title: Special endpoint and product specific considerations in pharmaceutical acceptable daily exposure derivation.
abstract: Recently, a guideline has been published by the European Medicines Agency (EMA) on setting safe limits, permitted daily exposures (PDE) [also called acceptable daily exposures (ADE)], for medicines manufactured in multi-product facilities. The ADE provides a safe exposure limit for inadvertent exposure of a drug due to cross-contamination in manufacturing. The ADE determination encompasses a standard risk assessment, requiring an understanding of the toxicological and pharmacological effects, the mechanism of action, drug compound class, and the dose-response as well as the pharmacokinetic properties of the compound. While the ADE concept has broad application in pharmaceutical safety there are also nuances and specific challenges associated with some toxicological endpoints or drug product categories. In this manuscript we discuss considerations for setting ADEs when the following specific adverse health endpoints may constitute the critical effect: genotoxicity, developmental and reproductive toxicity (DART), and immune system modulation (immunostimulation or immunosuppression), and for specific drug classes, including antibody drug conjugates (ADCs), emerging medicinal therapeutic compounds, and compounds with limited datasets. These are challenging toxicological scenarios that require a careful evaluation of all of the available information in order to establish a health-based safe level.
authors.affiliation: Bristol-Myers Squibb, USA. Electronic address: janet.gould@bms.com.
authors.forename: Janet
authors.initials: J
authors.lastname: Gould
authors.affiliation: Eli Lilly and Company, USA.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Callis
authors.affiliation: Amgen Inc., USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Dolan
authors.affiliation: MedImmune, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Stanard
authors.affiliation: Genentech, Inc., USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Weideman
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004340:Drug Contamination / Q000517:prevention & control; D004342:Drug Hypersensitivity / Q000276:immunology / Q000517:prevention & control; D004345:Drug Industry / Q000331:legislation & jurisprudence / Q000592:standards; D064420:Drug-Related Side Effects and Adverse Reactions / Q000276:immunology / Q000517:prevention & control; D017408:Guidelines as Topic; D006291:Health Policy; D006801:Humans; D009152:Mutagenicity Tests; 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; D011506:Proteins / Q000009:adverse effects* / Q000145:classification / Q000592:standards; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods* / Q000592:standards; D066007:Toxicokinetics
chemical_list: D004364:Pharmaceutical Preparations; D011506:Proteins
keywords: Acceptable Daily Exposure (ADE); Cross-contamination; Cytotoxicity; Developmental toxicity; Hypersensitivity; Immune response; Permitted Daily Exposure (PDE); Protein therapeutics; Reproductive toxicity; Risk assessment