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ARGOM Appendix 2: Guidelines on quality aspects of OTC applications

Version 1.1

30 May 2014

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2. Active substance

The term 'active substance' has been used in this chapter when referring to the raw material (i.e. before it is mixed with the other ingredients in the finished product formulation). The term 'active ingredient' is used to refer to the therapeutically active component in the finished product formulation after manufacture, in line with the definition of 'active ingredient' in the Therapeutic Goods Order No. 69 (TGO 69) - General requirements for labels for medicines and Therapeutic Goods Order No. 78 (TGO 78) - Standard for Tablets and Capsules.

The term 'active pharmaceutical ingredient' (or 'API') is commonly used as a synonym for 'active substance'. However, as defined in the Therapeutic Goods (Manufacturing Principles) Determination No. 1 of 2009, 'active pharmaceutical ingredient' can refer either to a single substance or a mixture of substances (that become an active ingredient in the finished product). Therefore, to avoid confusion, its use will be minimised in this document.

2.1 Manufacturer of active substance(s)

Details regarding the active substance manufacturer, manufacturing process and process validation, are not generally required to be submitted to the TGA for OTC product registration applications. However, these details may be required where the active substance is a new chemical entity (NCE). Other additional data requirements for NCEs are detailed in the ARGOM Appendix 4 Guidelines on OTC application for new substances.

For OTC medicines, it is the responsibility of the sponsor to ensure that the active substance is manufactured to a standard consistent with the principles of the Code of Good Manufacturing Practice (GMP) (or in the case of overseas manufacturers, with an appropriate standard of GMP comparable to that required for Australian manufacturers). Evidence of licensing or approval of the manufacturer of the active substance does not need to be submitted to the TGA, except where it is an intermediate product (e.g. premixes).

Where the active substance is a component of an intermediate product that is purchased already manufactured, the manufacture of the intermediate product is considered a significant step in the manufacture of the medicines. Under these circumstances, evidence of licensing or approval of the manufacturer of the intermediate product will be required (irrespective of whether it is a proprietary ingredient). For further information refer to 'Section 5 Manufacture of the medicine'.

2.2 Control of active substance [active pharmaceutical ingredient (API) specifications]

Applications to register OTC products should include information concerning the specifications applying to the active substance(s).

This information should include:

In all cases, the specifications must characterise the active substance and ensure that all batches are of suitable and consistent quality for use in the manufacture of the finished product.

2.2.1 Pharmacopoeial active substances

A pharmacopoeial active substance is an active substance that is the subject of a monograph in at least one of the default standard pharmacopoeias (see 'Section 7 Control of finished product' on default standards).

Where an active substance is the subject of a monograph in the default standard mandated or adopted for the product the active substance 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 an active substance, but that active substance is the subject of a monograph in one or more of the other default standard pharmacopoeias, the active substance should comply with the requirements of one of these monographs.

If the active substance is the subject of a Certificate of Suitability (CEP) issued by the European Directorate for the Quality of Medicines (EDQM), the sponsor is encouraged to provide a copy of the CEP together with a letter of access.

Where all of the tests, limits and test methods are those of a monograph from a default standard pharmacopoeia and none of the compendial tests has been deleted, it is usually sufficient to state that this is the case and no additional justification is required. However, the acceptance specifications for the substance must be updated as necessary in order to be consistent with the new editions of the substance monograph in the current edition of the relevant pharmacopeia.

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 British Pharmacopoeia (BP)/European Pharmacopoeia (Ph. Eur.) monograph with some tests and/or limits from the United States Pharmacopoeia (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 High Performance Liquid Chromatography (HPLC) for assay rather than titration or Infra Red (IR) for identification rather than a colourimetric test, this should be stated and full details of the test methods should be provided (especially in respect of related substances tests). 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. Validation data to support the test method may be requested in certain cases.

In some cases, it may be necessary to include tests and limits in the active substance specifications that are not included in the relevant pharmacopoeial monograph. For example:

Usually, the need for any such additional tests will have been investigated as part of selection and characterisation of the active substance during development of the product.

Where a default standard monograph exists but a sponsor wishes to substitute an in-house set of tests and limits, for example replacing a test and limits for density with refractive index, full details should be provided for evaluation (see 'Section 2.2.2 Non-Pharmacopoeial active substances'). The sponsor should justify the use of non-pharmacopoeial specifications. In particular, it must be clear that the in-house tests and limits will ensure compliance with the requirements of the default standard.

