title: Simulated Leaching (Migration) Study for a Model Container-Closure System Applicable to Parenteral and Ophthalmic Drug Products.
abstract: A simulating leaching (migration) study was performed on a model container-closure system relevant to parenteral and ophthalmic drug products. This container-closure system consisted of a linear low-density polyethylene bottle (primary container), a polypropylene cap and an elastomeric cap liner (closure), an adhesive label (labeling), and a foil overpouch (secondary container). The bottles were filled with simulating solvents (aqueous salt/acid mixture at pH 2.5, aqueous buffer at pH 9.5, and 1/1 v/v isopropanol/water), a label was affixed to the filled and capped bottles, the filled bottles were placed into the foil overpouch, and the filled and pouched units were stored either upright or inverted for up to 6 months at 40 °C. After storage, the leaching solutions were tested for leached substances using multiple complementary analytical techniques to address volatile, semi-volatile, and non-volatile organic and inorganic extractables as potential leachables.The leaching data generated supported several conclusions, including that (1) the extractables (leachables) profile revealed by a simulating leaching study can qualitatively be correlated with compositional information for materials of construction, (2) the chemical nature of both the extracting medium and the individual extractables (leachables) can markedly affect the resulting profile, and (3) while direct contact between a drug product and a system's material of construction may exacerbate the leaching of substances from that material by the drug product, direct contact is not a prerequisite for migration and leaching to occur.LAY ABSTRACT:The migration of container-related extractables from a model pharmaceutical container-closure system and into simulated drug product solutions was studied, focusing on circumstances relevant to parenteral and ophthalmic drug products. The model system was constructed specifically to address the migration of extractables from labels applied to the outside of the primary container. The study demonstrated that (1) the extractables that do migrate can be correlated to the composition of the materials used to construct the container-closure systems, (2) the extent of migration is affected by the chemical nature of the simulating solutions and the extractables themselves, and (3) even though labels may not be in direct contact with a contained solution, label-related extractables can accumulate as leachables in those solutions.
authors.affiliation: Baxter Healthcare Corporation, Round Lake, IL, USA; dennisjenke@triadscientificsolutions.com.
authors.forename: Dennis
authors.initials: D
authors.lastname: Jenke
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ingelheim/Rhein, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Egert
authors.affiliation: Becton Dickinson, Research Triangle Park, NC, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Hendricker
authors.affiliation: Pharma Interface Analysis, LLC.
authors.forename: James
authors.initials: J
authors.lastname: Castner
authors.affiliation: Scio Analytical Consulting, Chapel Hill, NC, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Feinberg
authors.affiliation: iuvo BioScience, Rush, NY, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Houston
authors.affiliation: United States Pharmacopeoia, Rockville, MD, USA.
authors.forename: Desmond G
authors.initials: DG
authors.lastname: Hunt
authors.affiliation: Pfizer, Groton, CT, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lynch
authors.affiliation: Bureau of Pharmaceutical Sciences, Health Canada, Ottawa, ON, Canada.
authors.forename: Kumudini
authors.initials: K
authors.lastname: Nicholas
authors.affiliation: Scio Analytical Consulting, Chapel Hill, NC, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Norwood
authors.affiliation: West Pharmaceutical Services, Lionsville, PA, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Paskiet
authors.affiliation: Materials Needs Consulting LLC, Montvale, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ruberto
authors.affiliation: Packaging Science Resources, King of Prussia, PA, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Smith
authors.affiliation: United States Food and Drug Administration, Washington, DC, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Holcomb
authors.affiliation: United States Food and Drug Administration, Washington, DC, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Markovic
mesh_terms: D004340:Drug Contamination / Q000517:prevention & control*; D004349:Drug Packaging / Q000592:standards*; D007263:Infusions, Parenteral / Q000592:standards; D008962:Models, Theoretical; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000592:standards; D010288:Parenteral Nutrition / Q000592:standards; D010969:Plastics / Q000737:chemistry / Q000592:standards*
chemical_list: D009883:Ophthalmic Solutions; D010969:Plastics
keywords: Extractables; Leachables; Leaching (migration) study; Parenteral and ophthalmic drug products; Simulation studies