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ARGOM Appendix 2: Guidelines on quality aspects of OTC applications

Version 1.1

30 May 2014

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10. Microbiological testing

The TGO 77 Microbiological standards for medicines specifies the minimum microbiological requirements with which a medicine must comply throughout its shelf life.

The guidance document Guidance on Therapeutic Goods Order No. 77 Microbiological Standards for Medicines provides a plain English explanation of the various requirements of TGO 77 and their application. It does not form part of TGO 77 and is intended only to assist sponsors to achieve compliance with TGO 77.

Note: The TGA Laboratories' guidelines for assessing the results of microbiological tests on non-sterile pharmaceuticals for human use will be revoked on 1 January 2010.

10.1 Sterile medicines

10.1.1 Policy and procedures

  • A sterile medicine must comply with the requirements of the harmonised Test for Sterility as specified in the current edition of a default standard, that is Appendix XVI of the British Pharmacopoeia, Chapter 2.6.1 of the European Pharmacopoeia or Chapter <71> of the United States Pharmacopoeia-National Formulary. This requirement is specified in Clause 7 of TGO 77.
  • Each batch of sterile medicine must be tested for sterility prior to batch release unless approval has been obtained from the TGA for parametric release of the medicine.
  • The TGA Guidelines for sterility testing of therapeutic goods provides guidance for laboratory staff performing the Test for Sterility in accordance with the harmonised pharmacopoeial requirements. These guidelines are not mandatory.

10.2 Non-sterile medicines

Non-sterile medicines should not contain excessive numbers of microorganisms. Under the requirements of TGO 77, they should be free from contamination with specified microorganisms and should be free from contamination with other microorganisms that might be objectionable in the dosage form.

Note: Specified microorganisms are the indicator organisms identified in the default standards and TGO 77, for example Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Salmonella, Bile tolerant Gram negative bacteria and Candida albicans.

10.2.1 Policy and procedures

  1. The release and expiry specifications for a non-sterile medicine should include suitable microbial quality acceptance criteria for the dosage form.
  2. The microbial quality acceptance criteria for a non-sterile medicine must comply at a minimum with the harmonised pharmacopoeial acceptance criteria for microbiological quality of non-sterile dosage forms, as specified in the current edition of a default standard, that is:
    1. Appendix XVI.D of the British Pharmacopoeia
    2. Chapter 5.1.4 of the European Pharmacopoeia
    3. Chapter <1111> of the United States Pharmacopoeia-National Formulary.

This requirement is specified in Clause 9(1) of TGO 77. The harmonised pharmacopoeial acceptance criteria for microbiological quality of non-sterile dosage forms are summarised in Table 10.1 of this chapter.

  1. In addition to ensuring that a medicine is free from contamination with specified microorganisms the TGA will expect a sponsor to:
    1. assess the risk of contamination of the medicine with other objectionable microorganisms
    2. ensure that this risk assessment is available for review should it be required by the TGA.

A single risk assessment may cover a group of products having similar formulations (e.g. the same excipients but a different quantity of the active), dosage forms, manufacturing processes, etc.

  1. Where a sponsor claims that a non-sterile medicine cannot, or need not include microbial quality acceptance criteria in the finished product specifications, then the sponsor will be required to provide cogent reasons to the TGA to justify the absence of microbial quality acceptance criteria.

For example, specifications for solid oral or dry powder products may not need to include microbial quality acceptance criteria if it can be justified in the application by establishing during product development that the product is at a very low risk of contamination and microbial growth is not supported.

Products with significant water content (e.g. creams, gels and oral liquids) are likely to support microbial growth. Such products should include tests and limits for microbial content in both the batch release and expiry specifications.

Note: The sponsor should be aware that the TGA might test a medicine for microbial quality irrespective of whether the finished product specifications include microbial quality acceptance criteria.

