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Part-1. USP <382>: Think Systems, Not Components - Fragmentation, Penetration and Sealability of Vial Systems
United States Pharmacopeia (USP) requirements for elastomeric components of container closure systems used for parenteral products are changing. The original USP chapter for elastomeric components used in injectable drug packaging was <381> Elastomeric Components in Injectable Pharmaceutical Production Packaging/Delivery Systems. This addressed characterizing for biological reactivity, physicochemical testing and functionality testing and compliance was typically a supplier responsibility. The new chapter, USP <382> Elastomeric Component Functional Suitability in Parenteral Product Packaging/Delivery Systems, will become effective on December 1, 2025. This will update the functionality tests for elastomers, whereas the functionality testing portion of USP <381> will be omitted. Under the new chapter, it will be the drug manufacturer’s responsibility to meet the functionality requirements on the final system.
USP <382> focuses on vial and bottle packaging, blow-fill-seal (BFS) packaging, plastic packaging (including film bags and blow-molded containers), cartridge packaging systems and syringes (both pre-filled and single-use) and applies to all elastomeric components in direct and indirect contact with the drug product in primary packaging and combination product kits. The USP chapter specifically states that, “[t]he tests for functional suitability described in this chapter are intended to evaluate the fitness of an elastomeric component as part of a specific, final, parenteral product packaging/delivery system.” This is a change from USP <381> in that the whole container-closure system must be certified for functionality rather than simply the individual component. The USP describes this type of holistic testing as “fitness-for-intended-use functional suitability.”
The USP chapter prescribes specific testing to be performed for the packaging/delivery system as a starting point but warns that the prescription is not exhaustive and should be used as appropriate, with justification. The chapter further states that functional suitability assessment studies for each specific drug product in its final drug packaging/delivery system should be developed based on a) the system design/mechanics, b) the nature of the dosage form, c) the environment and clinical use setting of the finished drug product and d) the assessed safety of those using and/or exposed to the drug during administration, all with justification. In other words, the USP instructs the drug manufacturer to perform a risk assessment to determine the best test strategy for the given application.
The present blog will focus on the application of USP <382> prescribed testing to vials, from a mechanical testing perspective. A upcoming concurrent blog from Jen Roark, USP <382>: Think Systems; Not Components Part 2, Packaging/Delivery System Integrity and Needle Self-Sealing Capacity of Vial Systems, discusses how USP <382> addresses packaging integrity testing and needle self-sealing capacity for vials. Future blogs will focus on cartridges and syringes.
The test samples to be used for the USP <382> testing are intended to closely resemble the final drug product packaging configuration. For vials, that should include identical closures, vials, seals, optimized capping force, sample processing (e.g., sterilization) and sample handling (e.g., storage conditions and aging). Depending on the risk assessment of the packaging configuration, one may want to perform ASTM D4169, Standard Practice for Performance Testing of Shipping Containers and Systems, transportation conditioning on the samples prior to testing to assure that samples truly represent what may be used in the field. In contrast, USP <381> simply required that elastomer samples be placed in water, autoclaved at 120oC for a period of time, cooled and air-dried.
Mechanical testing for vial-packaged drug products described in the chapter involves testing of fragmentation, penetration force and spike-retention/sealability-capacity. These tests pertain to needle and spike (e.g., vial adapter, CSTD, vial spike) connections to crimped-on stoppers. If a product is intended to be used with different piercing devices, then multiple test methods must be employed. The chapter further differentiates products that require initial piercing of the stopper to add diluent (e.g., powdered, lyophilized or concentrated drug product) versus products that are ready to be withdrawn from the vial undiluted. The pre-penetration of the stopper prior to the test penetration can have an impact on the test results and must be incorporated into the testing, again, to simulate as closely as possible the intended use conditions, piercing with a device as similar to the actual device as possible. Along the same lines, if different piercing devices are anticipated in the real world, tests should be designed to test the most challenging version or to use bracketing to test different extremes (i.e., CSTD spikes come in different sizes so using the smallest and largest would bracket the range of spike dimensions).
