U.S. & EU Package Integrity Testing Guidelines
What is package integrity?
Suppose we break down the term package integrity. The definition of a package is a wrapped object or group of objects. The state of integrity is a state of being whole and undivided. Thus, package integrity testing has to do with testing how well a package stays complete and undivided to keep wrapped objects protected and sterile. In the context of package integrity and package integrity testing, a product package is considered both the product packaging itself and the product’s contents. The European Union’s Good Manufacturing Practices (EU GMP), FDA GMP medical device standards, and FDA package integrity testing will be covered in this article.
What is a container-closure system?
A container–closure system includes primary packaging (packaging in direct contact with the product) and secondary packaging (packaging that supports package assembly such as an aluminum cap as a secondary seal for a stoppered vial). Container-closure systems for sterile product-package integrity must keep product contents within and environmental contaminants out.
What must U.S. and E.U. regulations be meet for package integrity testing?
Before the mid-1990, only sterility of the packaged product and verification of package integrity were required by the U.S. Food and Drug Administration (FDA). Since 1994, the U.S. FDA has issued more than one guidance modifying the requirements for package integrity testing.
As a part of the 1994 guidance shifts, sterility testing alone was insufficient for verifying the integrity of a container’s closures ability to protect against microbial ingress through its shelf life. Instead, a sterilization process validation was needed to demonstrate the container-closure system could maintain the integrity of its microbial barrier and provide indirect verification of product-packaging sterility through the product’s shelf life. Sound scientific principles are recommended in selecting integrity tests, considering the container–closure system, product formulations, and product administration routes. In some instances, limits to sterility testing may result in substituting other integrity tests instead of sterility for stability protocols.
In 1999, the FDA issued additional guidelines for packaging systems for human drugs and biologics. All pharmaceutical packaging needed to show that it was suitable for its intended use, including providing the drug or biologic with protection from temperature, light, or anything that could degrade the therapeutic quality over its shelf life. Examples of causes of degradation that can occur due to package integrity failure include solvent loss, exposure to reactive gasses (such as oxygen), absorption of water vapor, microbial contamination, and gross particulate contamination. As a result of this guidance, any new product must show a package integrity study that proves the package integrity failures were absent throughout the product’s shelf life. A recommendation in 2008 further addressed the pre-approval and post-approval stability protocols for sterile biological products, human drugs, animal drugs, investigational drugs, and bulk drugs.
The 2004 U.S. FDA Sterile Drug Products Aseptic Processing GMPs (good manufacturing practices) are complementary standards to EU GMP standards set in 2008. These 2004 FDA GMP medical device standards refer to the inspection of container–closure systems. In container-closure inspection, damaged or defective final sealed products are to should be removed. Safeguards are put in place to ensure that any product that may lack container integrity be kept from shipment. If damage is not detected leads to loss of container-closure integrity, new procedures and evaluations must be rapidly implemented to prevent and detect the previously undetected container-closure damage. In appendix 2 of the 2004 FDA GMP standards, a special section was added pertaining to risks with blow-fill-seal (BFS) technologies. This appendix warns that container closure defects can be a significant problem in controlling a BFS operation. The inspection of each BFS batch should include a reliable and sensitive product examination capable of identifying leaky units. Potential defects due to heat or mechanical problems, such as wall thickness variance, poorly formed closures, or other deviations from normal, must be covered in the inspection as well.
In the 2008 EU GMP for sterile products, the integrity testing of containers closed by fusion, e.g., glass or plastic ampoules) is addressed. The 2008 EU GMP (good manufacturing practices) also states the samples of other containers must be checked for integrity as well. Specifically, containers sealed under vacuum should be tested for maintaining that vacuum over pre-determined acceptance criteria.
Additionally, vial container-closure systems with missing or displaced stoppers should be rejected prior to capping. Furthermore, filled containers should be inspected individually for inappropriate contamination or other defects. For container-closure inspection, the direction is given for human inspection, or validated automated processes are used. If automated processes are used, the equipment which performs the container-closure examination must regularly be assessed for its functionality.
While not an official FDA document, the 1998 Parenteral Drug Association (PDA) Technical Report No. 27 clarifies the selection of appropriate container–closure integrity test methods for different types of packaging. This report covers package leakage tests and requirements and discusses the importance of designing package integrity for the life of the product in early product development. Eighteen different integrity tests are described and referenced in the PDA’s Technical Report No. 27. These eighteen integrity tests are linked to a decision tree to help the reader select the most appropriate methods. As a caution, package integrity tests have evolved since 1998, so we do not recommend relying on Report No. 27 alone when designing your product’s packaging system.
Summary
Overall, the FDA and EU have provided additional guidance for container-closure systems package integrity testing from the 1990s onwards. Most of the FDA GMP (good manufacturing practices) medical device guidelines require sterilization validation testing as well as protocols for preventing and detecting any defective product packages. When creating protocols for your product packaging system, ensure you choose a contract testing organization that can support you with your unique medical device or product needs.
MycoScience is a contract manufacturing organization that specializes in filling sterile syringes and vials for parenteral products. MycoScience also offers Package Integrity Testing, Environmental Monitoring, Microbial Aerosol Challenge Testing, Sterilization Validations, Bacterial Endotoxin Testing, Preservative Efficacy Testing, Bioburden Testing, Cleaning Validations, Accelerated Aging, Microbiology Testing, Cytotoxicity Testing, and EO Residual Testing services for medical device companies, and allied industries. MycoScience is an ISO 13485 certified facility.
References
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
