Extractables and Leachables
Simulated Leaching (Migration) Study for a Model Container-Closure System Applicable to Parenteral and Ophthalmic Drug Products.
D. Jenke, et al. PDA Journal of Pharmaceutical Science and Technology, 71, 68-87 (2017)
This article presents a simulated leaching study comprising a polymer/elastomer container system and model solvent systems. Data indicated leachate profile correlated qualitatively with container materials of construction, leachate profile was affected by solvent, direct contact with drug product is not required for leaching to occur.
United States Pharmacopeia (USP) Chapter <1663> - Assessment of Extractables Associated with Pharmaceutical Packaging/ Delivery Systems
This chapter presents a framework for the design, justification, and execution of an extractables assessment for pharmaceutical packaging and delivery systems.
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United States Pharmacopeia (USP) Chapter <1664> - Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems
This chapter presents a framework for the design, justification, and implementation of assessments for drug product leachables derived from pharmaceutical packaging and delivery systems.
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Controlled Extraction on Rubber Elastomer (RE).
D. Paskiet, et al.
This poster, comprising collaborative work between West Pharmaceutical Services, Inc. and Product Quality Research Institute, describes an approach to determining extractable from a bromobutyl-based elastomer formulation. Said approach comprises multiple solvents/conditions and multiple analytical methods.
Guideline for Elemental Impurities - Q3D (December 2014)
This document is ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidance on elemental impurities in drug products. In particular, document addresses toxicologically relevant permitted daily exposure (PDE) limits and risk-based assessment strategies.
See also in this section Q3D Elemental Impurities Guidance for Industry which gives FDA position on this guideline.
Q3D Elemental Impurities Guidance for Industry (September 2015)
This FDA report considers ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidance on elemental impurities in drug products. Specific areas considered are: (a) evaluation of the toxicity data for potential elemental impurities, (b) establishment of a permitted daily exposure (PDE) for each element of toxicological concern, and (c) application of a risk-based approach to control elemental impurities.
See also in this section Guideline for Elemental Impurities - Q3D - the document on which this report is based
Extractables and Leachables Testing.
A. Siew. Pharmaceutical Technology, 38 (5) (May 2014)
This article gives the views of several industry experts on how to design studies to examine for extractables and leachables using a risk-based approach.
Implementation of ICH Q3D Elemental Impurities Guideline: Challenges and Opportunities.
A. Teasdale, et al. Pharmaceutical Technology, 39 (3) (May 2015)
This article describes strategies and challenges in implementing ICH Q3D guidelines.
The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP)
Paskiet D. Jenke D, Ball D, Houston C, Norwood DL, Markovic I.
The Product Quality Research Institute (PQRI) is a non-profit consortium of organizations working together to generate and share timely, relevant, and impactful information that advances drug product quality and development. The collaborative activities of PQRI participants have, in the case of orally inhaled and nasal drug products (OINDPs), resulted in comprehensive and widely-accepted recommendations for leachables assessments to help ensure patient safety with respect to this class of packaged drug products. These recommendations, which include scientifically justified safety thresholds for leachables, represent a significant milestone towards establishing standardized approaches for safety qualification of leachables in OINDP. To build on the success of the OINDP effort, PQRI's Parenteral and Ophthalmic Drug Products (PODP) Leachables and Extractables Working Group was formed to extrapolate the OINDP threshold concepts and best practice recommendations to other dosage forms with high concern for interaction with packaging/delivery systems. This article considers the general aspects of leachables and their safety assessment, introduces the PODP Work Plan and initial study Protocol, discusses the laboratory studies being conducted by the PODP Chemistry Team, outlines the strategy being developed by the PODP Toxicology Team for the safety qualification of PODP leachables, and considers the issues associated with application of the safety thresholds, particularly with respect to large-volume parenterals. Lastly, the unique leachables issues associated with biologics are described.
Extractables characterization for five materials of construction representative of packaging systems used for parenteral and ophthalmic drug products
Jenke D1, Castner J, Egert T, Feinberg T, Hendricker A, Houston C, Hunt DG, Lynch M, Shaw A, Nicholas K, Norwood DL, Paskiet D, Ruberto M, Smith EJ, Holcomb F.
Polymeric and elastomeric materials are commonly encountered in medical devices and packaging systems used to manufacture, store, deliver, and/or administer drug products. Characterizing extractables from such materials is a necessary step in establishing their suitability for use in these applications. In this study, five individual materials representative of polymers and elastomers commonly used in packaging systems and devices were extracted under conditions and with solvents that are relevant to parenteral and ophthalmic drug products (PODPs). Extraction methods included elevated temperature sealed vessel extraction, sonication, refluxing, and Soxhlet extraction. Extraction solvents included a low-pH (pH = 2.5) salt mixture, a high-pH (pH = 9.5) phosphate buffer, a 1/1 isopropanol/water mixture, isopropanol, and hexane. The resulting extracts were chemically characterized via spectroscopic and chromatographic means to establish the metal/trace element and organic extractables profiles. Additionally, the test articles themselves were tested for volatile organic substances. The results of this testing established the extractables profiles of the test articles, which are reported herein. Trends in the extractables, and their estimated concentrations, as a function of the extraction and testing methodologies are considered in the context of the use of the test article in medical applications and with respect to establishing best demonstrated practices for extractables profiling of materials used in PODP-related packaging systems and devices.
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