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Guidance on Therapeutic Goods Order No. 77 Microbiological standards for medicines

12 September 2008

This guidance document is intended to provide a plain English explanation of various requirements of Therapeutic Goods Order (TGO) No. 77 Microbiological Standards for Medicines (TGO 77) and their application, thereby assisting sponsors to achieve compliance. This document does not form part of the Order.

General

The requirements of the Order apply to a medicine that comes within the operation of Part 3-1 of the Therapeutic Goods Act 1989 ("the Act") which provides for the application of standards to therapeutic goods.

Such standards may relate to any matter relevant to the quality, safety or efficacy of a medicine and, generally, a medicine must not be imported, exported or supplied if it does not conform to an applicable standard.

Paragraph (b) of subsection 10(2) of the Act states that an Order establishing a standard for therapeutic goods may require that a matter relating to the standard be determined in accordance with a particular test.

Responsibility for compliance with the requirements of the Order rests with the sponsor of the medicine to which the Order applies.

Explanation of sections

Section 1 Name of Order

This section states the legal title of the Order.

Section 2 Commencement

This section states that the Order will come into effect on 1 January 2010. All sections of the Order will come into effect on the same date.

The Federal Register of Legislation (FRL) is the official repository of Commonwealth legislative instruments and is where the authoritative text of TGO 77 can be located.

Current and new medicines will be subject to the Order.

Stock that is released for supply/sale by a sponsor on and after 1 January 2010 will be subject to this Order. Stock that has been released for sale/supply (e.g. to warehouses, retailers and consumers) prior to 1 January 2010 will not be subject to this Order.

Sponsors should consult the regulatory guidelines for prescription medicines, over-the-counter (OTC) medicines, registered complementary medicines and listed medicines for information about notification or approval processes for specification or other changes that are consequent upon the requirements of a new Therapeutic Goods Order.

Section 3 Introduction

This section states the purpose of the Order.

Standards, including this Order, apply throughout the shelf life of the medicine.

The microbial attributes of a non-sterile medicine (Section 9) described in the Order and in the pharmacopoeias should not be regarded as comprehensive microbial limit specifications, but rather as the minimal requirements to be met throughout the shelf life of the medicine. The TGA will expect that a sponsor will determine the risk to their product from other objectionable microorganisms as well as the organisms specified by this Order. To ensure compliance with this standard, a prudent manufacturer will apply release specifications that are more exacting than those included in the Order.

Section 4 Interpretation

This section provides definitions of terms used in the Order and where relevant directs the reader to meanings given in the Act or Regulations. Readers should check the current compilation of the Act or Regulations.

Any term not defined in the Order has its usual English meaning.

The interpretation of "acceptance criteria" is the same as used in the British Pharmacopoeia, the European Pharmacopoeia and the United States Pharmacopoeia-National Formulary chapters mentioned in Section 9(1) of the Order. A medicine is considered to be non-compliant with a microbial count acceptance criterion if the CFU (colony forming unit) count exceeds two (2) times the stated limit. This factor of two (2) is intended to allow for the precision of the counting method and normal methodological variation. For example, when the Order establishes a limit of 102 CFU, the maximum acceptable count is 200.

The interpretation of "default standard" refers to a pharmacopoeia mentioned under "standard" in the Act. Only the British Pharmacopoeia is currently mentioned here; however, changes to this section of the Act are expected to occur prior to the commencement of the Order on 1 January 2010.

The British Pharmacopoeia is defined in the Act, as is the process for the adoption of new editions, additions or amendments. When the definition of the British Pharmacopoeia is amended under subsection 3(1) of the Act the new definition will apply in this Order. The current definition of the British Pharmacopoeia is British Pharmacopoeia 2008.

The European Pharmacopoeia and the United States Pharmacopoeia-National Formulary are not yet defined in the Act. Until definitions of these pharmacopoeias are included in the Act, the Order specifies particular editions of these publications.

This Section also advises that where a pharmacopoeia renames or renumbers a test (e.g., to remove the word 'harmonised' when a non-harmonised test no longer appears in the publication), then the Order incorporates that renamed or renumbered test.

Section 5 Application

The Order applies to medicines for human use that are within the operation of the Act.

The Order applies to listed medicines, registered medicines and medicines that are not required to be listed or registered, unless exempt from the Order.

There are two mechanisms for a medicine to be exempt from the Order:

  1. if the medicine is covered by Section 6 (see below), or
  2. if the Secretary of the Department of Health and Ageing, or a delegate of the Secretary, grants an exemption in accordance with section 14 and 14A of the Act.

Section 6 General Exemptions

This section describes the medicines that are not subject to the Order.

The standards that apply to an export only medicine are currently specified in Therapeutic Goods Order No 70B Standards for Export Only Medicine.

