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ARGOM Appendix 2: Guidelines on quality aspects of OTC applications

Version 1.1

30 May 2014

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4. Development pharmaceutics and formulation

Information which is relevant to the subheadings specified in the CTD under module 3.2.P.2 should be included in this section. For example, explanations for the choice of excipients, the use of a modified release dosage form, or justifications for overages. For most OTC medicines this section will be brief.

4.1 Overages and ranges

Details should be provided of any overage or range that is applied during manufacture, including a justification for the overage or range and supporting validation data where appropriate.

Any assay limits which are unusually wide as a consequence of the proposed overage should also be addressed. Refer to 'Section 7 Control of finished product', for examples of some commonly applied assay limits. Overages are not to be included in the formulation details section of the electronic application form.

Justifications for 'stability' overages would generally include comment on:

  • the intrinsic stability of the active substance, and any studies performed to investigate and/or control its stability in the product
  • any implications for safety or efficacy of the product, as a consequence of the wide range of the ingredient's content over the shelf life of the product
  • any implications for safety of the product resulting from the presence of any degradants.

For some substances the weight used in a batch may vary according to its moisture content or according to its potency. Variation of the quantity of active substance, to adjust for potency, may affect the proportions of excipients present in the finished product relative to the nominal formula. In some situations, the manufacturer may opt to compensate for the fluctuations in the weight of raw material by adjusting the amount of a nominated excipient in order to maintain a target weight for the batch. In this case, the following information should be provided regarding the proposed range in quantity:

  • estimated potency and/or water content
  • a formula showing how the amount of adjustment will be calculated
  • an indication of which other excipients will be varied correspondingly, if any, and within what limits

Validation data may be necessary to support a wide range. Such validation data can be generated using 'side batches' (small scale batches or modified portions of production batches) with the formulation or properties (e.g. pH) at the extremes of the proposed range. Validation data may include:

  • compliance with the finished product specifications
  • stability data
  • in some circumstances, comparative dissolution profiles may also be appropriate.

4.2 Modified/sustained release products

Where a product has modified or unusual medicinal release characteristics (e.g. sustained release or enteric coated) or an unusual method of manufacture, the 'Development pharmaceutics' section of the application must include a detailed discussion of product development, and the relationship with the finished product specifications where relevant (e.g. the reasons for choosing a particular dissolution test method and limit). For further guidance see ARGOM Appendix 1 Guidelines on efficacy and safety aspects of OTC applications: Section 10 Modified Release Products.

4.3 Reformulation of existing products

Where a reformulated product is to replace an existing product the changes should be identified. A statement of the reasons for the reformulation should be provided. The application must also include a table comparing the old and new formulations. Where a sponsor wishes to reformulate a product, the impact on the specifications and stability of the reformulated product must be addressed. Stability data generated on the reformulated product are required to support such applications, unless otherwise justified (refer to 'Section 9 Stability of the finished product').

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