The Parenteral Drug Association (PDA) has a technical monograph (#27) on Pharmaceutical Packaging Integrity that cites helium mass spectrometry methods. There are dozens of published articles that compare helium leak methodology to microbial ingress for testing container closure integrity and for pharmaceutical packaging. Most of the published articles are in the PDA Journal of Pharmaceutical Science and date from the 1980s to the present. Other standards that could be referenced include the following:

• ASTM E493-06—Standard Test Methods for Leaks Using the Mass Spectrometer Leak Detector in the Inside-Out Testing Mode

• ASTM E499-95 (2006)—Standard Test Methods for Leaks Using the Mass Spectrometer Leak Detector in the Detector Probe Mode

• ASTM E908-98 (2004)—Standard Practice for Calibrating Gaseous Reference Leaks

• ASTM E1603-99 (2006)—Standard Test Methods for Leakage Measurement Using the Mass Spectrometer Leak Detector or Residual Gas Analyzer in the Hood Mode

According to the ISO 10993 standard, the ophthalmic instrument would be considered an external communicating device with limited contact. Thus, because of this type of contact, you would be looking for cytotoxicity, irritation, and sensitization using Limulus amebocyte lysate testing to discover the presence of a pyrogen. Without knowing the material in the device, this is the testing I would suggest. If you are using known materials and processing methods, you might be able to limit the animal tests by performing more chemical comparisons.

I am not sure of any silicone product with the density of water. But we have commonly used Wacker 3003/40 and Momentive LIM 6050— to name a few LSRs—on respirator and other mask applications.

You are correct that you cannot just meet ISO 10993-4 requirements for the FDA. In fact, we have been told that the FDA does not accept ISO 10993-4 and is requiring more testing than that standard. If your sample maintains contact with circulating blood for more than three hours, we recommend both direct and indirect hemolysis, complement activation, and an in vivo thrombosis test. Unfortunately, these requirements are not reflected in a standard, they are just what we have seen from the FDA in recent months. There is another issue with nitinol products and the FDA: nickel ions leaching off the sample. Companies have been asked to do nickel leaching studies to demonstrate that nickel is not an issue.

There are at least four issues involved here: How long does the product maintain the desired organoleptic properties? How long will the packaging maintain the desired state (carbonation, sterility [barrier?]? How long are the preservatives supposed to be effective? What is the desired or labeled shelf life?

The study should be as long as necessary to cover the shortest of the product requirements. For example, if the product changes color, taste, etc. at 180 days, it should be tested to 180+ days. If the package maintains product integrity for only 120 days, 120+ days should suffice. If there is any possibility that the product will be on the shelf longer than the organoleptic or microbial data support, shelf-life labeling for the validated interval would be appropriate. All studies should be longer than the labeled shelf life or longer than the shortest interval that the product safety test data support.

There is not a direct comparison between time and temperature for steam sterilization for 100% LIM silicone material. Time and temperature are based on the complexities of the device, material, packaging, etc. We recommend validating the common sterilization cycles as performed in health care facilities and as outlined in ANSI/AAMI ST79:2006 and A1:2008, A2:2009.

This would depend on the sample. If multiple materials make up one complete sample, then you can pool all of the patient-contacting materials into one test. If the materials are independent samples, then we recommend testing them individually since you can ‘hide’ an unsafe material by grouping it with many safe materials.

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