Standard Guide for Derivation of Health-Based Exposure Limits (HBELs)

Importancia y uso:

4.1 Guidelines for unintended human exposure to active pharmaceutical ingredients (APIs) are required by various global regulations as part of international quality requirements, needed as good product stewardship, and are considered the industry standard.

4.2 Application of the approach described within this guide applies a scientifically justified, data-driven, approach to deriving safe limits for unintended exposures to individual substances. These limits can then be further used to calculate cleaning limits used in quality risk assessment for the manufacture of pharmaceuticals. The HBEL approach considers substance-specific properties (type of effect, potency, pharmacology, safety profile, and so forth). Specific approaches are applicable to different categories of substances and in specific stages in drug development.

4.3 The basis for the HBEL derivation is all available substance-specific data. Interpretation of these data considers the quantity and robustness of the database and the reliability and relevance of the data. Typically, adjustment factors (AFs) are used to address variability and uncertainty in different parameters to determine a safe human exposure limit, although alternative, purposefully conservative, approaches (for example, in addition to the threshold of toxicological concern (TTC) where applicable, read-across based on structural or physical-chemical attributes, and toxicokinetics and toxicodynamics (sometimes identified through a common mechanism of action, or adverse outcome pathways), or use of new approach methodologies (NAMs) using in vitro assays and in silico modeling) may be used as appropriate (34-41). However, recent studies have suggested that the PoD from in vitro studies may underestimate the traditional in vivo PoD by a median value of approximately 100-fold (42-44). In addition, the correlation between in vitro and in vivo PoDs has been reported as poor (45, 46).

4.4 This guide supports, and is consistent with, elements of the European Commission (EU) Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use (47, 48) and the HBEL guideline from the Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-Operation Scheme (17) in which it is mentioned that relevant residue limits should be based on a toxicological evaluation.

4.5 Key Concepts—This guide applies the following steps: (1) hazard characterization, (2) identification of the critical effect(s) including dose-response assessment, (3) determination of one or several points of departure (PoD)s, (4) application of PoD-specific AFs, and (5) calculation of HBELs including justification of selected HBEL (21) (see Fig. 1).

Note 1: This figure represents an example where three possible PoDs have been selected based on three distinctive critical effects, followed by PoD-specific application of AFs and calculation of three HBELs.

Subcomité:

E55.14

Referida por:

F3127-22, E3106-22, E3439-25, E3263-22E01, E3418-23E01

Volúmen:

14.01

Número ICS:

11.120.10 (Medicaments)

Palabras clave:

ADE; hazard assessment; HBEL; health-based exposure limit; PDE; pharmaceutical manufacturing; risk assessment; SEL;