An independent pharmaceuticals manufacturer.
Health-Based Exposure Limits (HBELs) are used to control risk when different medicinal products are manufactured in shared facilities. In this case, carryover of a hormone ester used in topical products into other products applied to the skin was considered possible.
The client asked bibra to calculate a dermal HBEL for the hormone ester, following guidance from the European Medicines Agency (EMA) and ICH. The HBEL would assist with a programme of cleaning validation to ensure any carryover of product from one batch to another would pose no risk to human health.
 The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.
Approach and outcome
The client supplied bibra with information regarding the use conditions of the hormone, as well as products made in the same facilities for which carryover was possible. Toxicity and ADME searches were carried out using the bibra TRACE database and a range of external data sources, and a Summary of Product Characteristics (SPC) provided by the client was also considered. As the ester is rapidly hydrolysed upon entry to the body, data on the hydrolysed hormone were also interrogated, as were data on similar read-across chemicals.
It was determined that the ester and hormone can considered non-genotoxic threshold toxins. HBELs were calculated following the approach for the determination of a Permitted Daily Exposure (PDE) recommended in the ICH Q3C and Q3D guidelines on residual solvents and elemental impurities. Potential Points of Departure (PoDs) for HBEL derivation included No-Observed-Adverse-Effect Levels (NOAELs) and Lowest-Observed-Adverse-Effect Levels (LOAELs) from repeated-dose studies on the ester and hormone, and oral Acceptable Daily Intakes (ADIs) set for the hormone by Expert Groups from read-across data. A number of candidate HBELs were calculated, and the lowest was recommended for use.