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Information required to demonstrate the quality of a new complementary medicine substance
ARGCM Part C: New complementary medicine substance evaluation
Information on quality is required to characterise (identify the physical and chemical properties of) a complementary medicine substance. Where a substance is the subject of a default standard (Type 1 substance) the substance must comply with all requirements of that standard.
For herbal ingredients where there is no default standard (Type 2 substance), characterisation (including a detailed evaluation of the botanical and phytochemical aspects of the plant and the manufacture of a preparation) is essential to develop a compositional guideline that is comprehensive and relevant to safety and quality. The quality of a herbal ingredient is determined by the quality of the herbal raw material, in-process controls, good manufacturing practice controls, process validation and compositional requirements applied to them throughout development and manufacture.
The quality of herbal raw materials is determined by such things as:
- botanical characteristics of the plant part
- phytochemical characteristics of the plant part - known therapeutic or marker constituents, toxic constituents (identity, assay, limit tests)
- biological/geographical variation
- cultivation/harvesting/drying conditions (microbial levels, aflatoxins, toxic elements)
- pre/post-harvest chemical treatments (pesticides, fumigants)
- profile and stability of the constituents.
In addition to the above, the quality of a herbal preparation is determined by:
- method of preparation, including any diluents and extraction solvents
- profile chromatogram and stability of the constituents
- microbial stability.
For herbal complementary medicine substances, the following scientific guidelines provide guidance on general quality aspects:
- Quality of herbal medicinal products/ traditional herbal medicinal products EMA/CPMP/QWP/2819/00 Rev. 2
- Test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional herbal medicinal products EMA/CPMP/QWP/2820/00 Rev. 2.
The general monographs of the BP, Ph. Eur. and the USP are also relevant, for example: the BP monographs 'Herbal Drugs', 'Herbal Drug Preparations' and 'Extracts'.
TGA encourages data on quality in an application to be presented in a manner consistent with the document: ICH M4Q CTD for the Registration of Pharmaceuticals for human use - Quality (CPMP/ICH/2887/99 Rev 1).
The following TGA guidance on information required to demonstrate quality uses headings largely consistent with those provided in 'ICH M4Q'. The amount of information required will vary depending upon whether the substance is classified as a Type 1 or Type 2 substance.
Provide a description of the substance.
State if the substance is derived from or contains genetically modified substances.
For simple substances, provide the molecular formula, molecular weight and Chemical Abstracts Service (CAS) Registry Number and any nominated characterised constituents or similar information that will demonstrate identity.
For complex substances, where applicable, a description of the constituents with known therapeutic activity or markers and other constituents should be provided.
Provide information about the physico-chemical properties relevant to the characterisation of the substance or that may be important for the manufacture, performance or stability of its intended final dosage form, for example: solubility, particle size. Provide qualitative and quantitative particulars of the substance, including information on all physical properties such as appearance, colour, texture and smell.
Manufacturing details of complementary medicine substance
Provide the manufacturer's name, address and addresses of all sites involved in the manufacture/testing of the substance. This information will assist in the evaluation process should it be necessary to obtain confidential information directly from the manufacturer - see text box below.
Where a manufacturer is unwilling to supply manufacturing details to the applicant, the information can be supplied directly to the TGA with written authorisation from the applicant. In this case, any matters arising from the review of data will be pursued with the manufacturer. The applicant will be notified that matters have been raised with the manufacturer, the details of which will only be provided to the applicant if authorised by the manufacturer.
Description of manufacturing process and process controls
Provide a flow chart of the process which identifies the starting materials, reagents and solvents used, yield ranges and operating conditions for all manufacturing steps.
Provide a sequential, procedural narrative of the manufacturing process, including a detailed description covering the quantities of raw materials, solvents, catalysts and reagents that reflect a representative batch scale for commercial manufacture; critical steps and process controls; equipment; and operating conditions, for example: temperature, pressure and pH.
Identify any reprocessing steps and provide evidence that they have no significant effect on the final quality of the substance.
For herbal substances, information to adequately describe the plant production and collection, including geographical source cultivation, harvesting, drying and storage conditions and batch size, should be provided. Any changes in the manufacturing process, and degradation products produced during storage, may result in a herbal substance that differs from that used to establish safety. The significance of these changes should be considered. Linking compositional guidelines/specifications to a manufacturing process is important, as it aids in identifying any potential process-related constituents and process-related impurities.
Control of materials
Materials used in the manufacture of the substance (such as: raw materials, starting materials, solvents, reagents and catalysts) should be listed identifying where each material is used in the process. Provide the measures used for quality and control of these materials. These are usually given in the form of specifications or a reference to an acceptable standard, for example: 'ethanol BP'.
