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ARGOM Appendix 2: Guidelines on quality aspects of OTC applications

Version 1.1

30 May 2014

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5. Manufacture of the medicine

5.1 Status of manufacturer(s)

5.1.1 Medicine

Where Australian manufacturers are nominated in an application, each manufacturer must be licensed by the TGA to perform manufacturing of the type proposed. The manufacturer's licence carries details of the types of manufacture permitted under the licence.

Where a product is imported, each nominated overseas manufacturer is required to comply with the equivalent standard of GMP as would be required of an Australian manufacturer. GMP clearance of overseas manufacturers by the TGA is required.

The TGA website contains information regarding the manufacture of therapeutic goods; and details of the information required to establish the standard of an overseas manufacturer and the procedure for GMP clearance.

5.1.2 Excipients

For excipients in OTC medicines, evidence of licensing or approval of the excipient manufacturer is not required. Information regarding requirements for control of excipients is included in 'Section 6 Control of excipients'.

5.1.3 Intermediate products

Intermediate products are partly processed materials which must undergo further manufacturing steps before they become final medicines. Where an intermediate product is purchased already manufactured and its manufacture is considered a significant step in the manufacture of the medicine [e.g. a tablet granulation, an active pre-mix (see also 'Section 2.1 Manufacturer of active substance(s)'), or a vehicle for a topical product], evidence of licensing or approval of the manufacturer will be required (irrespective of whether it is a proprietary ingredient).

Where the manufacture of an ingredient that is a mixture is not considered a significant step in medicine manufacture, GMP evidence is not required (e.g. most colours, printing inks, flavours and fragrances, and proprietary ingredients whose sole purpose is as a source of the preservative system for the medicine).

5.2 Manufacturing information

The following information must be provided:

  • The steps of manufacture undertaken at each manufacturing site. A manufacturing site must be nominated for each of the following steps; the manufacture of the dosage form, packaging and labelling, chemical and physical testing, microbial testing, release for supply and, for sterile products, sterilisation.
  • A brief outline of the method of manufacture. This should preferably include a flow diagram or chart showing steps in the manufacturing process, including filling, packaging and in-process controls. Sponsors and manufacturers must ensure that all steps in manufacture comply with the Code35 of GMP (or in the case of overseas manufacturers, with an acceptable standard of GMP comparable to that required for Australian manufacturers).
  • Details or an assurance regarding the validation of the manufacturing process. The extent of information required depends on the nature of the product (see 'Section 5.2.1 Manufacturing process validation' below).

  1. The 'Code' is defined in the Therapeutic Goods (Manufacturing Principles) Determination No. 1 of 2009. Links to the Code of GMP can be found at Australian code of good manufacturing practice for medicinal products

5.2.1 Manufacturing process validation

The manufacturing process must be validated in accordance with the requirements of GMP. The document Note for Guidance on Process Validation (CPMP/QWP/848/96) contains useful additional information.

The manufacture of the following 'higher risk' OTC products requires particular attention to manufacturing process validation:

  • Microdose products (solid oral dosage forms where the active ingredient is present in an amount of less than 2mg or 2% w/w of the dosage form).
  • Sterile products.
  • Products with a sustained release characteristic (not including enteric coated products).
  • Metered dose inhalers.
  • Novel dosage forms.
  • Nasal corticosteroids

Note: 'higher risk' in this context means that there are likely to be critical parts of the manufacturing process for which inadequate control could have adverse consequences for the safety and/or efficacy of the finished product [see also Annex II to Note for Guidance on Process Validation (CPMP/QWP/848/96) and EMEA/CVMP/598/99 Non Standard Processes (CPMP/QWP/2054/03) available on the TGA website].

For the above products, the following information should be provided:

  • The type of validation (for these products, prospective validation would usually be expected).
  • The critical steps in manufacture and acceptance criteria for these steps.
  • A summary of the manufacturer's process validation report including the manufacturer's analysis and conclusions.
  • For microdose products, the full validation report should be provided.
  • For sterile products, the expected validation information is outlined in module 3.2.P.3.5 of the CTD.

Note: Batches should normally be full production scale. However, pilot scale validation data [normally at least 1/10th of the proposed production scale, as defined in Note for Guidance on Process Validation (CPMP/QWP/848/96)] may be acceptable if the sponsor can demonstrate that pilot scale data will be predictive of production scale.

For other OTC products it will be sufficient to provide a written assurance that the manufacturing process has been validated on two or three production scale batches according to the requirements of the Code of GMP, or that the process will be validated as detailed below.

Where a manufacturing process has not been fully validated on production scale batches at the time of approval of a new medicine, the sponsor should provide a written assurance that the manufacturing process will be validated, consistent with the requirements of the Code of GMP, for the first two or three production scale batches, and also provide an assurance that the manufacturer's validation reports on these batches will be made available, if requested for review by the TGA, within three months of release of the batches. The performance of this validation will be made a condition of registration of the medicine.

5.3 Batch to batch variations in quantities of certain excipients

In accordance with the principles of GMP and with the goal of minimising batch to batch variation in stability (and bioavailability), all batches should be manufactured to the nominal formula without variation. To this end, thorough product development studies and process validation studies should be undertaken.

However, it is recognised that it may sometimes be necessary to vary the quantities of certain excipients from batch to batch in order to achieve acceptable results during the manufacturing process.

Changes to the nominal amounts of certain excipients that are in conformity with the table below will not be regarded as changing the product's registered details and need not be referred to the TGA. It is expected that appropriate validation studies will be performed and that the results will be available on request or during the course of GMP inspections.

Table 5.1 Nominal amounts of certain excipients.
# Excipient type Acceptable range
1 pH adjusting ingredients qs*
2 Volume adjusting fluids qs
3 Quantity of ingredients whose function is to contribute to viscosity ± 10%
4 Colour in tablet coating (but not in body of tablet) qs
5 Solvent in granulating fluid qs
6 Granulating fluid (fixed composition) ± 10%
7 Disintegrant (even if the excipient serves more than one role in the formulation) to +25%
8 Coating solution qs**
9 Talc and water soluble lubricants and glidants -25% to +100%
10 Water insoluble lubricants and glidants except talc (e.g. magnesium stearate, stearic acid) ± 25%
11 Filler (bulking agent) in hard gelatin capsules ± 10%

*Definition of 'qs': As much as is needed to bring the quantity up to its target measurement or specification.

**Does not apply to modified release products - approval is required for any variation from the registered formulation.

Prior approval of the TGA is required if a batch or batches are manufactured outside the ranges specified in the above table or the ranges approved by the TGA for the product. Where there is a repeated need for variation outside the allowed ranges an application to change the formulation should be submitted.

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