  1. There is no requirement for every batch of non-sterile medicine to be tested for microbial quality prior to release. If justified, periodic testing or 'skip-lot' testing can be performed. The frequency of testing should be determined based on the bioburden history of the medicine, the manufacturing process for the medicine, and the controls that are inherent in GMP. A bioburden history for the medicine can be determined by testing a series of consecutive routine production batches. It is generally expected that the first 5 to 10 batches of a new medicine should be tested for microbial quality prior to release. If test results for these batches are satisfactory, then testing could be performed periodically, rather than on every batch. For example, where justified, microbial quality testing could be performed on selected batches for example every tenth batch, or once every 6 to 12 months.
  2. If the medicine is one that cannot be easily tested for microbial quality (e.g. a metered dose inhaler), then the final bulk product can be tested. The bulk product must comply with the microbial quality acceptance criteria that apply to the medicine in its final form.
  3. There are no mandatory microbial quality acceptance criteria for starting materials unless an ingredient is the subject of an individual monograph of a default standard that includes requirements regarding microbial quality. The following harmonised chapters of the default standards include a non-mandatory recommendation about suitable microbial quality acceptance criteria for non-sterile 'substances for pharmaceutical use':
    1. Appendix XVI.D of the British Pharmacopoeia
    2. Chapter 5.1.4 of the European Pharmacopoeia
    3. Chapter <1111> of the United States Pharmacopoeia-National Formulary.

10.2.2 Microbial quality acceptance criteria for non-sterile medicines

TGO 77 adopts the harmonised BP, Ph. Eur. and USP-NF microbial quality acceptance criteria for the various non-sterile OTC medicine dosage forms. The acceptance criteria for the various non-sterile dosage forms are summarised table below.

Table 10.1 TGO 77 Microbial quality acceptance criteria for non-sterile OTC medicines.
Non-sterile dosage form Acceptance criteria
Rectal use

TAMC ≤103 CFU in 1 g or 1 mL

TYMC ≤102 CFU in 1 g or 1 mL

Oromucosal, gingival, cutaneous, nasal or auricular use

Note: Antiseptic and corticosteroid preparations intended for topical use are included in this category.

TAMC ≤102 CFU in 1 g or 1 mL

TYMC ≤101 CFU in 1 g or 1 mL

Staphylococcus aureus absent in 1 g or 1 mL

Pseudomonas aeruginosa absent in 1 g or 1 mL

Vaginal use

TAMC ≤102 CFU in 1 g or 1 mL

TYMC ≤101 CFU in 1 g or 1 mL

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*

*Includes adhesive layer and backing.

TAMC ≤102 CFU/patch

TYMC ≤101 CFU/patch

Staphylococcus aureus absent per patch

Pseudomonas aeruginosa absent per patch

Inhalation use#

#Liquid preparations for nebulisation to be manufactured sterile.

TAMC ≤102 CFU in 1 g or 1 mL

TYMC ≤101 CFU in 1 g or 1 mL

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

Non-aqueous preparations for oral use

TAMC ≤103 CFU in 1 g or 1 mL

TYMC ≤102 CFU in 1 g or 1 mL

Escherichia coli absent in 1 g or 1 mL

Aqueous preparations for oral use

TAMC ≤102 CFU in 1 g or 1 mL

TYMC ≤101 CFU in 1 g or 1 mL

Escherichia coli absent in 1 g or 1 mL

Substances for pharmaceutical use

TAMC ≤103 CFU in 1 g or 1 mL

TYMC ≤102 CFU in 1 g or 1 mL

Ph. Eur./BP special provision criteria for oral dosage forms containing raw materials of natural origin (animal, vegetal or mineral) for which antimicrobial pretreatment is not feasible and for which the competent authority accepts TAMC of the raw material exceeding 103 CFU per g or per mL

TAMC ≤104 CFU in 1 g or 1 mL

TYMC ≤102 CFU in 1 g or 1 mL

BT gram-negative bacteria ≤102 CFU in 1 g or 1 mL

Escherichia coli absent in 1 g or 1 mL

Staphylococcus aureus absent in 1 g or 1 mL

Salmonella absent in 10g or10 mL

TAMC: Total aerobic microbial count, TYMC: Total yeast and mould count, BT: Bile tolerant, CFU: Colony forming unit

The microbial quality acceptance criteria in TGO 77 (and in the default standards) should not be regarded as comprehensive microbial quality acceptance criteria, but rather as the minimal requirements to be met throughout the shelf life of a non-sterile medicine. Demonstrating the absence of only the specified microorganisms might not be sufficient to ensure the microbial quality of a non-sterile medicine.