Controls of critical steps and intermediates
Provide details of critical steps of the manufacturing process and details of how it is ensured that the process is controlled. This should include tests performed, acceptance criteria and experimental data.
Provide information on the quality and control of any intermediates isolated during the process.
Manufacturing process development
Provide a description of the development of the manufacturing process. Describe any significant changes made to the manufacturing process of the substance used in producing scale-up, pilot and production-scale batches that may affect the composition of the substance.
Process validation and/or evaluation
Process validation and/or evaluation studies should be provided, if available.
Characterisation of complementary medicine substance
Elucidation of structures and other characteristics
Provide the graphic chemical structure of the substance and any characterised constituents in the substance, including potential isomerism. Specifically, provide information on any known constituents with a toxicological risk profile. Also provide information on the basis for confirming the structure, for example: spectral analysis.
Literature reports may be used to support this component of a submission.
Impurities and incidental constituents of complementary medicine substances
Incidental constituents and impurities are those constituents that may be present in a substance - as contaminants, as by-products of production, or arise during processing or storage of a substance, for example:
- residual solvents
- process related impurities arising from the manufacturing process
- incidental metals and non-metals, for example: lead, arsenic, selenium
- agricultural and veterinary chemicals, for example: pesticides, fumigants
- general contaminants, for example: dioxins, polychlorinated biphenyls
- manufacturing by-products, for example: reagents, catalysts, co-extractives
- degradation products
- radionuclides - particularly where substances might be sourced from contaminated areas
- radiolytic residues
- microbial contamination
- mycotoxins, for example: aflatoxins, ochratoxin A.
Their presence should be minimised consistent with legal and appropriate production, processing and storage practices, for example: principles of Hazard Analogy Critical Control Point or Good Manufacturing Practice. Reliance upon finished product testing alone is not a comprehensive means of managing their presence.
Pharmacopoeial monographs do not include a comprehensive list of all impurities and incidental constituents. Where there is a default standard for the substance, provide information concerning impurities that are not dealt with in the monograph. While this information is not mandatory, you should be aware that the manufacturing process for the substance may differ from the process for the substance upon which the monograph is based and, consequently, different impurities may be present.
The potential for the manufacturing process to concentrate residues should be addressed. A summary should be provided of any degradation studies carried out to identify impurities arising from exposure to stress conditions, for example: heat, light, pH or moisture.
Where there is no default standard for the substance, the draft compositional guideline must include requirements for all known or likely impurities and incidental constituents.
Specifications and descriptions of analytical procedures must be submitted. As a starting point, the tests or methods used in pharmacopoeial references should be used. Other useful references include the methods used by the US Environmental Protection Agency (US EPA) and the US Food and Drug Administration (FDA).
Where non-compendial methods are used, appropriate validation, rationale and justification should be provided.
Analytical procedures should be validated in accordance with the scientific guideline Note for guidance on validation of analytical procedures: Text and Methodology (CPMP/ICH/381/95) Rev 1.
Any solvent(s) that may be used in the production, preparation, manufacturing or formulation should be controlled as per the requirements of the BP supplementary chapter for 'Residual Solvents'.
Incidental metals and non-metals
The material should comply with default standard limit tests for heavy metals, for example: lead, cadmium, mercury and arsenic.
The Poisons Standard may stipulate a particular limit for a metal or non-metal constituent in a substance, for example: a substance containing more than 10 mg/kg lead would be subject to the conditions of the Poisons Standard. If a substance is subject to the conditions of a Schedule (or applicable Appendix) to the Poisons Standard, then it is not acceptable as a permitted ingredient.
If the Poisons Standard requirements are not applicable, limits for metal or non-metal constituents can be determined using a similar approach similar to that used in the default standards for pesticide residues. This is based on the amount of a residue from a daily dose of a therapeutic good being less than 1 per cent of the acceptable daily intake (ADI) of that residue. The equation for calculating the upper limit is:
Limit = (ADIxM)/(MDDx100)
where: ADI = the acceptable daily intake in mg/kg bodyweight per day for the metal or non-metal, as specified by a source such as the Food and Agriculture Organization – World Health Organization, US EPA, US FDA or Food Standards Australia New Zealand
M = body weight in kilograms (for example. 60 kg)
MDD = daily dose of the formulation/substance in kilograms
Example: calculation of the limit for lead
ADI of lead= 0.0036 mg/kg bodyweight.
