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General chapter USP <382> Elastomeric Component Functional Suitability in Parenteral Product Packaging/Delivery Systems is slated to become official on December 1, 2025. This allows five years from the date of publication in December of 2020 for stakeholders to implement the new testing requirements for full compliance. While that date seems to be far off in the future, there has been interest in early adoption of the new chapter and implementation of the various tests it requires.
The scope of USP Chapter <382>
The scope of USP <382> introduces a paradigm shift away from testing elastomeric components individually by the supplier, as was done historically under USP <381>, to a holistic evaluation of these components when assembled into drug product packaging and delivery systems. In addition, the testing is performed on the final package configuration as produced by the manufacturer, using product-filled systems or systems filled with a suitable proxy, where applicable.
West can perform the testing required in USP <382>, including container closure integrity testing, as described in section 4 Packaging/Delivery System Integrity Tests and section 5.3 Needle Self-Sealing Capacity. Both sections of USP <382> refer to USP <1207> Package Integrity Evaluation – Sterile Products and its sub-chapters for guidance on container closure integrity testing. This blog describes the testing required in USP <382> sections 4 and 5.3 and discusses why helium leak detection is an ideal leak test for both evaluations for vial systems. Syringe and cartridge systems will be discussed in a later blog in this series.
The testing described in USP <382> section 4 Packaging/Delivery System Integrity Tests examines the fit of an elastomeric closure with its container. The resulting packaging/delivery system must protect the therapeutic from product loss and contamination from microorganisms or other environmental contaminants, while preserving product quality, safety, and efficacy. Therefore, packaging/delivery systems must be evaluated for two key attributes: 1) inherent container closure integrity, which is “the leakage rate of a well-assembled package/delivery system with no system defects”; and 2) the ability of the system to achieve the maximum allowable leakage limit (MALL).
USP Chapter <1207>
USP <1207> defines the maximum allowable leakage limit as “the greatest leakage rate (or leak size) tolerable for a given product packaging/delivery system that poses no risk to product safety and has no impact, or inconsequential impact, on product quality.” For the packaging/delivery system integrity test, USP <382> requires that thirty (30) samples of each packaging/delivery system are tested for inherent container closure integrity. The systems are acceptable if the inherent container closure integrity results conform to the MALL established for the specific drug product that is contained in the system. When the sterility of a product must be preserved, USP <1207> indicates that a conservative MALL for drug products contained in rigid packaging is a defect size of approximately 0.2 microns ± 0.1 micron, which correlates with a helium leak rate of approximately 6 x 10-6 std cc/sec or the “Kirsch limit.” Lee Kirsch established the relationship between microbial ingress and helium leak rate in glass vial systems. Kirsch determined that at this leakage rate, the probability of microbial ingress is less than 10%; however, well-sealed West vial systems can achieve helium leak rates in the range of 10-7 to 10-8 std cc/sec. It is important to understand the kinds of defects that could result in critical leaks for vial systems (i.e., loose or damaged crimp seals; cracks or chips anywhere on the body of the vial; and stopper defects, such as malformation, mold cavity damage, voids, splits or tears, and trim defects) and to employ a leak test that can reliably detect these leaks.
The testing described in USP <382> section 5.3 Needle Self-Sealing Capacity applies to multiple-dose product packaging/delivery systems with closures that are punctured multiple times with a needle. Piercings of the closures may be made during dosage form preparation and subsequently for product access for patient administration. Multi-dose systems must be evaluated for two key attributes:
1. in-use system integrity, which is “the ability of the punctured closure to prevent microbial ingress and product loss between and during periods of dosage form preparation and/or product access”;
2. in-use maximum allowable leakage limit, which is “the level of protection required that ensures maintenance of product physicochemical and microbiological quality attributes between and during periods of dosage form preparation and/or product access.”
USP <382> testing procedure
USP <382> section 5.3 provides detailed instructions for the preparation of vial systems, and states that thirty (30) samples are to be evaluated. When a vial system requires an initial puncture of the closure for dosage form preparation, a single puncture is made using the designated dosage form preparation needle. Multiple punctures are then made in the closure using the designated product access needle to “simulate the most challenging in-use directions.” A new needle is used to puncture each closure. If the dosage form preparation needle or the product access needle are not specified, or if the intended in-use directions are not specified, then the chapter provides default sample preparation instructions for each type of multi-dose packaging/delivery system.
To evaluate in-use system integrity at the in-use MALL for multi-dose vial systems, USP <382> again refers to USP <1207> and its sub-chapters for package integrity evaluation, recommending the use of deterministic leak tests rather than the probabilistic dye immersion test previously performed under USP <381> section 4.3.3 Self-Sealing Capacity. When selecting the most appropriate leak test for USP <382> needle self-sealing capacity, one must consider the in-use MALL because the leak test technology must be sensitive enough to detect leaks at or below this limit. Because sterility must be preserved throughout usage, a conservative in-use MALL for rigid multi-dose vial systems would be the Kirsch limit.
So which type of leak test is most suitable for packaging/delivery system integrity and needle self-sealing capacity for vial systems? Let’s weigh our options. Leak tests such as high-voltage leak detection (HVLD), vacuum decay, and dye immersion are not sensitive enough to detect leaks down to the MALL because the detection limits for these technologies range between 2-20 microns. Therefore, these techniques are not considered appropriate for demonstrating inherent container closure integrity. Laser-based gas headspace analysis, such as oxygen headspace analysis, is sensitive enough to detect leaks down to a MALL of 0.2 microns, so this leak test is suitable for packaging/delivery system integrity testing.
FDA Helium leak detection
Helium leak detection is an ideal leak test for both packaging/delivery system integrity and needle self-sealing capacity for vial systems. With this technology, an ultra-high vacuum is applied to the vial system to force helium tracer gas through any leak path that may be present in the vial system into a mass spectrometer for detection and leak rate quantitation. The mass spectrometer is tuned to the mass of helium, making detection specific to only helium tracer gas. Helium leak detection is deterministic and sensitive down to and below the Kirsch limit, with a quantitation limit of 10-9 std cc/sec. This quantitation limit is 1,000-fold more sensitive than the Kirsch limit. In addition, helium leak detection generates quantitative helium leak rate results within a 60-second test cycle due to the application of the ultra-high vacuum.
Fran DeGrazio’s paper, Holistic Considerations in Optimizing a Sterile Product Package to Ensure Container Closure Integrity, which was published in the PDA Journal of Pharmaceutical Science and Technology, discusses the use of helium leak detection to evaluate the inherent container closure integrity of vial systems in order to achieve the MALL. West’s Technical Service Bulletin TSB How to Apply the New USP Chapter <382> To Vial Systems provides a comprehensive overview of the new requirements detailed in USP <382>. Information specific to the mechanical testing requirements detailed in USP <382> is discussed in Mike Ulman’s blog. Learn more on container closure integrity testing or refer to West’s Knowledge Center for a comprehensive library of supporting information regarding West’s products and services. Contact us for more information on partnering with West for your USP <382> testing needs.
Look for the part 3 and 4 of the next blog series where we will focus on USP <382> testing requirements for syringes and cartridges.
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