Container-Closure Systems Provide Critical Protection for Stability and Sterility

The container closure system for a drug product provides critical protection for stability and sterility. It consists of all components intended to seal and protect the package/delivery system and its contents. Container-closure integrity (CCI) is the ability of the system to keep contents in, and to keep harmful environmental contaminants out.

CCI testing (CCIT) detects leaks in the container closure system. A passing test result indicates the packaging system can maintain sterility and relevant physicochemical specifications. Three types of leaks that can be detected during CCIT include:

  • entry of microorganisms
  • escape of the product dosage form or entry of liquids or solids
  • escape of nitrogen gas or entry of oxygen, water vapor, or air gases

In February 2008, the Food and Drug Administration (FDA) introduced CCIT in lieu of sterility testing as a component of a stability written testing program for sterile products. A stability study measures the extent to which a product retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics it possessed at the time of compounding. Sterility is a stability characteristic that should be conducted throughout a stability study to confirm a product's shelf life.

According to the FDA, there are scientific limitations to sterility tests when evaluating a drug product's quality over time:

  • Sterility tests detect viable microorganisms present only at the time of the test
  • Viable organisms present during the test can be detected only if they are capable of growth in specified culture media
  • Sterility tests may be subject to potential interference due to adventitious microbial contamination introduced at the time of testing, resulting in false positive readings; and
  • Sterility tests are destructive and do not offer the opportunity to reexamine the same samples in the event of either a positive or negative finding

The FDA states that using alternatives to sterility testing as part of the stability protocol may be more useful than sterility testing in demonstrating the potential for product contamination over the product's shelf life or dating period. CCITs are a valuable alternative when evaluating package integrity throughout a stability study.

Advantages of CCI tests in lieu of sterility tests include:

  • May detect a breach of the container and/or closure system before product contamination
  • Conserves samples that may be used for other tests, depending on the type of CCIT utilized
  • May require less time than sterility test methods which require at least 7 days incubation; and,
  • Potential of false positive results may be reduced with some alternative test methods when compared to sterility tests

The guidance document allows for CCIT to be used as an alternative to sterility testing after time 0 in a stability study. FDA does not allow CCIT to replace a sterility test for release testing as CCIT cannot demonstrate a product's initial sterility.

Demonstrating CCI throughout the compounding process from product development and continuing through stability studies helps prevent recalls and reduces costs downstream. FDA 503B guidance requires CCIT when using an expiration date or beyond use date (BUD) before a batch is released. Some state regulatory agencies also require CCIT to extend beyond use dates for sterile and non-sterile products in state board of pharmacy guidelines. Ensuring the package integrity of a drug product throughout its shelf life safeguards against harmful environmental contaminants and keeps patients safe.

For more information on container closure integrity testing, contact 800-393-1595 orinfo@arlok.com.

Resources:

  • USP 1 Injections and Implanted Drug Products (Parenterals)-Product Quality Tests
  • USP 659 Packaging and Storage Requirements
  • USP 797 Pharmaceutical Compounding-Sterile Preparations
  • USP <1207> Package Integrity Evaluation-Sterile Products
  • USP <1211> Sterility Assurance
  • USP 1382 Assessment of Elastomeric Component Functional Suitability in Parenteral Product Packaging/Delivery Systems
  • FDA Guidance for Industry - Container Closure System Integrity Testing in Lieu of Sterility Testing as a Component of Stability Protocol for Sterile products
  • FDA Draft Guidance - Current Good Manufacturing Practice - Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act