How To Evaluate Sterile Products For Package Integrity
What does USP 1207 cover?
USP 1207 describes how to assure the integrity of non-porous packages used for sterile pharmaceutical products (small and large volume container-closure systems). Examples of pharmaceutical packaging include syringes, cartridges, flexible bags or pouches, plastic or glass ampules, capped vials or bottles, and packages for drug/device combination products. This document provides details on leaks, leakage rates, leakage limits, package sealing types, and closure mechanisms. USP 1207 also describes package integrity leak tests, seal quality tests, and guidance in selecting, validating, and using leak test methods. The USP 1207 guidance is specific to non-porous packages. Thus, packages with porous barriers (such as materials allowing volumetric airflow while preventing airborne contaminants) are not covered in this guidance. Furthermore, USP 1207 does not contain advice for the packaging systems and processing equipment used to prepare, store, and manufacture pharmaceutical products. Additionally, USP 1207 does not cover packages used for sterile diagnostic products or medical devices. An overview of leak rates, inherent package integrity, closure mechanics, and package integrity testing profiles are covered in this article.
What are the guidelines provided by USP 1207 for package integrity testing?
USP 1207 covers four primary bodies of material:
- Leaks and leak rates
- Closure types and mechanics
- Product-package quality requirements
- Inherent package integrity and package integrity profiling
Product packaging leaks, leak rates, closure types, closure mechanics, inherent package integrity, and package integrity profiling are described in further detail below.
Leaks
Leaks are holes or channels in a packaging system. Leaks are irregular. Even artificially created leaks are inconsistent in shape, size, and depth. Package integrity testing often measures leak size by leakage rate. However, more significant leaks can be measured by their dimensions.
Leak rates
A package’s leakage rate is most commonly measured as a gaseous leakage rate. Gaseous leakage rates are calculated as the rate of volumetric gas flow that passes through the leak under controlled pressure and temperature conditions (25°C and atmospheric pressure). The standard unit for gaseous leak rates is a pascal cubic meter per second (Pa · m3 · s−1).
For non-porous packaging materials, the permeation rate of gas through the packaging material is insignificant compared to gas escaping through a packaging leak. Thus, packaging leaks can be identified and sized using gas leak detection techniques. For example, packaging leaks may be detected through monitoring changes in the headspace pressure of the package over time.
Most leakage rates for package integrity testing will be determined using gaseous leakage rates. This is because liquid leakage rates can only be measured for leaks of a greater size. Liquid leakage rates are calculated as the volume of liquid that moves through a leak over time under controlled pressure and temperature conditions (25°C and atmospheric pressure). Liquid can only move through a leak if the leak site is unobstructed, and the size of the hole and shape of the gap allows for fluid to move into the package. In the context of sterile packages, sterile packaging should prevent all liquid leaks from occurring. Thus, most tests for sterile packaging test the presence or absence of fluid leaks and do not calculate a liquid leakage rate.
Closure Mechanics
Knowledge of the closure mechanics used for packaging your medical device allows for better monitoring and control of packaging integrity over the product’s lifetime. Below you will find additional knowledge on standard closure systems for maintaining package integrity and how each type of closure functions.
Physically Mated Closures
Packaging materials can be fitted together through close physical mating of the two packaging material surfaces. The tight fit of a plunger inserted into a syringe barrel is an example of a physically mated closure system. Other examples include a screw-cap for a bottle or an elastomeric closure cap on the top of a vial. The physical mating of these materials requires no bonding, so tiny gaps do exist between the components. However, these packaging closure systems fit hand-in-glove such that there is no liquid leakage and minimal gas migration. Caution should be used for screw-thread closure systems in specific sterile packaging applications. The screw threads winding path doesn’t provide an ideal barrier to gas or liquid leakage and thus poses a contamination threat should liquid be present in the threads of the cap.
Bonded Closures
Packaging seals are commonly formed via bonded closures when two packaging materials are physiochemically joined together. The mating of sheets of material through heat or ultrasonic welding processes can create bonded closures. Two packaging materials can also be joined together using a bonding material. Bonded closures also cover contiguous containers of a single material, such as glass or plastic ampoules . Bonded closures are excellent at blocking liquid leakage and microbial contaminants. However, packaging used for bonded seals is still subject to gas leakage or permeation.
Multiple-Dose Package Closures
Multidose packages enable access to a product while restricting microbial contamination. Elastomeric closures for injectable medications reseal quickly after a needle has been inserted to draw up a patient’s dosage. This quick reseal prevents microbial contamination and product loss between doses. Other multidose packages have filters, plugs, or other mechanisms (such as pinch closure systems) that allow the product to be dispensed while minimizing contamination.
Inherent Package Integrity
Inherent package integrity is the leak tightness of a defect-free, perfectly assembled container-closure system. Inherent package integrity is a metric obtained during product packaging development and eligibility assessment. Anticipated metrics for material composition, packaging dimensions, package processing (such as sterilization), and assembly are considered in inherent package integrity measurement. Product storage, distribution, and use are additional variables that are also factored into inherent package integrity. Inherent package integrity for a product-package system must meet the maximum allowable leakage limit to be acceptable for use. Package integrity testing is used to confirm that the anticipated inherent package integrity meets regulatory standards leakage limits. Many of these package integrity tests are pass or fail evaluations.
Package Integrity Profiling
Packaging integrity is a quality metric that needs control and monitoring throughout a medical device or product’s life cycle. A package integrity profile is the data repository (or archive) for all package integrity tests throughout a product’s life cycle (package leak assessments, seal strength tests, etc.). This database provides information on package integrity as package or product designs, product storage conditions, or distribution processes change over time. All packages and all leak testing cannot be assessed with a single package integrity test. Instead, a series of assessments must be explicitly selected for the unique packaging system to be tested. Thus, it is beneficial to have a robust package integrity profile. The more data you have on your packaging system, the better you can control and monitor the integrity of your current product’s packaging system. Then you can use the data from your existing package integrity profile to design packaging systems with comparable success rates for future assets in your pipeline.
All in all, a product–package system has integrity if its inherent package integrity meets the maximum allowable leakage limit. The package integrity profile for your packaging system is a critical tool for package integrity risk management. It ensures your product’s sterility and functional integrity until use or expiry.
How does USP 1207 relate to testing for package integrity?
USP 1207 covers package integrity testing topics, including leaks, leak rates, closure types and mechanics, package quality requirements, inherent package integrity, and package integrity profiling. Closure types inform what types of package integrity tests would be best to perform to ensure the integrity of your product’s packaging system. Information on leaks and leak rates provides the raw data needed for proform testing of your product-packaging system. Inherent package integrity and package integrity profiling allow you to appropriately assess the integrity of your packaging over your product’s lifecycle. Overall, USP 1207 provides essential details about package integrity testing for non-porous packaging systems. This guidance helps prepare the appropriate package integrity tests for regulatory approval of your medical product’s packaging system.
MycoScience is a contract manufacturing organization specializing in sterile syringe and vial filling. MycoScience also offers Preservative Efficacy Testing, Sterilization Validations, Bioburden Testing, Cleaning Validations, Microbial Aerosol Challenge Testing, Accelerated Aging, Microbiology Testing, Cytotoxicity Testing, Bacterial Endotoxin Testing, EO Residual Testing, Package Integrity Testing & Environmental Monitoring services medical devices and allied industries. MycoScience is an ISO 13485 certified facility.
References
United States Pharmacopeial Convention. <1207> Package Integrity Evaluation- Sterile Products. Rockville, MD, USA. 2021. (USPC <1207>).
