Container and Closure System Integrity Testing as an Alternative to Sterility Testing for Stability Protocols
This guidance provides recommendations for manufacturers to use alternative methods to sterility testing for confirming container and closure system integrity as part of stability protocols for sterile biological products, human/animal drugs, and medical devices. It applies to both pre- and post-approval stability protocols but does not apply to initial product sterility testing prior to release.
Recommended Actions
- Review current stability protocols and consider replacing sterility testing with validated container closure integrity testing
- Select and validate appropriate alternative test method(s) specific to product container/closure system
- Prepare documentation demonstrating validation of chosen alternative method(s)
- Submit appropriate regulatory supplement for approved products:
- Human drugs: Special Supplement - Changes Being Effected
- Animal drugs: Supplement - Changes Being Effected
- Biologics: Supplement - Changes Being Effected
- Medical devices: PMA supplement
- Include in submissions:
- Discussion of test method and applicability
- Validation data
- Justification for media-filled container use if applicable
- Statistical rationale for sample sizes
- Implement annual and expiration date testing once approved
Key Considerations
Non-clinical testing
- Container and closure system integrity testing should be conducted annually and at expiration
- Alternative test methods must be properly validated
- Number of samples should be statistically appropriate
- Samples passing integrity testing may be used for further stability testing if method is non-destructive
Safety
- Container and closure system integrity tests must demonstrate continued capability to maintain sterility throughout shelf life
- Preservative effectiveness tests alone are not acceptable alternatives for monitoring container integrity
Other considerations
- Alternative test methods may include:
- Physical/chemical tests (bubble tests, pressure/vacuum decay, trace gas permeation/leak tests, etc.)
- Microbiological container integrity tests
- Validation can use media-filled containers instead of product-filled containers if justified
- Bracketing matrix approach acceptable for validating multiple products using same container system
Relevant Guidances
- Quality System Information Requirements for Premarket Submissions
- Manufacturing Site Inspections and PMA Review Process for Medical Devices
- Submission Requirements for Terminally Sterilized Medical Devices
Related references and norms
- USP: Methods for sterility testing and container closure integrity testing
Original guidance
- Container and Closure System Integrity Testing as an Alternative to Sterility Testing for Stability Protocols
- HTML / PDF
- Issue date: 2008-02-25
- Last changed date: 2020-05-06
- Status: FINAL
- Official FDA topics: Medical Devices, Postmarket, Drugs, Animal & Veterinary, Biologics, Administrative / Procedural
- ReguVirta summary file ID: 07f6ae6eeb7211a650f3efe75bf9ac25
This post is licensed under CC BY 4.0 by the author.