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This guidance will assist sponsors and manufacturers of prescription and over-the-counter (OTC) medicines (excluding complementary medicines) to comply with Therapeutic Goods (Microbiological standards for medicines) (TGO 100) Order 2018.
TGO 100 specifies the minimum microbiological quality requirements (including preservative efficacy requirements) that a medicine should comply with throughout its shelf life, unless it is exempt (see 'General exemptions from TGO 100'). TGO 100 does not cover the requirements for microorganism components used in a medicine.
Medicines may be exempt from meeting the requirements set out in TGO 100 if they meet specific conditions (under Clause 7).
TGO 100 came into effect on 8 December 2018.
TGOs 77 and 98 that were in use before December 2018 were repealed on 1 October and 8 December 2018, respectively.
are adopted as in force from time to time as permitted under subsection 10(4) of the Therapeutic Goods Act 1989 (the Act).
Dosage forms to be supplied sterile include, but are not restricted to, those that are:
Sterile dosage forms should comply with the harmonised pharmacopoeial Test for Sterility and, where applicable, the Bacterial Endotoxins Test of a default standard.
When applying to enter a sterile dosage form medicine on the ARTG, include a specification for sterility, and where applicable for bacterial endotoxins, in the release and expiry specifications.
A sterile medicine should comply with the harmonised pharmacopoeial Test for Sterility in the current edition of a default standard, as specified in Clause 9 of TGO 100.
Relevant sections in default standards are:
TGA guidelines for sterility testing of therapeutic goods
Where applicable, a sterile medicine should comply with the harmonised requirements of the Bacterial Endotoxins Test in the current edition of a default standard, as specified in Clause 9 of TGO 100.
Guidance on bacterial endotoxin limits can be found in relevant pharmacopoeial monographs or in the following chapters of the default standards:
Each batch of a sterile medicine is to be tested for sterility before release, unless the TGA has approved parametric release of the medicine.
If a test for bacterial endotoxins is required for a sterile medicine, then this test is to be performed before the release of each batch.
Tests for sterility and bacterial endotoxins should be carried out according to the default standards, unless a suitable alternative method has been reviewed and approved by the TGA.
The default standards and TGO 100 permit the use of a suitable, alternative method of analysis to the pharmacopoeial Test for Sterility (for example, a rapid microbiological test method).
An alternative test method needs to be reviewed and approved by the TGA before it is implemented.
When applying to enter a medicine on the ARTG, include information and data to demonstrate:
Any alternative bacterial endotoxin test method needs to be reviewed and approved by the TGA before it is implemented.
When applying to enter a medicine on the ARTG, include information and data to demonstrate that the alternative test method:
A nonsterile medicine should not contain excessive numbers of microorganisms. It should be free from contamination with specified microorganisms and free from contamination with other microorganisms that might be objectionable in the dosage form.
When applying to enter a nonsterile dosage form medicine on the ARTG:
The TGA may test a medicine for microbiological quality irrespective of whether the drug product specifications include microbiological quality acceptance criteria.
The microbiological quality acceptance criteria for a nonsterile medicine should comply, at a minimum, with the harmonised pharmacopoeial acceptance criteria for microbiological quality of nonsterile dosage forms (as specified in Clause 11(1) of TGO 100).
The microbiological quality criteria are summarised in Table 1 Microbiological quality acceptance criteria for nonsterile medicinal dosage forms and are specified in the default standards:
The microbiological quality acceptance criteria in TGO 100 (and in the default standards) should not be regarded as comprehensive.
They are the minimal requirements to be met throughout the shelf life of a nonsterile medicine.
Demonstrating the absence of only the specified microorganisms might not be sufficient to ensure the microbiological quality of a nonsterile medicine.
| Route of administration | Acceptance criteria (CFU per gram or per millilitre, unless otherwise specified) |
|---|---|
| Non-aqueous preparations for oral use | TAMC ≤103 TYMC ≤102 Escherichia coli absent in 1 g or 1 mL |
| Aqueous preparations for oral use | TAMC ≤102 TYMC ≤101 Escherichia coli absent in 1 g or 1 mL |
| Rectal use | TAMC ≤103 TYMC ≤102 |
| Oromucosal, gingival, cutaneous, nasal or auricular use | TAMC ≤102 TYMC ≤101 Staphylococcus aureus absent in 1 g or 1 mL Pseudomonas aeruginosa absent in 1 g or 1 mL |
| Vaginal use | TAMC ≤102 TYMC ≤101 Staphylococcus aureus absent in 1 g or 1 mL Pseudomonas aeruginosa absent in 1 g or 1 mL Candida albicans absent in 1 g or 1 mL |
| Transdermal patches (including adhesive layer and backing) | TAMC ≤102 CFU/patch TYMC ≤101 CFU/patch Staphylococcus aureus absent per patch Pseudomonas aeruginosa absent per patch |
| Inhalation use (Note: liquid preparations for nebulisation to be manufactured sterile) | TAMC ≤102 TYMC ≤101 Staphylococcus aureus absent in 1 g or 1 mL Pseudomonas aeruginosa absent in 1 g or 1 mL BT gram-negative bacteria absent in 1 g or 1 mL |
| EP/BP special provision criteria for oral dosage forms containing raw materials of natural origin (animal, vegetal or mineral) for which antimicrobial pre-treatment is not feasible and for which the competent authority accepts TAMC of the raw material exceeding 103 CFU per g or per mL (see 'Material of natural origin in nonsterile medicines') | TAMC ≤104 TYMC ≤102 BT gram-negative bacteria ≤102 Escherichia coli absent in 1 g or 1 mL Staphylococcus aureus absent in 1 g or 1 mL Salmonella absent in 10 g or 10 mL |
| Substances for pharmaceutical use | TAMC ≤103 CFU TYMC ≤102 CFU |
BT = bile tolerant, CFU = colony forming unit, TAMC = total aerobic microbial count, TYMC = total yeast and mould count, BP = British Pharmacopoeia, EP = European Pharmacopoeia
In addition to being free from contamination with specified microorganisms, a nonsterile medicine should also be free from contamination with other microorganisms that might be objectionable in the dosage form.