MDD= 200 mg tablet three times a day, expressed in kg=0.0006 kg
Limit = (ADIxM)/(MDDx100)=(0.0036mg/kg X 60kg)/(0.0006 kg X 100)=3.6 mg/kg
If a raw material is intended for the preparation of extracts, tinctures or other pharmaceutical forms the preparation method of which modifies the content of metals and non-metals in the finished product, the limits are calculated using the following equation:
Limit = (ADIxMxE)/(MDDx100)
where: E = the extraction factor of the method of preparation, determined experimentally.
If typical levels are above the acceptable limits calculated from the expressions above, the reason for this should be determined. There are materials that contain elevated levels of incidental metals and non-metals, for example: seaweed contains high levels of iodine. You should justify that the levels of the incidental metal or non-metal are typical and are not associated with contamination of the substance or indicative of poor quality. Proposed limits must be indicative of typical levels in the substance and take into account any expected or typical variation. Limits that would result in exposure greater than the ADI for a metal or non-metal are not acceptable.
Having established limits for relevant incidental metals or non-metals, appropriate means of determining compliance with these limits should be provided. Limit tests in the default standards are a useful starting point, provided they are suitable for the substance being analysed. 'In house' methods should be validated. Applicants should consider adopting tests where the limit of reporting is at least 10 per cent of the limit proposed for the incidental metal or non-metal in the substance or therapeutic good. This may not always be possible where a very low limit is proposed. However, results that are well below the proposed limits provide greater confidence that the limits proposed will not be exceeded.
Pesticide residues and environmental contaminants: (including agricultural and veterinary substances)
Pesticide residues may be found in a raw material as a result of intentional treatment or from inadvertent environmental contamination, of particular relevance are:
- organochlorins (for example: dichlorodiphenyltrichloroethane and endosulfan)
- organophosphates (for example: chlorpyrifos and parathion)
- carbamates (for example: carbaryl and methomyl).
The effects of processing and storage may affect these residues and result in a concentration or reduction of residues in finished goods.
The method, acceptance criteria, methodology and limits stipulated for pesticide residues in the default standards, for example: BP Appendix XI L – 'Pesticide Residues', should be followed as well as any additional residue limits that may be relevant. If a complementary medicine substance contains a pesticide residue that is not specifically restricted in the BP, then the risk associated with that pesticide should be assessed based on the generic approach described in the BP. Applicants should identify the likely pesticide residue risks; determine the likelihood and consequences of these risks; and develop, implement and review approaches for managing these risks.
Information from the US Environmental Protection Agency or the Codex Committee on Pesticide Residues can often provide good information about the effects of processing for specific chemicals. Other sources of information include pesticide manufacturers.
Other organic or inorganic impurities or toxins
Other organic or inorganic impurities or toxins may include:
- foreign matter
- total ash
- sulfated ash/residue on ignition
- ash insoluble in hydrochloric acid
- related substances, for example: synthetic impurities, degradation products
- other manufacturing by-products, for example: reagents, catalyst residues or process impurities
- radionuclides: where substances are sourced from contaminated areas
- radiolytic residues: for substances sterilised using ionising radiation
- residues of decontamination treatments
- any other organic or inorganic impurities or toxins (for example: dioxins, polychlorinated biphenyls and microbial toxins such as aflatoxins, ochratoxins).
The likely presence of manufacturing by-products (for example: catalyst residues, synthesis or process impurities and degradation products) should be determined and typical levels in regular production batches documented, particularly where they are of significance to safety or quality. Attention should also be given to the presence of isomers, metabolites and co-extractives.
Substances may be sterilised using ionising radiation. You should consider what radiolytic products may be formed in the substance and what constituents of the substance may be affected by such treatment, for example: vitamin A. You should have documentation about substances that have been irradiated, monitor levels of radiolytic products or constituents and, if necessary, establish and document limits.
If a decontaminating treatment has been used, it must be demonstrated that the quality of the substance has not been adversely affected and that no harmful residues remain.
In relation to other pharmaceutical raw materials and finished products, it is recommended that ethylene oxide be used only when essential and where alternative processes and/or decontamination agents cannot be used. Refer to the scientific guideline: Note for Guidance on Limitations to the use of ethylene oxide in the manufacture of medicinal products CPMP/QWP/159/01. In relation to herbal materials, the BP dictates that 'the use of ethylene oxide for the decontamination of herbal products is prohibited'.
Depending upon the substance, specific contaminants (for example: dioxins and polychlorinated biphenyls) may be present and the range of their concentrations should be given.
