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Preservative Efficacy Testing

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Australian Regulatory Guidelines for

Prescription Medicines

June 2004
Australian Regulatory Guidelines for Prescription Medicines

APPENDIX 16: PRESERVATIVE EFFICACY TESTING

Sponsors should note that Preservative Efficacy Testing should be conducted in


accordance with the relevant British Pharmacopoeia (BP) monograph.

The Australian Regulatory Guidelines for Prescription Medicines (ARGPM) Appendix


14 (Stability Testing) and the Committee for Medicinal Products for Human Use
(CHMP) Note for Guidance on Stability Testing of New Drug Substances and
Products (CPMP/ICH/2736/99)1 require that stability testing for preservatives
includes both the level of preservative and its efficacy:

The range of testing should cover not only chemical and biological stability
but also loss of preservative, physical properties and characteristics,
organoleptic properties, and where required microbiological attributes.
Preservative efficacy testing and assays on stored samples should be
carried out to determine the efficacy and content of antimicrobial
preservatives.

and:

Any differences between the release and shelf life specifications for
antimicrobial preservatives should be supported by preservative efficacy
testing.

These requirements are elaborated in three further Notes for Guidance adopted in
Australia:

1. Note for Guidance on the Inclusion of Antioxidants and Antimicrobial


Preservatives in Medicinal Products (CPMP/CVMP/QWP/115/95)2

2. Note for Guidance on Developmental Pharmaceutics


(CPMP/QWP/155/96)3

These documents address the requirements for preservatives in liquid and semi-
solid formulations that are not self-preserving. Preservative efficacy testing should be
performed at the end of shelf-life and at the lower preservative limit in the end of
shelf-life specification. Testing for content only is not sufficient because chemical
concentration is not necessarily indicative of antimicrobial efficacy. In addition, for
multi-dose containers, the efficacy must be established under simulated in-use
conditions, to justify the proposed in-use shelf-life. If it is not logistically possible to
conduct the complete in-use testing schedule in the original container, the use of an
alternative container is acceptable provided that the product has been stored in the
original container prior to the start of the in-use test.

1
http://www.tga.gov.au/docs/html/euguide/euad_qual.htm#qualityactive
2
http://www.tga.gov.au/docs/html/euguide/euad_qual.htm#qualitymedicinal
3
http://www.tga.gov.au/docs/html/euguide/euad_qual.htm#qualitygeneral

Appendix16 -page 1 of 2
Australian Regulatory Guidelines For Prescription Medicines - Preservative Efficacy Testing

This testing could take the form of pharmacopoeial preservative efficacy testing with
additional microbial challenges. Guidance may be obtained from the normative part
of the international standard ISO 14730: 2000 Ophthalmic Optics – Contact lens care
products – Antimicrobial preservative efficacy testing and guidance on determining
discard dating45 which describes a test procedure and performance criteria for
preservative efficacy over an open shelf life period of 28 days. The informative
annexes include protocols where an open shelf-life of longer than 28 days is
required. Where the open shelf-life is less than 28 days, the testing schedule should
be adapted accordingly.

Alternatively, testing for microbial limits, preservative efficacy or sterility testing may
be conducted on containers that have been used by patients or exposed to a pattern
of use similar to that likely to be encountered during routine use.

3. Note for Guidance on Maximum Shelf Life for Sterile Products After
First Opening or Following Reconstitution (CPMP/QWP/159/96 Corr)2

This document requires that information on how long sterile products may be used
after opening should be included in the Product Information (PI). The information
must be based on data generated in appropriate studies (described above), and
recommendations.

4
http://www.iso.ch/iso/en/ISOOnline.frontpage
5
It should be noted that this reference is not being identified as a standard that must be applied to the
product. It does, however, demonstrate the elements of the type of tests that may be applied to
support an open shelf-life period.

Appendix16 -page 2 of 2

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