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ARGOM Appendix 2: Guidelines on quality aspects of OTC applications
6. Control of excipients
The information concerning the specifications applying to the excipients should include:
- a critical summary and justification for the acceptance testing specifications applied by the finished product manufacturer
- test methods and validation data, where required (see 'Section 6.1 Pharmacopoeial excipients' and 'Section 6.2 Non-pharmacopoeial excipients').
In all cases, the specifications must characterise the excipients and ensure that all batches are of suitable and consistent quality for use in the manufacture of the medicine.
Where all of the tests, limits and test methods are of a default standard monograph (and none of the compendial tests has been deleted) it is generally sufficient to state this.
Where non-pharmacopoeial specifications are applied, a description of the tests, test methods and limits should be provided [e.g. assay (non aqueous titrimetry: 99.0 101.0%]. The specifications applied should be justified in respect of their ability to assure the quality and consistency of the ingredients used. Similarly, where a pharmacopoeial monograph is used as the specification any deviation from the pharmacopoeial tests, test methods or limits should be justified.
6.1 Pharmacopoeial excipients
A pharmacopoeial excipient is an excipient that is the subject of a monograph in at least one of the default standard pharmacopoeias (see 'Section 7 Control of finished product' for further details on default standards).
Where an excipient is the subject of a monograph in the default standard mandated or adopted for the product, the raw material must comply with the requirements of that monograph, as interpreted in accordance with the General Notices of that standard.
Compliance with the requirements of a monograph is most clearly demonstrated by including all of the tests and limits from the relevant monograph in the acceptance specifications; however, it may also be possible to use a monograph from an alternative default standard pharmacopoeia where this will ensure compliance with the monograph in the default standard for the product.
Where the default standard mandated or adopted for the product does not include a monograph for the excipient, but the excipient is the subject of a monograph in one or more of the other default standard pharmacopoeias, the excipient should comply with the requirements of one of these monographs.
Where all of the tests, limits and test methods are of a monograph from a default standard pharmacopoeia it would be sufficient to state that this is the case. However, it is generally not acceptable to:
- adopt only some of the tests from a pharmacopoeial monograph
- selectively combine some tests and/or limits from the relevant BP monograph with some tests and/or limits from the USP monograph (without having ensured full compliance with either one or the other monograph).
Where a sponsor applies pharmacopoeial limits but wishes to use different test methods, for example using HPLC for assay rather than titration or IR for identification rather than a colourimetric test, this should be stated and full details of the test methods should be provided. This will permit the TGA to assess whether the in-house and compendial methods are equivalent and/or whether the modified specifications ensure the overall quality of the substance.
Where the use of a particular grade of an excipient is known to be critical to achieve acceptable finished product attributes, control of additional properties (e.g. physical and functional characteristics such as viscosity, powder fineness, moisture content, or sterility) may be necessary for individual manufacturing processes or formulations.
Where a pharmacopoeial monograph exists but a sponsor wishes to substitute in-house specifications, for example replacing a test and limits for density with refractive index, full details of the limits and test methods should be provided for evaluation. Validation data may be required in support of certain test methods (see 'Section 6.2 Non-pharmacopoeial excipients'), and the sponsor should justify the use of non-pharmacopoeial specifications.
6.2 Non-pharmacopoeial excipients
A non-pharmacopoeial excipient is an excipient that is not the subject of a monograph in any of the default standard pharmacopoeias (consult 'Section 7 Control of finished product' for further details on default standards).
Where there is no pharmacopoeial monograph, full details of the limits and test methods should be provided for evaluation. In some cases, validation data may be required to support test methods [for guidance on the types of analytical methods required to be validated see Note for guidance on validation of analytical procedures: text and methodology (CPMP/ICH/381/95)].
Specifications for excipients should include tests and limits, unless otherwise justified for:
- impurities (e.g. water, residual solvents, loss on drying, sulfated ash, heavy metals, synthetic impurities and degradants).
In some cases the assay and/or impurities test(s) may be replaced or supplemented by physicochemical tests such as clarity, colour and/or pH of solutions, or melting point. Requirements for microbial contamination and particle size distribution may also be relevant in relation to use in some finished product formulations.
Excipients which are intrinsically mixtures (e.g. synthetic polymers or fatty acid esters of glycerol where mono, di, and triacyl glycerol species are present and where a range of different fatty acid residues is also present for example surfactants) should include relevant additional tests which control the composition of the mixture such as:
- acid value
- iodine value
- saponification value
- density; and/or
- refractive index.
6.3 Solvent/Sterilant residues
Refer to 'Section 2 Active substances: 2.2.4 Solvent/Sterilant residues'.
6.4 Proprietary ingredients
Where a proprietary ingredient is used in medicine manufacture or an intermediate product is purchased already manufactured, details of the medicine manufacturer’s acceptance specifications for this material must be provided.
The specifications applied to the material should be appropriate for the nature of the ingredient, its function in the medicine and its proportion in the medicine. For example, for proprietary ingredients that are fragrances, flavours or colourings (which are normally minor components present at no more than 2% in the product formulation), some relevant requirements are detailed under the relevant headings, below.
6.5 Perfumes (fragrances) and flavours
For a perfume or flavour that is a proprietary ingredient, or otherwise supplied as a complex mixture, the specifications should include, unless otherwise justified, tests for:
- description (odour, colour, general appearance)
- any relevant general tests that contribute to identification (and control of composition), such as refractive index or density
- identification by prominent peaks in a gas chromatography (GC) or HPLC trace, or major spots in a thin layer chromatogram.
Where there is an applicable default standard monograph for any constituent, the constituent must conform to the specifications in that monograph. In the case of artificial flavourings, where there is no applicable default standard monograph, the excipient would be expected to comply with any relevant monograph in the internationally accepted purity criteria in food use (FAO/WHO).
6.6 Colourings in medicines for topical and oral use
The guidance Colourings used in medicines for topical and oral use details the specifications that apply.