In addition to the specified microorganisms mentioned in Table 10.1, the TGA will expect a sponsor to evaluate the significance and risk of other microorganisms in the medicine not specifically mentioned in Table 10.1, to determine whether the other microorganisms are objectionable in the dosage form. The significance of, and risk from these other microorganisms should be evaluated in terms of the formulation of the medicine, its route of administration and method of application, and the population for which the medicine is intended. This latter point should consider the possibility of underlying illness/disease in the user of the medicine and/or the possible use of immunosuppressive agents or corticosteroids by the user. It will not be unusual for a finished product specification to include acceptance criteria for additional microorganisms that are not specified in TGO 77.

Note: Annex 20 'Quality Risk Management' of the Pharmaceutical Inspection Co-operations Scheme (PIC/S) 'Guide to GMP 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.

For example, pseudomonad-type bacteria are considered to be objectionable in aqueous dosage forms intended for inhalant, cutaneous, nasal, auricular, oromucosal, gingival and vaginal use, and in transdermal patches. As such, the TGA will expect these dosage forms to be free from contamination with these types of bacteria.

Note: Pseudomonads include bacteria previously identified as belonging to the genus Pseudomonas but because of advances in molecular identification of bacteria they have been reclassified into a number of other genera including Burkholderia, Ralstonia, Stenotrophomonas, Sphingomonas and Brevundimonas.

10.2.3 Products containing material of natural origin

The types of products that are classified as being 'of natural origin' are oral dosage forms which contain raw materials of natural origin (animal, vegetal or mineral) that have not been fully processed.

Appendix XVI.D of the British Pharmacopoeia and Chapter 5.1.4 of the European Pharmacopoeia include special provision criteria 'for oral dosage forms containing raw materials of natural origin (animal, vegetal or mineral) for which antimicrobial pretreatment is not feasible and for which the competent authority accepts TAMC of the raw material exceeding 103 CFU per g or per mL'. Chapter <1111> of the United States Pharmacopoeia-National Formulary does not include the special provision criteria. The special provision criteria of the BP and Ph. Eur. are summarised in Table 10.1.

10.2.4 Microbiological test methods

TGO 77 does not specify the microbiological test methods to be used for routine quality control testing of medicines.

Note: TGO 77 only specifies the microbiological test methods that must be used for referee testing of a medicine that is where a sponsor contests the test results obtained by an official testing laboratory for a medicine. For referee testing TGO 77 requires the testing to be performed in accordance with the harmonised pharmacopoeial Tests for Microbial Contamination, as described in the default standards.

The harmonised pharmacopoeial Tests for microbial contamination (as described in the default standards) can be used for routine quality control testing of medicines, as can alternative microbiological test methods, including rapid microbiological test methods.

Where the pharmacopoeial test methods are to be used to test a medicine it is important to note that these test methods were originally designed to demonstrate that a medicine/substance meets monograph requirements. They were not designed for use as test methods 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 reliable recovery of pseudomonads, other than for Pseudomonas aeruginosa. For medicines where the presence of pseudomonads is considered objectionable, the Pseudomonas aeruginosa test method would need to be modified to include an additional non-selective culture medium incubated at 30°-32°C for 48 hours.

Where alternative microbiological test methods are to be used they should be validated to be at least equivalent to the harmonised pharmacopoeial test methods, and to be suitable for recovery of specified microorganisms and other objectionable organisms from the medicine to be tested.

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