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Guidance 17: Microbial quality of prescription and over-the-counter medicines
17.4 Preservative efficacy criteria for medicines for multidose use
A multidose-use medicine should be adequately preserved for the duration of its claimed shelf life (see the TGA guidance Stability testing for prescription medicines). This is to prevent microbial proliferation in a nonsterile medicine, and to prevent microbial contamination of a sterile or nonsterile medicine, during the normal conditions of storage and use.
Unless the formulation of a medicine is 'self-preserving', one or more suitable antimicrobial preservatives are included in the formulation.
A medicine (other than a liquid oral antacid medicine) that is intended for use on more than one occasion (multidose use) should comply with the requirements of the current edition of Appendix XVI C of the BP, 'Efficacy of antimicrobial preservation', or Chapter 5.1.3 of the Ph. Eur., 'Efficacy of antimicrobial preservation'. A liquid oral antacid medicine may comply with the requirements of the relevant test in the USP-NF, Chapter 51 'Antimicrobial effectiveness test'. These requirements are specified in Clause 8 of TGO 77.
Note on preservative efficacy testing
A chemical assay of the content of the preservative(s) in the formulation is not accepted as a substitute for an antimicrobial preservative efficacy test. Chemical concentration alone is not sufficient to assess the biological activity of a formulation, because other chemical and physical changes in the formulation can influence the efficacy of the antimicrobial preservative(s). However, a chemical assay can be used for routine batch testing of a preserved medicine.
Include real-time antimicrobial preservative efficacy information and data for the medicine formulation:
- in its immediate container for market (see Note)
- from test samples stored in accordance with label storage conditions
- at both the beginning and end of the proposed closed shelf life:
- from at least two (preferably three) separately manufactured batches tested at the beginning of shelf life
- from at least one primary stability batch tested at the proposed shelf life.
Testing can be performed in an alternative container if testing in the immediate container for market is not possible. Prior to testing ensure that the medicine has been filled into and stored in the immediate container for market.
For oral powders or granule preparations that are reconstituted before use, demonstrate adequate preservation for the reconstituted preparation over the proposed reconstituted shelf life.
If real-time preservative efficacy data is not available at the end of the proposed closed shelf life, then include:
- data up to and including the last testing point from ongoing stability studies
- an assurance that end-of-shelf-life data will be provided to the TGA when it is available, if the TGA requests it
- an assurance that the TGA will be informed of any preservation problems detected during ongoing stability studies.
Sometimes accelerated ageing studies might be used to support a proposed shelf life. If using accelerated ageing studies, then include test samples for storage at the higher temperature.
In an application for registration, justify the open shelf life for a sterile medicine that is intended for multidose use (e.g. a multidose injectable or ophthalmic preparation).Also, provide one of the following information and data to support an open shelf life period:
- results of preservative efficacy tests that involve repeated microbial challenges of the medicine over the open shelf life period (as this most closely mimics the in-use situation). A sponsor can use a modification of a pharmacopoeial preservative efficacy test (preferably the Ph. Eur. or BP preservative efficacy test) that includes rechallenges of the medicine with reduced numbers of challenge organisms (compared with the initial challenge). Guidance can be obtained from the normative part of the International Standard ISO 14730 Ophthalmic optics - Contact lens care products - Antimicrobial preservative efficacy testing and guidance on determining discard dating, which describes a test procedure and performance criteria for preservative efficacy over an open shelf life period of 28 days.
- results of preservative efficacy tests on the contents of containers of the medicine after simulated in-use
- results of sterility tests on the contents of containers of the medicine after simulated in-use
- results of microbial content tests on the contents of partially used containers of the medicine that have been used by patients for the full duration of the open shelf life (including details of the number of samples tested, the test method used, method validation, and numbers and types of organisms recovered from the partially used containers).
An antimicrobial preservative efficacy test is not usually included in the release and expiry specifications for a medicine because this testing is normally performed during product development and stability studies. During product development, preservative efficacy should be assessed at the lower limit for preservative content in the end-of-shelf-life specification.