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USP seeks input from stakeholders on new and revised standards to mitigate extractables and leachables in plastic packaging systems.
Prefilled syringes, parenteral drugs, and many therapeutic biologics delivered through infusions are contained in plastic packaging systems. Packaging systems must protect and be compatible with the drug product and not compromise the stability, efficacy, or safety of the drug product. In turn, the ingredients of a drug product should not be absorbed onto the surface or migrate into the body of the plastic packaging system.
The US Pharmacopoeial Convention (USP) is currently revising its existing quality standards and developing new standards for plastic packaging systems. Because these standards will have a significant impact on drug manufacturers and packaging-material suppliers, USP is actively seeking feedback from drug manufacturers, packaging manufacturers, and suppliers as well as other stakeholders who may be affected by the new standards.
Extractables and leachables
Plastic-packaging systems can include not only the container that holds the drug product, but also gaskets, rubber stoppers, tubing, and other components that may be a part of the overall system that delivers the drug to the patient. For the manufacturer, understanding and mitigating risks associated with extractable and leachable aspects (unintended migration into or out of packages) is an important part of ensuring the quality and safety of the medicine delivered to patients.
Extractables are chemical compounds that can be extracted from a material under laboratory conditions, which can include the use of solvents and/or extreme temperatures. Leachables are extractables that may migrate into the drug product over the course of a drug product’s shelf life. Drug-product leachables can affect the stability and efficacy of the product, and in some extreme cases, pose significant patient safety risks
Plastic materials are used in a variety of ways within the pharmaceutical sector, from packaging systems and medical devices to tubing and single-use components used in the manufacturing process. A question faced by the manufacturer is, “What ultimate impact does a plastic material or component have on the drug product?” Because the makeup of most packaging materials is proprietary, drug manufacturers must rely on their own testing for extractables and leachables to determine if a material is suitable. With a robust compendial standard, knowledge of a material can be obtained that will provide the manufacturer with an ability to make more informed decisions about materials during the drug-development process, which ultimately saves time and effort. USP introduced a biocompatability standard for plastic materials in 1965 and physiochemical standards in 1970. Improvements in analytical techniques in recent years have prompted pharmaceutical manufacturers to take a closer look at potential risks associated with plastic materials used to package pharmaceutical products, and therefore, a need to update the standards.
Plastics used in packaging systems are composed of polymers with a range of molecular weights and contain additives such as antioxidants, stabilizers, lubricants, colorants, and other additives. The nature and amount of additives for packaging systems are dictated by the type of polymer used, its application, and the process used to convert that polymer into components, containers, or packaging systems.
As drug products are manufactured, packaged, stored, and administered, these drug products come into direct contact with packaging systems and their plastic materials of construction. Because such contact may result in an interaction between the product and its packaging system, it is important that both the drug product and the packaging materials are not adversely affected by such interactions. The use of well-characterized plastic materials of construction in components, containers, and packaging systems and the appropriate testing of packaging systems help to determine if such adverse interactions are taking place and whether the packaging material of choice is suitable for its intended use.
USP’s new and revised standards for plastic packaging systems have been proposed as a suite of interconnected chapters in the
United States Pharmacopeia--National Formulary (USP-NF):
General Chapter <661> Containers--Plastics is being revised and will be titled Plastic Packaging Systems and Their Materials of Construction. The chapter will provide the testing rationale for plastic materials of construction and packaging systems used for the pharmaceutical industry. USP recognizes that the use of well-characterized materials to construct a packaging system is a primary means of ensuring that the packaging system is suited for its intended use as the properties and characteristics of the materials can be matched to the performance requirements of the packaging system.
New General Chapter <661.1> Plastic Materials of Construction will help determine whether a material is deemed well characterized by establishing its identity, biocompatibility (biological reactivity), general physicochemical properties, additives, and extractable metals. The objective of <661.1> is to provide tests, procedures, and acceptance criteria for plastic materials of construction used in pharmaceutical packaging systems, because proper characterization of these materials facilitates the identification and use of appropriate materials in pharmaceutical systems.
The testing of packaging systems to establish that they are suitable for their intended use is addressed in new General Chapter <661.2> Plastic Packaging Systems for Pharmaceutical Use. The applicant who seeks regulatory approval of a packaging system or packaged pharmaceutical product is responsible for establishing that the product’s packaging system meets the expectations of <661.2>. This chapter establishes what is meant by “appropriately tested,” which includes the requirement that the packaging system has been established to be safe by way of appropriate chemical testing, which could include extractables testing, leachables testing, and appropriate toxicological assessments.
Screening the materials used in a packaging system and its components for ingredients that are probable extractables and possible leachables is an important step for establishing suitability. New General Chapter <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems presents and describes best-demonstrated scientific practices for accomplishing an extractables assessment. New General Chapter <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems outlines a framework for the design, justification, and implementation of assessments for drug-product leachables derived from pharmaceutical packaging and delivery systems. Accompanying <1664> is General Chapter <1664.1>, which addresses specific considerations for leachables in metered dose inhalers, nasal sprays, dry powder inhalers and inhalation solutions, suspension, and sprays. General Chapter <1664.1> is intended to incorporate into USP’s chapters specific best practice recommendations of the Product Quality Research Institute (PQRI) related to leachables in orally inhaled and nasal drug products, including the first safety-based thresholds for leachables characterization and safety qualification.
Revised General Chapter <661> and the suite of related new chapters have been published for comment in the September-October 2013 issue of Pharmacopeial Forum (PF), USP’s free-access, online publication for posting proposals and receiving public comments to its developing standards. A 90-day comment period for receiving feedback to these chapters as they appear in PF will end on Nov. 30, 2013. Once finalized, the general chapters will be published in USP-NF. However, USP’s Packaging, Storage, and Distribution Expert Committee will carefully review the comments received through PF during this period and further revisions to the chapters may result.
Like USP, the PQRI Extractables and Leachables Working Group is also working to develop guidelines, specifically for packaging systems used for parenteral and ophthalmic drug products. On Dec. 9-10, 2013, USP and PQRI will co-host a workshop, “Suitability and Compatibility for Packaging and Delivery Systems: Extractables and Leachables.” The workshop will take place at USP’s headquarters in Rockville, Maryland, and both organizations invite stakeholders to provide input on each organization’s developing work related to plastics packaging systems.
For more detailed information on the December workshop and to access USP’s suite of proposed general chapter changes, visit uspgo.to/extractables-leachables.
Desmond Hunt, PhD, is senior scientific liaison, General Chapters, US Pharmacopeial Convention