELs are a measure for minimizing worker exposure to hazardous substances in the workplace. The OEL calculation is set by considering, all available information on the hazards of a substance, particularly with respect to its acute or chronic toxicity, carcinogenicity, mutagenicity, and toxicity to reproduction.
Although not mandated for pharmaceuticals, the OEL calculation has been recommended by the Occupational Safety and Health Administration (OSHA) and several other Agencies including the American Conference of Governmental Industrial Hygienists (ACGIH), National Institutes of Occupational Safety and Health (NIOSH), Japan Society for Occupational Health (JSOH) and European Chemical Agency (ECHA).