While substance manufacturers are encouraged to include limits for objectionable microorganisms, it is the product into which those substances are formulated that is subject to a legally binding set of criteria. The Therapeutic Goods Order No. 77 Microbiological Standards for Medicines mandates that any finished product that contains the ingredient, alone or in combination with other ingredients, must comply with the microbial acceptance criteria set by the Order.
While the TGA applies limits for certain micro-organisms in finished products, it is advisable to implement appropriate controls at the raw-material stage. There may be a need to specify the total count of aerobic micro-organisms, the total count of yeasts and moulds and the absence of specific objectionable bacteria. Microbial counts should be determined using pharmacopoeial procedures or other validated procedures. The source of material should be taken into account when considering the inclusion of possible pathogens, for example: Campylobacter and Listeria species.
Control of a complementary medicine substance
You must include information on the controls used to ensure the quality of the complementary medicine substance. Relevant guidance can be found in:
- Compositional guidelines for complementary medicine substances
- Guideline on Specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/ traditional herbal medicinal products EMA/CPMP/QWP/2820/00 Rev. 2
- Note for Guidance on Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances CPMP/ICH/367/96
The following major points must be addressed.
Default standard/compositional guideline
For Type 1 substances, provide the TGA default standard. For Type 2 substances, provide the draft compositional guideline with justification of tests and limits.
Specification with justification
The specification of the substance must be provided.
Provide justification of the specification of the substance.
Analytical procedures with validation data
Provide analytical tests and methods used to demonstrate quality.
Provide validation data for analytical test methods. This is not applicable where the procedures described in the monograph or standard are employed.
Validation should be conducted based on the scientific guideline: Note for guidance on validation of analytical procedures: Text and Methodology (CPMP/ICH/381/95).
Provide certificates of analysis for at least two recent, commercial-scale production batches to demonstrate routine compliance with the monograph or proposed compositional guideline. If data on commercial-scale batches are not available, provide certificates of analysis for pilot-scale batches manufactured using the same process as intended for commercial-scale batches.
The date of manufacture, batch size and number, place of manufacture, analytical methods used, should be provided. Tests results should be expressed numerically, for example, impurity levels. Results which merely state that the material 'complies' with the test are insufficient.
If available, provide certificates of analysis for any batches of material used in toxicity tests and clinical trials reported in support of the application. This will help the TGA to determine if the substance intended for supply is the same as that on which safety data have been provided.
Authentication of reference materials
Provide information about the reference standards used in tests, for example: identification, assay and impurities testing. Information should also be provided about how these reference substances were established, and where applicable, how their potencies were assigned. Where 'in-house' reference materials are used, provide information on how the reference material has been characterised.
For more information on the requirements of herbal reference standards, applicants should refer to the scientific guidelines referred to above and Identification of herbal materials and extracts on the TGA website.
A profile chromatogram or 'fingerprint' chromatogram is a chromatographic profile of a botanical raw material or other substance that can be compared with that of an authenticated reference sample or standard.
Provide chromatograms in the application accompanied by complete details of the extraction steps and procedures (including detectors or detection systems) involved in their production. The information should be of sufficient detail to allow an independent authority to generate the same profile chromatogram.
A profile chromatogram is useful for both qualitative and semi-quantitative assessments. Even in situations where some or all of the constituents are unknown, profiling can identify variations due to differences in quality of raw materials including contamination issues, batch-to-batch consistency concerns and stability issues. If profiling is used semi-quantitatively as part of quality control for a substance, for example it is included in the compositional guideline, consideration would need to be given to the amount of variability that is acceptable.
On its own, a profile chromatogram is not suitable where a constituent of toxicological or therapeutic activity has been identified in a substance. In this case, specific methods to determine the amount of the toxicologically or therapeutically active constituent are required.
Importantly, a profile chromatogram may not be indicative of all components within a substance. For example, a profile chromatogram may be generated for the flavonoids in a substance and yet the majority of the substance comprises other components, such as starches or sugars. If known and where practicable, a profile chromatogram should be accompanied by information about the other constituents in the substance that are not profiled. Justification for not profiling these other constituents should be provided in the application.
Container closure system
Provide a description of the general characteristics of the container closure system where this might influence the stability of the substance, for example: protection from moisture and light.
Stability testing should be conducted in accordance with the TGA-adopted scientific guidelines for stability testing of drug substances.
The application should include a summary of the studies undertaken (conditions, batches, analytical procedures). The summary should also include results, for example, from forced degradation studies and stress conditions (light stress, higher temperature) as well as a brief discussion of the results, conclusions, the proposed storage conditions; retest date or shelf life where relevant.
A tabulated summary of the stability results, with graphical representation where appropriate should be provided.