reviewonfdas“containerandclosuresystemin

Preface:

The food and drugs administration has published the guidelines for accepting container closure testing in lieu of sterility testing as one of the component of the stability protocol for sterile products. The guidelines are published on February 22, 2008 i.e. yesterday.

As the Manufacturers of drug products etc. have to ensure that the product conforms to sterility requirements through out its entire shelf life. Such drug products are also subject to stability testing requirements. The stability testing requirements include maintaining a written testing program designed to assess stability characteristics. Stability testing should be part of the design validation of such devices.

This guidance document applies only to the replacement of the sterility test with an appropriate container and closure system integrity test in the stability written testing program (referred to in this guidance as the "stability protocol"), recommending an alternative to sterility testing for supporting the continued capability of containers to maintain sterility. The guidance document does not apply to sterility testing methods for product sterility testing prior to release, as container and closure system integrity tests cannot demonstrate a product's initial sterility.

The minimum sterility testing generally performed as a component of the stability protocol for sterile products is at the initial time point (release) and final testing interval (i.e., expiration). Additional testing is often performed at appropriate intervals within this time period (e.g., annually). However, as discussed below sterility tests for the purpose of demonstrating continuing sterility have limitations, with respect to the method's reliability, accuracy, and the conclusions that may be derived from the results. Because of the limitations of sterility tests described below, sterility tests are not recommended as a component of a stability program for confirming the continued sterility throughout a product's shelf life or dating period. Alternative methods may be more reliable in confirming the integrity of the container and closure system as a component of the stability protocol for sterile products.

• This guidance document does not suggest specific test methods and acceptance criteria (except for references to USP methods), nor does it provide comprehensive lists of tests.

Why the guidance was required?

The sterility testing has scientific and practical limitations, which are well known. Some of these are:

1. Sterility tests will only detect viable microorganisms present at the time of the test;

2. Viable organisms present at the time of the test can only be detected if they are capable of growth in the specified culture media;

3. 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

4. Sterility tests are always destructive of the samples tested and do not offer the opportunity to reexamine the same samples in the event of either positive or negative findings. and,

The ability of the container-closure system to maintain the integrity of its microbial barrier, and, hence, the sterility of a drug product throughout its shelf life, should be demonstrated. […] As previously stated, sterility testing at the initial time point is not considered sufficient to demonstrate the microbial integrity of a container-closure system. […].

"Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products" (December 3, 1993, 58 FR 63996). Section V. A., page 16

So what are the alternatives?

Alternatives to sterility testing as part of the stability protocol, such as replacing the sterility test with container and closure system integrity testing, might include any properly validated physical or chemical container and closure system integrity test (e.g., bubble tests, pressure/vacuum decay, trace gas permeation/leak tests, dye penetration tests, seal force or electrical conductivity and capacitance tests, etc.), or microbiological container and closure system integrity tests (e.g., microbial challenge or immersion tests). Such tests may be more useful than sterility testing in demonstrating the potential for product contamination over the product’s shelf life or dating period. The advantages of using such container and closure system integrity tests in lieu of sterility tests in the stability protocol for sterile products include:

• 1. Such alternate methods may detect a breach of the container and / or closure system prior to product contamination;

  2. Some of the alternate methods used to evaluate container and closure integrity can conserve samples that may be used for other stability tests;

  3. Alternative test methods may require less time than sterility test methods which require at least seven days incubation; and

1. The potential for false positive results may be reduced with some alternative test methods when compared to sterility tests.

The guidance paper further elaborates that the applicants also proposed the use of a preservative effectiveness test in lieu of the appropriate sterility test for products containing antimicrobial preservatives. However, these tests only measure the effectiveness of preservatives against a panel of five different test organisms. This method cannot confirm product sterility since it does not confirm the presence or absence of contamination, but rather only demonstrates the microbiological effectiveness of the preservative system against the five test organisms in question. For these reasons, preservative effectiveness tests are not acceptable alternative tests for monitoring container and closure system integrity or for demonstrating maintenance of sterility. However, such tests are appropriate to perform as part of the stability protocol on multi-dose containers at the end of the product's shelf life or dating period, to verify antimicrobial preservative effectiveness and preservative content.