Section 7 Sterility and Bacterial Endotoxin testing

A medicine must comply with the Test for Sterility, and the Bacterial Endotoxin Test if applicable, when this test is required by an individual or general monograph in a "default standard".

Where a sponsor labels or packages a medicine in a way that states or implies that the medicine is sterile, even though there is no requirement in a "default standard" for this, then the medicine must comply with the test for sterility of a "default standard".

The Order refers to the "default standard". At the current time, the "default standard" is the British Pharmacopoeia. However, the testing methods and assessment criteria for sterility and bacterial endotoxins have been the subject of extensive international collaborative efforts towards the harmonisation of regulatory requirements. In practice, the testing methods and assessment criteria for sterility and bacterial endotoxin testing in the British Pharmacopoeia, the European Pharmacopoeia and the United States Pharmacopoeia-National Formulary are the same.

Section 8 Efficacy of antimicrobial preservation of multidose medicines

This section is about the requirements to demonstrate the efficacy of an antimicrobial preservation system of a multidose medicine.

This section applies to multidose sterile medicines (e.g. eye drops) and multidose non-sterile medicines (e.g. oral liquids).

The medicine must comply with the Efficacy of Antimicrobial Preservation test of the British Pharmacopoeia or European Pharmacopoeia; these tests are identical.

However, a liquid oral antacid medicine may instead comply with the United States Pharmacopoeia – National Formulary's Antimicrobial Effectiveness Test, including the use of the acceptance criteria nominated in the chapter.

Section 9 Microbiological attributes of a non-sterile medicine

This section specifies the microbiological attributes with which a non-sterile medicine must comply. Subsections 1 and 2 are comprehensive and together cover all non-sterile medicines.

Subsection 9(1) applies to prescription medicines, OTC medicines, and many complementary medicines. A non-sterile medicine, other than a complementary medicine oral dosage form containing raw material of natural (animal, vegetal or mineral) origin, must comply with the relevant acceptance criteria of the British Pharmacopoeia, the European Pharmacopoeia or the United States Pharmacopoeia-National Formulary when tested by the nominated test methods. In practice, the testing methods for microbiological quality of pharmaceuticals preparations in the three pharmacopoeias are the same.

In addition to the microorganisms specified in the acceptance criteria in the pharmacopoeias, the pharmacopoeias also require that the significance of other microorganisms recovered is evaluated in terms of a number of specified criteria. The TGA does expect that a sponsor will determine the risk to their product from objectionable microorganisms not specifically mentioned in the pharmacopoeias.

Determination of the absence of objectionable organisms is the responsibility of the sponsor and requires access to a competent microbiology group. The pharmacopoeial test methods were designed to determine aerobic microbial counts and to detect the presence of specific "indicator" organisms in the presence of low to medium levels of competing microorganisms. These test methods might not be optimal for the detection of other objectionable organisms.

Subsection 9(2) applies to a complementary medicine oral dosage form containing raw material of natural (animal, vegetal or mineral) origin. Such a medicine must comply with the acceptance criteria specified in Schedule 1 of the Order, other than when the medicine consists solely of one or more herbal substances (whole, reduced or powdered) to which boiling water is added before use, in which case the acceptance criteria are specified in Schedule 2 of the Order.

As mentioned above in relation to subsection 9(1), the TGA expects that a sponsor will determine the risk to their product from microorganisms not specifically mentioned in the Order. Sponsors of listed herbal teas should particularly note that the pharmacopoeial test methods are not optimal for the detection of low numbers of enteric pathogens in the presence of high numbers of competing microorganisms.

Questions and answers relating to microbiological standards for medicines

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The Therapeutic Goods Committee (TGC) is the committee established by the Therapeutic Goods Regulations 1990 to advise the Minister on standards.

Therapeutic Goods Order No. 77 Microbiological Standards for Medicines has been made by the delegate for the Minister for Health and Ageing following consideration of advice provided by the TGC. The TGC includes representatives of the manufacturers of prescription medicines, non-prescription medicines and complementary medicines, and consumers.

There are other matters relating to microbiological quality that sponsors may need to address. For example, the evaluation process for a registered medicine may identify that the chemical concentration of the preservative or the level of aflatoxins needs to be controlled.

Sponsors should also refer to the Order on labelling for requirements such as declarations on the presence of preservatives, the labelling of 'single use' medicines, and the inclusion of suitable directions for use (e.g. the addition of boiling water to herbal teas).

The Order specifies the testing procedures that will be used as a referee test by an official analyst to assess the quality of any sample from any batch of a medicine.

The requirement to carry out the tests and methodology as specified in the Order is only obligatory where a sponsor wishes to contest the test results obtained by an official analyst.

