Container Closure Integrity Testing Regulations

Since 1938 The FDA has been empowered by the United States Congress to enforce the Federal Food, Drug, and Cosmetic Act, which authorizes the agency to demand evidence of safety for new drugs, issue standards for food, and conduct factory inspections of relevant manufacturing facilities. Today, the FDA regulates $1 trillion worth of products a year. It ensures the safety and effectiveness of all drugs, biological product and medical devices. Throughout the Code of Federal Regulations and numerous FDA Guidance Documents, there are numerous references to Container Closure Integrity requirements:

One key element from current and future versions of EU GMP Annex 1 is highlighted as a specific element of a pharmaceutical quality system:

21CFR211.94 Specific to Drug Product Containers and Closures clearly outlines the following requirements: (a) Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements; (b) Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product; (c) Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use; (d) Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures.

In addition, the FDA Compliance Program Guidance Manual states that the integrity of the container / closure system is critical to assuring that all units of drug products remain sterile through shipment, storage and use. Leaking containers or closures lead to product contamination. The FDA’s 1994 Guidance for Industry for the Submission of Sterilization Process Validation in Applications for Human and Veterinary Drug Products requires that companies / manufacturers evaluate the tests and studies performed to demonstrate the integrity of container / closure systems for all sterile drugs, including:

  • Verify that all incoming container-closure components meet specifications, including all appropriate dimensions.
  • Determine studies adequately simulate the stress conditions of the sterilization process, handling and storage.
  • Verify that the units tested in validation are appropriate
  • Sensitivity of the test is specified.
  • Container-closure integrity is demonstrated during validation and as part of the stability program (in lieu of sterility testing) over the shelf life of the product.

Just a sampling of the container closure integrity testing guidelines referenced show the complexity and importance of insuring an adequate and effective container and package system is being used to insure the integrity of the product it contains. The Leak Detection Associates team collectively has more than 100 years of CCI experience and possesses an intimate knowledge and understanding of the regulatory requirements especially as it relates to insuring integrity issues for a container system.

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