For example, pseudomonad-type bacteria are considered to be objectionable in:
These dosage forms are expected to be free from contamination with these types of bacteria.
Pseudomonad-type bacteria include bacteria that were previously identified as belonging to the genus Pseudomonas. Advances in molecular identification have resulted in the reclassification of some of these bacteria to other genera, including Burkholderia, Ralstonia, Stenotrophomonas, Sphingomonas and Brevundimonas.
Drug product specifications for these dosage forms should include an absence of pseudomonads in 1 g or 1 mL, or per patch.
Evaluation of the significance of, and risk from, other objectionable microorganisms should consider:
When applying to enter a medicine on the ARTG:
Annex 20, 'Quality risk management', of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) Guide to good manufacturing practice for medicinal products includes information and guidance on the principles and some of the tools of quality risk management, and their application to different aspects of medicine quality.
There are no mandatory microbiological quality acceptance criteria for starting materials, unless an ingredient is the subject of an individual monograph of a default standard that includes requirements for microbiological quality.
Non-mandatory recommendations about microbiological quality acceptance criteria for nonsterile 'substances for pharmaceutical use' (i.e. starting materials) are found in:
A medicine that might be classified as being 'of natural origin' is an oral dosage form that contains a raw material(s) of natural origin (animal, vegetal or mineral) where the raw material has not been fully processed.
A nonsterile medicine that is intended for oral use and that contains natural ingredients is to comply with Clause 11(1) of TGO 100 (the internationally harmonised pharmacopoeial microbiological quality acceptance criteria for this type of dosage form).
Appendix XVI.D of the BP and Chapter 5.1.4 of the EP include special provision criteria 'for oral dosage forms containing raw materials of natural origin (animal, vegetal or mineral) for which:
Chapter 1111 of the USP-NF does not include these special provision criteria.
If an aqueous or non-aqueous oral dosage form that contains material of natural origin cannot meet the microbiological quality acceptance criteria in Table 1 Microbiological quality acceptance criteria for nonsterile medicinal dosage forms, apply to the TGA for approval to use the special provision criteria of the BP and EP instead.
There is no requirement for every batch of a nonsterile medicine to be tested for microbiological quality before release. Periodic testing or 'skip-lot' testing can be performed, if justified.
The frequency of testing should be based on:
It is expected that the first 5-10 batches of a new medicine should be tested for microbiological quality before release.
If test results for these batches are satisfactory, testing could be performed periodically, rather than on every batch (for example, every 10th batch, or once every 6-12 months).
TGO 100 specifies the microbiological test methods that are to be used for referee testing of a medicine (for example, where a sponsor contests the test results obtained by an official testing laboratory for a medicine).
Referee testing is to be performed in accordance with the harmonised pharmacopoeial Tests for Microbial Contamination, as described in the default standards.
TGO 100 does not specify the microbiological test methods to be used for routine quality control testing of a nonsterile medicine.
Routine quality control testing can use the harmonised pharmacopoeial Tests for Microbial Contamination (as described in the default standards), or suitable alternative microbiological test methods, including rapid methods.
The pharmacopoeial test methods were designed to demonstrate that a medicine or substance meets monograph requirements. The methods were not designed to detect all potential pathogens, and therefore should not be regarded as rigorous quality control tests for all dosage forms.
For example, the Pseudomonas aeruginosa test method is not suitable for the reliable recovery of pseudomonads other than P. aeruginosa. For a medicine where pseudomonads are considered to be objectionable in the dosage form, the P. aeruginosa test method should be modified to include an additional nonselective culture medium that is incubated at 30-32 °C for at least 48 hours.
If alternative microbiological test methods are to be used for testing a medicine, you should demonstrate that the alternative methods:
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 preservative are to be included in the formulation.
An aqueous-based 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:
A liquid oral antacid medicine may comply with the requirements of the relevant test in:
These requirements are specified in Clause 10 of TGO 100.
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.
When applying to enter an aqueous-based multidose medicine on the ARTG, include real-time antimicrobial preservative efficacy information and data for the medicine formulation:
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:
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.
When applying to enter a sterile aqueous-based multidose medicine (for example, a multidose injectable or ophthalmic preparation) on the ARTG, include a justification for the open shelf life period and, to support the open shelf life period, provide one of the following information and data:
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.
If the harmonised pharmacopoeial microbiological content test method is used, then the method is validated and only needs to be verified for the product under test.
An antimicrobial preservative efficacy test is not usually included in the release and expiry specifications for a medicine, as 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.
Title changed from 'Microbiological quality of prescription and over-the-counter medicines' to 'Meeting microbiological standards for non-prescription and prescription medicines' as part of migration to new 'Guidance' content type:
Updated name from 'Guidance 17: Microbial quality of prescription and over-the-counter medicines'
Updated to be in line with new TGO 100.
Original publication
Previously ARGPM Appendices 16 & 17: Preservative efficacy testing and Microbial quality of medicines.
Title changed from 'Microbiological quality of prescription and over-the-counter medicines' to 'Meeting microbiological standards for non-prescription and prescription medicines' as part of migration to new 'Guidance' content type:
Updated name from 'Guidance 17: Microbial quality of prescription and over-the-counter medicines'
Updated to be in line with new TGO 100.
Original publication
Previously ARGPM Appendices 16 & 17: Preservative efficacy testing and Microbial quality of medicines.
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