The Order does not prevent sponsors from continuing to use existing validated culture based methods, or rapid methods, where these have been shown to be equivalent to the methods nominated in the Order. Sponsors are reminded that microbiological quality control testing is a step of manufacture that must be undertaken by a manufacturer (e.g. testing laboratory) that holds an appropriate manufacturing licence from the TGA.

The Order specifies the referee test and acceptance criteria that will be used by an official analyst to assess the quality of any sample from any batch of a medicine.

Each batch of sterile medicine is required to be tested for sterility prior to batch release, unless approval has been obtained from the TGA for parametric release.

The inclusion of a standard for efficacy of antimicrobial preservation does not require that this test be used for quality control purposes. This test is performed during product development and stability studies to demonstrate adequate preservation of aqueous-based preparations. Products such as tinctures with high concentrations of ethanol, and non-aqueous preparations, should not require preservative efficacy testing. A matrix/product family approach in relation to preservative efficacy testing is acceptable.

There is no specified frequency for the test for microbiological attributes of a non-sterile medicine. Frequency of microbiological testing should be determined based on the bioburden history, the manufacturing steps, and the controls that are inherent in good manufacturing practice.

The standards required for export only medicines are specified in Therapeutic Goods Order No. 70B Standards for export only medicine.

Not necessarily. The requirements of this Order must be reflected in the finished product specification. Nothing in this Order can be applied directly to starting material specifications, as starting materials do not have a route of administration or directions for use. In the case of a medicine that is a single ingredient (e.g. a single herb in a teabag), the appropriate microbial attributes for the finished product would need to be considered in establishing the specification for the starting material.

Starting materials are therapeutic goods, but not medicines. While the requirements of this Order do not apply to a starting material, an individual monograph for an ingredient in a "default standard" may include requirements regarding microbial quality.

Currently, compliance with a British Pharmacopoeia monograph for a starting material is mandatory, as the British Pharmacopoeia is currently the only "default standard" and constitutes the standard that applies to an ingredient (a therapeutic good) in the absence of a Therapeutic Goods Order to specify the standard for that therapeutic good (ingredient).

For an ingredient for which the British Pharmacopoeia individual monograph does not include a requirement regarding microbial quality, the British Pharmacopoeia includes a non-mandatory recommendation about suitable acceptance criteria for microbiological quality; see the harmonised method in Appendix XVI D in the British Pharmacopoeia 2008 or the "Substances for pharmaceutical use" monograph in the British Pharmacopoeia 2009. The "Substances for pharmaceutical use" monograph does not apply to herbal drugs, herbal drug preparations or extracts.

Some, but not all, of the individual monographs of the British Pharmacopoeia 2008 for preparations for inhalation require the medicine to be sterile. The general monograph of the British Pharmacopoeia 2008 for preparations for inhalation does not require such medicines to be sterile. This situation may change prior to 1 January 2010, the date by which all medicines are required to comply with the Order.

The TGA's preference would generally be for nebuliser solutions to be sterile.

The TGA Guidelines for sterility testing of therapeutic goods (2006) provide guidance for sterility testing of both sterile medicines and medical devices supplied in Australia for human use, whereas TGO 77 applies only to medicines. The Guidelines complements the Order. The Guidelines are revised as needed when changes are made to the harmonised pharmacopoeial Test for Sterility.

The requirement of the Order is that of the British Pharmacopoeia and the European Pharmacopoeia: "The A criteria express the recommended efficacy to be achieved. In justified cases where the A criteria cannot be attained, for example for reasons of an increased risk of adverse reactions, the B criteria must be satisfied".

For a registered medicine, the sponsor's data on the preservative efficacy test will be evaluated. For a listed medicine, the sponsor is required to hold data for auditing, in the same way as required for compliance with other standards.

No.

Subsection 5(2)(b) of the Order indicates that an exemption from the requirements of the Order can be granted by the Secretary in accordance with sections 14 and 14A of the Act. Those sections of the Act relate to approvals for the supply, importation or export of a medicine that does not conform to an applicable standard, such as this Order or parts of this Order. Such approvals may be granted unconditionally or subject to conditions, and can relate to one batch or all batches of a medicine.

Where exemption from any aspect of this Order is sought, the sponsor should apply in writing to the TGA, stating precisely the particular section or sections of the Order against which the exemption is sought and providing justification for the exemption. When an exemption is granted, information concerning the exemption is published in the Commonwealth Government Notices Gazette.

A sponsor can apply for, and may be granted, an exemption from TGO 77 prior to 1 January 2010. The exemption would not take effect until 1 January 2010.

Industry and TGA experience has shown that the recommendations in the British and European Pharmacopoeias regarding the efficacy of antimicrobial preservation of oral liquids cannot be successfully applied to some oral liquid antacids.