2.2.2 Non-pharmacopoeial active substances

A non-pharmacopoeial active substance is an active substance that is not the subject of a monograph in any of the default standard pharmacopoeias (see 'Section 7 Control of finished product' on default standards).

The critical summary should include a list of the tests, limits and test methods [e.g. assay (non aqueous titrimetry): 99.0 101.0%].

In proposing tests and limits, sponsors should consider the relevant European Union active substance guidelines adopted by the TGA as well as general pharmacopoeial monographs such as the BP/Ph. Eur. monograph Substances for Pharmaceutical Use.

Specifications for active substances should include tests and limits for:

  • appearance/description
  • identification
  • content/assay
  • impurities such as residual solvents, sulfated ash, heavy metals and related substances (synthetic impurities and degradants)
  • other parameters which are relevant to the individual substance, such as water content/loss on drying, the presence or proportion of isomers, optical rotation, melting point and the clarity, colour and pH of solutions.

Control of additional properties such as particle size distribution or microbial contamination may be necessary in association with individual finished product manufacturing processes or formulations.

The specifications applied should be justified in respect of their ability to ensure the quality and consistency of the substance.

Full details of the test methods should be provided for evaluation. Validation data may be required in support of certain test methods (consult 'Section 7.9 Analytical procedures and validation' for further information).

2.2.2.1. Related substances

For a NCE, the related substances specifications should be based on the approach detailed in the ICH document Impurities Testing Guideline: Impurities in new drug substances (CPMP/ICH/2737/99).

Note: Other additional data requirements for NCEs are detailed in the ARGOM Appendix 1 Guidelines on efficacy and safety aspects of OTC applications

For other active substances, the following limits can generally be applied without a detailed justification:

  • Individual identified impurities: not more than 0.5%
  • Individual unidentified impurities: not more than 0.1%
  • Total impurities: not more than 1.0%

2.2.3 Specifications for intermediate products

Where the active substance is purchased already manufactured as part of an ingredient blend or premix; the finished product manufacturer’s acceptance specifications for this material must be provided.

For an ingredient blend containing the active substance, the specifications should, as a minimum, normally include tests for:

  • identification of the active
  • content of the active
  • impurity tests
  • any other tests relevant to manufacture or quality of the finished product, for example particle size distribution/sieve analysis where the blend is to be used in direct compression or in suspensions.

Omission of some of these tests may be justifiable if the relevant quality parameter is assured by other means such as impurity testing of the individual components, or testing of subsequent intermediate or final product (or is shown to be irrelevant to the particular blend).

The sponsor should also state whether the components of the blend or premix are of pharmacopoeial grade and comply with any relevant default standards.

2.2.4 Solvent/Sterilant residues

Where organic solvents or sterilants are used in manufacture, it is the sponsor's responsibility to ensure that residues are appropriately controlled. Compliance with a specific default standard does not necessarily assure appropriate control of solvent residues.

The limits applying to solvent/sterilant residues are detailed in the following default standards and TGA-adopted documents:

  • BP Supplementary Chapter IV D Residual Solvents, which incorporates Ph. Eur. Section 5.04 Residual Solvents, and is applied via the BP general monograph Substances for Pharmaceutical Use (Ph. Eur. 2034)
  • Ph. Eur. Section 5.04 Residual Solvents, which is applied via the general monograph Substances for Pharmaceutical Use (Ph. Eur. 2034)
  • USP <467> Residual Solvents
  • Note For Guidance On Impurities: Residual Solvents (CPMP/ICH/283/95).
  • Annex 1: Specifications for Class 1 and Class 2 Residual Solvents in active substances
    Annex 2: Residues of solvents used in the manufacture of finished products (CPMP/QWP/450/03)
  • Note for Guidance on Limitations to the Use of Ethylene Oxide in the Manufacture of Medicinal Products (CPMP/ICH/159/01), with TGA annotation prohibiting use in decontamination of herbal products.

2.3 Stability of the active substance

Details of stability studies conducted on the active substance are not generally required for registration applications for OTC products. However, such details are required where the active substance is a NCE. Inclusion of such information with an application may provide a useful guide to the problems which may be encountered during stability studies on finished products.

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