title: Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics - Current challenges and approaches.
abstract: Leachables from pharmaceutical container closure systems can present potential safety risks to patients. Extractables studies may be performed as a risk mitigation activity to identify potential leachables for dosage forms with a high degree of concern associated with the route of administration. To address safety concerns, approaches to toxicological safety evaluation of extractables and leachables have been developed and applied by pharmaceutical and biologics manufacturers. Details of these approaches may differ depending on the nature of the final drug product. These may include application, the formulation, route of administration and length of use. Current regulatory guidelines and industry standards provide general guidance on compound specific safety assessments but do not provide a comprehensive approach to safety evaluations of leachables and/or extractables. This paper provides a perspective on approaches to safety evaluations by reviewing and applying general concepts and integrating key steps in the toxicological evaluation of individual extractables or leachables. These include application of structure activity relationship studies, development of permitted daily exposure (PDE) values, and use of safety threshold concepts. Case studies are provided. The concepts presented seek to encourage discussion in the scientific community, and are not intended to represent a final opinion or "guidelines."
authors: Merck KGaA, Darmstadt, Germany.
authors: Thomas H
authors: TH
authors: Broschard
authors: Novartis, Basel, Switzerland.
authors: Susanne
authors: S
authors: Glowienke
authors: Merck & Co, Whitehouse Station, NJ, USA.
authors: Uma S
authors: US
authors: Bruen
authors: Drinker Biddle & Reath, LLP, Washington, DC, USA. Electronic address: lee.nagao@dbr.com.
authors: Lee M
authors: LM
authors: Nagao
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: Andrew
authors: A
authors: Teasdale
authors: C&M Technical Consulting, LLC, San Mateo, CA, USA.
authors: Cheryl L M
authors: CL
authors: Stults
authors: Amgen, Thousand Oaks, CA, USA.
authors: Kim L
authors: KL
authors: Li
authors: MedImmune, Gaithersburg, MD, USA.
authors: Laurie A
authors: LA
authors: Iciek
authors: Abbvie, North Chicago, IL, USA.
authors: Greg
authors: G
authors: Erexson
authors: AstraZeneca, Cambridge, UK.
authors: Elizabeth A
authors: EA
authors: Martin
authors: Pfizer, Inc, Groton, CT, USA.
authors: Douglas J
authors: DJ
authors: Ball
mesh_terms: D001688:Biological Products / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry*; D062067:Chemical Safety; D065546:Drug Liberation; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012449:Safety
chemical_list: D001688:Biological Products; D004364:Pharmaceutical Preparations
keywords: Extractables; Leachables; Permitted daily exposure; Safety evaluation; Safety threshold; Structure activity relationship