Results updated 21 Jan 2025

Introduction

From July to September 2023, the TGA consulted with the public on the draft Guidelines for the quality of listed probiotic medicines (now known as 'Demonstrating the Quality of Listed Probiotic Medicines'). The purpose of this consultation was to seek stakeholder feedback on the clarity and presentation of information before publication. The feedback has been used to improve how the information is conveyed and the overall readability of the Guidelines.

The Guidelines are intended to help sponsors and manufacturers meet the technical, scientific and regulatory requirements to ensure the quality of their probiotic medicine is acceptable under the Therapeutic Goods Act 1989 (the Act), and thus to mitigate the risk of non-compliance.

Where the Guidelines provide interpretations of the legislation, they are not mandatory requirements, instead they provide transparency to sponsors by showing the various factors a TGA delegate considers when they assess the quality of listed and assessed listed probiotics in a compliance review.

Submissions to the consultation

The TGA thanks all stakeholders for their feedback.

14 submissions were received during the consultation.

• Industry peak bodies: 3
• Sponsors/manufacturers: 7
• Industry regulatory consultants: 2
• International pharmacopoeias: 1
• Individuals: 1

The submissions that provided consent to be published are available through the ‘view submitted responses’ link.

Summary of submissions and responses from the TGA

General readability and structure

Some stakeholders found the cross-referencing and back-and-forth between sections confusing and would like all information related to a topic to be in the one place in the document.

Some stakeholders found the Guidelines confusing because they include future states that are not presently available, such as the addition of a new multi-strain monograph in a default standard, and the addition of strains as active ingredients in column 2 of the Permissible Ingredients Determination.

A number of stakeholders wanted the document to be simplified and shortened by removing section 5 or replacing section 5 with a list of published guidelines or legislation.

One stakeholder suggested moving the general information about ministerial and default standards into a new guideline.

TGA response

The TGA acknowledges that the information in the Guidelines is complex, and has focussed on improving readability. The complexity is due to the multiple regulatory requirements (section 5) and the multiple options for how compliance can be demonstrated (section 4). For example, for any particular product there are options for how to demonstrate quantification and options for labelling, and these depend on the product formulation, whether efficacy is at the strain or species level and also which default standard is applicable and chosen. As such, a topic covered in one section can depend upon the requirements and options explained in another section. For instance, everything about labelling for a particular product will extend beyond the ‘labelling’ section, and the reader’s pathway through this document will branch via cross-‍references to other parts of the Guidelines and links to relevant information external to the Guidelines. The cross-referencing also allows the reader to obtain targeted information from the Guidelines in a non-linear manner.

The Guidelines include aspects that are not currently available but may be introduced or changed at any time. This is to future-proof the contents of the Guidelines. For example, changes to a default standard such as a new chapter or monograph could be introduced (e.g. a new monograph for a multi-strain product or for a new species or strain) or an existing chapter or monograph could be changed (e.g. for a new strain in an existing species). Since these changes could potentially occur at any time, they are acknowledged in the Guidelines. We have added more instances into the Guidelines where we suggest that the reader check the information in the current version of the Pharmacopoeia or legislative instrument for any changes.

Section 5 will be retained as it provides the legislative basis for the information in section 4. Some of the information in section 5 is mentioned in other guidelines but it is emphasised in these Guidelines as it names and explains the most relevant legislation for ensuring the quality of probiotic medicines and thus assists with sponsor and manufacturer compliance. Information about ministerial and default standards is included in the Guidelines as they are not currently in any other guideline. The TGA acknowledges that future guidelines may be prepared for topics applicable to all listed medicines, to complement the content in the Guidelines.

Strain-level identification, quantification and Quantified by Input (QBI)

Many stakeholders were concerned that the Guidelines were introducing a new requirement to test individual strains in a multi-strain medicine, rather than the current and common approach which is to use QBI plus a total quantification at the genus level for the final product. The stakeholders expressed a range of concerns: strain-level testing is not achievable due to the lack of equipment, analytical methods and laboratory expertise; the technical requirements for quantification are beyond the analytical capabilities of manufacturers; there is an absence of licensed commercial testing laboratories that have methods to quantify strains in multi-strain products; and if methods were developed, it would be time consuming and costly, and create a barrier to manufacturing in Australia. Some stakeholders requested that the TGA provide time for sponsors to develop methods and to bring products into compliance. Some stakeholders asserted that alternative options are needed and claimed that none are clarified in the guideline.

