ARGB Appendix 5 - Guidance on TGO 85

The definition of 'critical materials' is provided in ARGB Appendix 14 - Glossary.

In order to minimise extrinsic contamination of the starting material tissue, any container or packaging material in direct contact with the tissue material should be sterile, and collection/processing staff should wear appropriate clothing.

The requirements for the collection of ocular tissue from a deceased donor in the ocular order take precedence over those detailed in the Appendix 4, Annex 1.

Where ocular tissue is removed from the stated storage conditions to allow quality determination, e.g. warmed to room temperature to optimise microscopic evaluation and/or endothelial cell counting, the process must be strictly defined and sound scientific justification provided as to why the quality and safety is not compromised.

This section only applies to 7(4)c - excised cornea maintained in storage medium at 28°C to 37°C for no more than 30 days.

All storage and transport solutions used in processing ocular tissue should be sterile.

If the storage medium is intended to be sterile, then it should be tested and pass the harmonised test for sterility by the filtration method specified in the default standard pharmacopoeias. Validation of the test method is described as the "suitability of test" and involves a demonstration of neutralisation of antimicrobial agents that might interfere with the growth of contaminants. Alternatively, the filtration method as described in the microbial contamination chapters of the pharmacopoeias should be validated to demonstrate the absence of growth in solutions not required to be sterile.

Unless the entire tissue product is subject to bioburden testing, it is necessary to validate that a sample or portion is representative of the entire tissue. During sampling validation studies it is necessary to sample from a variety of areas across the tissue and to compare the bioburden test results. Routine bioburden samples should subsequently be taken from any area which represents the 'worst case' in terms of bioburden.

The microbial contamination sections of the pharmacopoeial default standards*, as well as ISO 11737-1**, and ISO 14160*** provide useful guidance on suitable bioburden test methods and their validation to demonstrate neutralisation/inactivation of antimicrobial substances. ISO 11737-1 specifically describes steps to establish the recovery efficiency and correction factor(s) to be applied when testing bioburden on or within solid and semi-solid starting materials and Annex A.5.3 of ISO 14160 provides guidance on performing bioburden tests on animal tissues.

Method validation involves challenging the method used for the material or product with low numbers (<100 cfu) of reference challenge microorganisms and recovering these organisms within the shortest test incubation time. Given that antimicrobial agents could be present in the starting materials and/or the end product, it is necessary to attempt to neutralise these agents to optimise the recovery of the challenge microorganisms, and ultimately, any product contaminants. Pharmacopoeial and ISO methods mandate this step under "suitability of test method" or "method validation". Antimicrobial activity can often be removed by filtration, dilution and/or chemical inactivation by use of a suitable neutralising agent. Tissue banks should attempt to identify antimicrobial agents used to treat donors and those agents used during processing to assist them to identify suitable neutralising agents. If, after exhaustive attempts, antimicrobial properties cannot be neutralised, then pharmacopoeias permit the product to be tested under the set of conditions established as optimal for recovery. This approach must be justified and details provided for assessment and/or audit by the TGA.

The packaging should be compatible with the method of sterilisation e.g the packaging should allow the ingress of ethylene oxide sterilant gas and allow for desorption of the gas during aeration. If this is the case, then the container is not sterile to begin with but it is sterilised along with the tissue, which is permissible. The use of new technology (e.g. critical CO₂) would be considered on a case-by-case basis based on evidence of validation to demonstrate an SAL of 10^-6 for a terminal sterilisation process. (Guidance on other sterilisation methods validation not covered by a specific ISO standard can be found in ISO 14937*).

*ISO 14937 Sterilization of health care products – General requirements for characterization of a sterilizing agent and the development, validation and routine control of a sterilization process for medical devices

If the tissue is aseptically manufactured, then it should be transferred into a sterile container and validated as an aseptic process according to the ISO 13408 (Aseptic processing of health care products).

"Other than for a gas sterilant if applicable" includes air and/or incubation gases.

Qualification and routine control of sterilisation processes should be in accordance with the relevant parts of international (ISO) sterilisation standards. For example: ISO 11135 (ethylene oxide), ISO 14937 (general methods), ISO 17665 (moist heat), ISO 11137 (radiation), ISO 14160 (chemical sterilisation), ISO 20857 (dry heat).

Some of these standards are relevant to the sterilisation of containers and ancillary materials used during tissue processing.

Please note that in addition, all relevant requirements of TGO 87 (Labelling) apply to ocular tissue. If further clarification is required then please contact the TGA.