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Compositional guidelines for complementary medicine substances
ARGCM Part C: New complementary medicine substance evaluation
What compositional guidelines are
A Therapeutic Goods Administration (TGA) compositional guideline is a summary of descriptions, tests and appropriate acceptance criteria (which are numerical limits, ranges or other criteria) that define the characteristics and specify the composition of an ingredient permitted for use in listed medicines. For the current list of compositional guidelines - refer to List of compositional guidelines.
How compositional guidelines are used
Compositional guidelines are used for an approved excipient or active ingredient where there is no default standard recognised in the Therapeutic Goods Act 1989 (the British Pharmacopoeia, United States Pharmacopoeia - National Formulary and the European Pharmacopoeia).
If an applicable new default standard is published for an ingredient where a compositional guideline exists, the compositional guideline is withdrawn and the ingredient must comply with the requirements of the new default standard.
Compositional guidelines assist sponsors to:
- understand the specific nature of the ingredient that has been approved for use
- determine whether their material conforms to the requirements for that ingredient
- minimise any risk associated with the ingredient by complying with the parameters of the specification.
While compliance with the compositional guideline is not a legal requirement, using an ingredient that does not meet the specifications of a compositional guideline may result in the TGA having concerns about the safety of that ingredient and any medicines containing it.
Where a sponsor wishes to include an ingredient in listed medicines that does not meet the compositional guideline, a request may be made to justify the safety of that specific material and/or the safety of any listed medicines containing that material. Where an ingredient is found to be unjustifiably different from the relevant compositional guideline, a sponsor may be requested to no longer use that material.
When compositional guidelines are generated
Compositional guidelines are usually generated when a new complementary medicine substance is approved for use as an ingredient in listed medicines. If the new ingredient is not subject to a specific default standard, a draft compositional guideline for the substance must be submitted in the application. The information the applicant includes in the proposed compositional guideline is based on the quality data submitted in the application.
On occasion a compositional guideline may be generated for some ingredients currently permitted for use in listed medicines, for example: 'grandfathered' ingredients that were available in Australia prior to the commencement of the Therapeutic Goods Act 1989 and are not subject to a default standard or have a compositional guideline. The TGA will work with relevant stakeholders, including industry stakeholders, to develop these compositional guidelines when required.
Publication of compositional guidelines on the TGA website
When a new ingredient is permitted for use in listed medicines, the compositional guideline for the ingredient is published on our website under current compositional guidelines.
Procedure for amending compositional guidelines
A stakeholder can request the TGA to consider amending a compositional guideline. The request must be accompanied by appropriate justification that the safety profile of the ingredient will not be compromised (which would make it unsuitable for use as an ingredient in listed medicines).
Consideration will be given to whether the compositional guideline should be amended or a separate ingredient recognised (which would require an application for evaluation of a new substance). If the amendment is considered warranted, we will seek initial comment from the original applicant prior to determining if a revised draft should be published.
Guidance for developing compositional guidelines
The following information assists prospective sponsors and substance manufacturers in drafting a compositional guideline for a new complementary medicine ingredient.
A compositional guideline template is available on our website that provides broad guidance to the type of information/data that should be included. However, if certain parameters included in the template are not relevant, these can be omitted provided that justification is given, for example: 'The production of this substance does not require the use of solvents and therefore the compositional guideline requirement for solvent residues has been omitted'.
Sources of data for development of compositional guidelines
Data from a variety of sources, including published literature, can be used in the development of compositional guidelines. The information on the compositional guideline should be justified (verified) from analysis of production batches of the material. The following documents may contain relevant information:
- The general monographs of the British Pharmacopoeia, for example: Herbal Drugs, Processed Herbal Drugs, Herbal Drug Preparations, and Extracts.
- European Medicines Agency guideline on specifications: Test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/ traditional herbal medicinal products CPMP/QWP/2820/00 Rev. 2.
Linking compositional guidelines to a manufacturing process is important in order to identify any potential process-related constituents and impurities.
General information required in a compositional guideline
In general, the information included in a compositional guideline should:
- provide the physical and chemical properties of the substance
- identify and quantify major components and any significant (that may affect the safety or quality of the substance) minor components
- distinguish the substance from similar substances, adulterants or substitutes
- be specific for components of safety and/or therapeutic significance
- provide the limits of possible contaminants and impurities
- describe the biological, botanical, chemical and physical variations that may reasonably occur between batches of the substance
- be capable of providing for objective validation of the substance's composition using described analytical methodology.
Information on methods and procedures in a compositional guideline
The method of analysis used to establish compliance with the limits must be included in the compositional guideline, for example: high-performance liquid chromatography (HPLC). Methods in pharmacopoeias for similar substances should be used wherever possible, for example: pH measurements. If the method and limits are based on a pharmacopoeia or published reference, these references must be provided.
If proprietary or company analytical non-compendial methods are employed, a brief description in the draft compositional guideline is acceptable, for example: 'Acetone extraction and analysis by HPLC with ultraviolet (UV) detection'. However, complete details of the analytical methods and their validation must be provided as part of the application for evaluation for a new complementary medicine substance.
Information on biological, chemical and physical variations in a compositional guideline
Complex complementary medicine substances, particularly those of herbal origin, may be subject to variation due to such factors as: genetic variation; geographic variation; growing conditions; maturity and time of harvesting; post-harvest treatment; storage conditions; and/or processing treatments. Limits taking into account this variation must be included in the compositional guideline and justification for the limits provided, for example: 'the constituents in certain plants may vary seasonally and batches may contain, at certain times of the year, less of a certain constituent'.
Information on objective validation in a compositional guideline
Any methods or procedures identified in the compositional guideline should be able to be reproduced by an independent authority. Methods should be fully validated. Guidance on validating analytical test methods can be found in Starting material analytical procedure validation for complementary medicines.