Analysis and Evaluation
When a needle or spike penetrates an elastomeric stopper, it sometimes results in fragmentation or coring. This is a topic that was extensively studied at West. Fran DeGrazio described the fundamentals that result in this phenomenon and West’s Knowledge Center has a presentation on factors that contribute to this issue. The USP <382> procedure for fragmentation calls for pre-piercing the partially water-filled vial with a needle, if reconstitution/dilution of the drug product is expected, followed by piercing with a needle or spike intended to simulate the drug withdrawal step. For needles, the stopper is to be pierced four or more times, while for a spike each stopper is to be pierced once. After each piercing, the needle/spike is to be flushed with water to ensure that any fragments are deposited into the water in the vial and the fragment containing water is to be poured onto a particle examination filter and examined under a microscope at 30 to 110 fold magnification, using lighting conditions and equipment as described in USP <788> Particulate Matter in Injections, reporting all particles greater than 150 microns in any dimension. This is a major change from USP <381>, where particle counting was performed with the naked eye and thus limiting the count to particles greater than 50 microns in diameter.
The force required to penetrate a stopper with a needle or spike helps determine the ease of use of the stopper as well as the ability of the system to avoid stopper push-in from spikes, as described by Zhao, et. al. here. USP <382> prescribes performing penetration testing of stoppers in parental drug packaging. In addition to testing the force required for pre-piercing the stopper with an 18-gauge hypodermic needle intended to simulate reconstitution or dilution of the drug, if applicable, the procedure calls for piercing with a 21-gauge needle or with a spike, at a specified piercing rate, and measuring the force required to penetrate the stopper. In the case where a specific spike is not intended for planned use of the stopper, a spike like that specified in ISO 8536-2 or ISO 8536-6 may be used.
When a stopper is pierced by a thin needle, the formed elastomeric orifice can readily seal around the needle and prevent leakage. However, in the case of a spike, that pierced orifice is larger and potentially jagged, possibly resulting in poor sealability around the spike shaft. USP <382> testing aims to qualify whether sealability is achieved in any given packaging system. The procedure calls for partially filling the vial with liquid product, or a reasonable proxy, piercing the stopper with a spike, suspending the vial in an inverted position, and hanging a 0.5 kg mass from the spike for a period of four hours. After the completion of the test, the spike and stopper are to be inspected for signs of slippage of the spike from the orifice or of liquid leakage around the puncture site.
West USP <381> & USP <382> Analytical Services
The Analytical Laboratory Services group at West can help drug manufacturers navigate the requirements being imposed by USP <382> and perform the necessary testing to assure that products are compliant with the latest regulations. Meanwhile, West’s Technical Customer Support group can help drug manufacturers select the best packaging system for their product, including using West’s new DeltaCube™ modelling platform to optimize vial, stopper and seal fit.
Contact us to learn more about how West can help you with your USP <382> testing needs before the December 1, 2025 deadline.
USP <381> Elastomeric Components in Injectable Pharmaceutical Product Packaging/Delivery Systems; United States Pharmacopeia
USP <382> Elastomeric Component Functional Suitability in Parenteral Product Packaging/Delivery Systems; United States Pharmacopeia
USP <788> Particulate Matter in Injections; United States Pharmacopeia
ISO 8536-2:2010; Infusion equipment for medical use - Part 2: Closures for infusion bottles; International Organization for Standardization
ISO 8536-6:2016; Infusion equipment for medical use - Part 6: Freeze drying closures for infusion bottles; International Organization for Standardization
Zhao, Cathy; Ho, Le; Bantz, Daniel; Hostetler, Doug; Fang, Liang. A Case Study to Address a Gap in the Device-to-Vial Interface Stopper Push-in by Chemo Spikes - An Overlooked Oncology Safety Risk. PDA Journal of Pharmaceutical Science and Technology. January 2019, 73 (1) 92-109; DOI: https://doi.org/10.5731/pdajpst.2018.008664
ASTM D4169: Standard Practice for Performance Testing of Shipping Containers and Systems
<em>The following is an excerpt of an article that appears in the Summer 2014 edition (Vol. 6, Issue 2) of International Pharmaceutical Industry magazine. To read the complete article, which begins on page 92 of the issue, visit: </em><a href="http://issuu.com/mark123/docs/ipi_-_volume_6_issue_2_june_2014"><span style="text-decoration: underline;">http://issuu.com/mark123/docs/ipi_-_volume_6_issue_2_june_2014</span></a>
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Sr. Director, Strategic Marketing, Containment Systems