A sponsor wishing to initiate a change to TGO 77 to allow medicines other than liquid oral antacid medicines to comply with the United States Pharmacopoeia – National Formulary, chapter <51> Antimicrobial Effectiveness Test should contact the TGA. Generally, a cogent justification together with supporting scientific data would need to be considered by the relevant expert advisory committee for the type of medicine affected.

Antimicrobial preservatives can be added to single-use, non-sterile dosage forms. The addition of a preservative must not be used as a substitute for good manufacturing practice. Testing of the effectiveness of the preservative would be part of normal product development and is not subject to TGO 77.

This anomaly has been noted by the TGC and the TGA.

Sponsors are referred to the further statement in the BP that "when the TYMC is expected to exceed the acceptance criterion due to the bacterial growth, Sabouraud-dextrose agar containing antibiotics may be used".

Pseudomonad bacteria are considered by the TGA to be objectionable organisms in a non-sterile medicine that is intended for topical use. The TGA will continue to expect these dosage forms to be free from contamination with these types of bacteria.

From a regulatory perspective, the sponsor is responsible for product quality and safety. The TGA's expectation is that a sponsor will determine the risk to their product from microorganisms other than those specified in TGO 77 and the pharmacopoeias.

Yes. The medicine would usually be of the dosage form "dried herb" with a container type such as "teabag" or "jar". The requirements in Schedule 2 apply when the directions of use require the addition of boiling water before use. This may be followed by directions to consume immediately, or to store and chill.

The Order on labelling requires that medicine labels include directions for use, including instructions for preparation and a statement of the conditions of storage and the maximum period of storage between preparation and use. When a medicine is intended to comply with subsection 9(2)(a) then its labelling should direct the consumer to prepare the infusion with boiling water.

TGO 77 applies to therapeutic goods regulated by the TGA. It does not apply to teas regulated as foods.

The medicine must meet the acceptance criteria relevant for each of the routes of administration nominated for the medicine by the sponsor.

The microbial attributes for a complementary medicine oral dosage form containing raw material of natural (animal, vegetal or mineral) origin in Schedule 1 specify the same microorganisms and limits as required in the "Special Ph Eur provisions" included in the European Pharmacopoeia, Table 5.1.4-1 and the British Pharmacopoeia, Appendix XVI D for a differently defined group of medicines (ie, oral dosage forms containing raw material of natural (animal, vegetal or mineral) origin for which antimicrobial pre-treatment is not feasible and for which the competent authority accepts TAMC of the raw material exceeding 103 per gram or per millilitre).

The TGC, and the TGA, acknowledge the position of the European Pharmacopoeia to include a microbial quality acceptance criterion for Staph aureus in an oral dosage form that contains a raw material of natural origin.

The microbial attributes for a complementary medicine oral dosage form containing raw material of natural origin that is a herbal medicine consisting solely of one or more herbal substances (whole, reduced or powdered) to which boiling water is added before use, as specified in Schedule 2, are derived from two sources:

  • the "Special Ph Eur provisions" included in the European Pharmacopoeia, Table 5.1.4-1 and the British Pharmacopoeia, Appendix XVI D for this type of product, for the requirements regarding total aerobic microbial count and total combined yeast/mould count; and
  • the TGA Laboratories' guidelines for assessing the results of microbiological tests on non-sterile pharmaceuticals for human use (1994) for this type of product, for the requirements regarding bile-tolerant Gram negative bacteria, E coli and Salmonella.

There is no international consensus in relation to microbiological quality acceptance criteria for herbal (botanical) medicinal products to which boiling water is added before use. There are a range of views among different countries, with some preferring more stringent, and some less stringent, requirements than those contained in TGO 77.

If this is a non-oral product, subsection 9(1) applies. Otherwise subsection 9(2) and Schedule 1 apply.

Where the Order specifies a Total aerobic microbial count (TAMC) limit of 100 CFU per gram (or per mL), the TAMC specification applied to the finished product should be less than or equal to 100 CFU per gram (or per mL). To allow for precision of the counting method due to inherent variability with microbial counts, the finished product would be considered to be non-compliant with the Order if the TAMC exceeded 200 CFU per gram (or per mL).

Compositional Guidelines are not 'monographs' for the purposes of TGO 77.

The TGA's expectation is that a sponsor will determine the risk to their product from microorganisms other than those specified in TGO 77 and the pharmacopoeias. It will not be unusual for a specification to set limits for more species than nominated in TGO 77.

Sponsors should consult the regulatory guidelines for prescription medicines, over-the-counter (OTC) medicines, registered complementary medicines and listed medicines for information about notification or approval processes for specification or other changes that are consequent upon the requirements of a new Therapeutic Goods Order.