title: Point of departure (PoD) selection for the derivation of acceptable daily exposures (ADEs) for active pharmaceutical ingredients (APIs).
abstract: The Acceptable Daily Exposure (ADE) derived for pharmaceutical manufacturing is a health-based limit used to ensure that medicines produced in multi-product facilities are safe and are used to validate quality processes. Core to ADE derivation is selecting appropriate point(s) of departure (PoD), i.e., the starting dose of a given dataset that is used in the calculation of the ADE. Selecting the PoD involves (1) data collection and hazard characterization, (2) identification of "critical effects", and (3) a dose-response assessment including the determination of the no-observed-adverse-effect-level (NOAEL) or lowest-observed-adverse-effect-level (LOAEL), or calculating a benchmark dose (BMD) level. Compared to other classes of chemicals, active pharmaceutical ingredients (APIs) are well-characterized and have unique, rich datasets that must be considered when selecting the PoD. Dataset considerations for an API include therapeutic/pharmacological effects, particularities of APIs for different indications and routes of administration, data gaps during drug development, and sensitive subpopulations. Thus, the PoD analysis must be performed by a qualified toxicologist or other expert who also understands the complexities of pharmaceutical datasets. In addition, as the pharmaceutical industry continues to evolve new therapeutic principles, the science behind PoD selection must also evolve to ensure state-of-the-science practices and resulting ADEs.
authors.affiliation: Gilead Sciences, Inc., United States. Electronic address: joel.bercu@gilead.com.
authors.forename: Joel P
authors.initials: JP
authors.lastname: Bercu
authors.affiliation: Genentech, Inc., United States.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Morinello
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sehner
authors.affiliation: Pfizer, Inc., United States.
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Shipp
authors.affiliation: Genentech, Inc., United States.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Weideman
mesh_terms: D000818:Animals; D019985:Benchmarking; D004305:Dose-Response Relationship, Drug; D004345:Drug Industry / Q000331:legislation & jurisprudence / Q000592:standards; D017408:Guidelines as Topic; D006291:Health Policy; D006801:Humans; D019055:No-Observed-Adverse-Effect Level; D016273:Occupational Exposure / Q000009:adverse effects / Q000331:legislation & jurisprudence / Q000517:prevention & control* / Q000592:standards; D016272:Occupational Health / Q000331:legislation & jurisprudence / Q000592:standards; D004364:Pharmaceutical Preparations / Q000145:classification / Q000592:standards; D010599:Pharmacokinetics; D011050:Policy Making; D018570:Risk Assessment; D018675:Toxicity Tests
chemical_list: D004364:Pharmaceutical Preparations
keywords: Acceptable Daily Exposure (ADE); Cleaning validation; Cross-contamination; Lowest-observed-adverse-effect-level (LOAEL); No-observed-adverse-effect-level (NOAEL); Permitted Daily Exposure (PDE); Pharmacodynamics (PD); Pharmacokinetics (PK); Point of departure (PoD)