A few stakeholders commented that the option to use QBI is not explicit in some sections. One stakeholder commented that Table 1 does not explain that when strain enumeration is required by the Ph. Eur./BP and USP monographs, QBI could be an option. Another stakeholder requested more information be added into Figure 2 at the footnote to line 7 to include QBI and that quantification will depend on the product formulation.

TGA response

The use of QBI supported by scientific evidence continues to be an option for controlling the strain identity and quantity in a single or multi-strain probiotic. This was explained in section 4.5.3 Quantified by input. As such, sponsors continue to have alternative strategies to control the active ingredient at strain-level in lieu of testing the final product, until testing becomes commercially available.

In response to the consultation feedback, extra information and examples have been added to multiple locations in the Guidelines to further clarify when and how QBI use can be supported by scientific evidence.

Assay limit for content and TGO 101 ‘not less than stated content’

Several stakeholders asserted that an additional measurement error (such as +/- 0.2 to 0.5 log) should be allowed in addition to the requirement in TGO 101: that the assay limit for the content of each active microbial ingredient in the final product must be not less than (NLT) the stated content (subsection 14(2) of Division 3 and item 4 of Schedule 2 of TGO 101). One stakeholder requested clarification. One stakeholder was concerned about potential non-compliance at product expiry if the measurement error is not allowed.

TGA response

In section 4.5.2 Assay limit for content, we have restructured existing information into dot points to clarify that measurement error, quantity losses throughout the shelf life of the medicine and the claimed quantity for efficacy on the medicine label should all be accounted for at the start of manufacturing when determining the amount of overage required for the final product and thus to comply with the assay limit for content.

The practices described in the Guidelines are in alignment with Good Manufacturing Practice and the pharmacopoeias.

3.10.20 in USP general notices, labelled as conforming to USP or NF

Several stakeholders disagreed with the requirement for probiotics in dosage forms other than tablets or capsules to be labelled as conforming to USP or NF in order to comply with an applicable USP monograph. Some stakeholders suggested to remove the USP conformance requirement from the Guidelines.

TGA response

The TGA agree that the USP conformance requirement is not ideal and does not align with the intent behind invoking default standards in the Therapeutic Goods Act 1989. All references to section 3.10.20 of the USP General notices ‘labelled as conforming to USP or NF’, have been removed from the guideline to avoid confusion about potential labelling in this way for dosage forms that are not tablets or capsules.

TGO 100 Microbiological standards for medicines is not relevant to probiotics

Two stakeholders believed that TGO 100 was applicable to probiotics and were concerned that it was not included in the guideline.

TGA response

In section 5.6.2 Ministerial standards, we added a paragraph to explain why TGO 100 is not applicable to the detection of microbial contamination (bioburden) in the presence of active probiotic ingredients in probiotic medicines. Section 11 of TGO 100 references test methods within Ph. Eur., BP and USP–NF that explicitly state they are not applicable to products that contain viable microorganisms as active ingredients. We then refer the reader to the tests and acceptance criteria for the enumeration of microbial contaminants in probiotics in either Ph. Eur. or USP–NF (guideline sections 5.7.2.2 Microbial contamination or 5.7.3.1 Microbial contamination, respectively).

Labelling

Two stakeholders were confused by Table 6 Label presentation of the AAN and quantity in a cohesive unit, which shows how to present the ingredient name and quantity on the label in order to be compliant with TGO 92 subclause 9(3) and a default standard applicable to the medicine (either Ph. Eur./BP 3053 or USP–NF 64).  

One stakeholder did not understand how Table 6 relates to a circumstance when strain quantity is not required, and they believed this was allowed under USP–NF 64. Another stakeholder believed the two scenarios in Table 6 (Genus species (strain) and Genus species, respectively) were different examples of the same thing and requested a standardised format to be shown in the guideline.

One stakeholder was concerned that the labelling requirements in the Guidelines (in Table 6) involved changes to existing practices and should therefore be supported by a transition period. They also suggested that the changes should ideally be captured in TGO 92 and should only come into force when the requirements within TGO 92 do.

TGA response

In response to the consultation feedback, we have added extra information to the Guideline to further clarify the labelling requirements.

The Guidelines do not introduce any changes to existing requirements for labelling. However, the labelling requirements in TGO 92 and the applicable default standard for how the label is to present the strain names have not previously been clarified in a publication by the TGA, and therefore when the Guidelines are published some labels may be non-compliant. A transition period will be provided to sponsors to allow time for product labels to be compliant with existing requirements in relation to TGO 92 subclause 9(3) and either Ph. Eur./BP 3053 or USP–NF 64.

 

Published responses

View submitted responses where consent has been given to publish the response.