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Explanatory note: Draft Guidance on the use of the term 'Quantified by Input' for Listed complementary medicines

Explanatory note to assist in the implementation of the principles outlined in the new draft of 'Guidance on the Use of the Term 'Quantified by Input' for Listed Complementary Medicines'

8 October 2009

This document is part of the consultation Draft Guidance on the use of the term 'Quantified by Input' for Listed complementary medicines and should be read in the context of that consultation.

Since the implementation of the original document 'Guidance on the Use of the Term 'Quantified by Input' for Listed Complementary Medicines' ('QBI guidance document') in January 2007, it has become evident that a number of issues central to its application require further clarification. Therefore the document has undergone extensive review by the TGA in consultation with industry. Although content changes have been largely restricted to an expression of the scope of the document and the provisions of background information, substantial formatting changes have been made to assist in its interpretation. The main points requiring further clarification are outlined below; however the revised document should be read in its entirety to ensure that the context of all revisions is understood.

Lack of clarity in the following areas has been identified by the Therapeutic Goods Administration (TGA):

  • Practical definition of the term 'suitably qualified supplier' and a contract manufacturer's responsibilities with regard to the analysis of raw materials; and
  • Confusion in the use of the term 'rotational testing' and its connection with the concept of quantifying by input as defined by the QBI guidance document.

It is apparent that there is confusion in sectors of the complementary medicines industry as to the overlap between rotation testing programs for raw materials and finished products and the use of QBI with respect to a finished product.

It is hoped that the changes made to the original QBI guidance document will assist in resolving these issues. Additionally, relevant questions have been added to the QBI 'Questions and Answers' supplement.

In Australia, medicines that contain only ingredients that have been approved for use in listed medicines and make only general and/or medium level claims, are eligible to be listed as complementary medicines. Such medicines can then be included in the Australian Register of Therapeutic Goods and are available for supply in Australia as therapeutic goods.

To provide assurance that each batch of a therapeutic good is safe, reliable and of consistent high quality, Australia applies the principle of good manufacturing practice (GMP). This principle is detailed in the 'Australian Code of Good Manufacturing Practice for Medicinal Products' (cGMP). Overseas based manufacturers supplying therapeutic goods to Australia are required to meet an acceptable standard of GMP comparable to that required by Australian manufacturers, although the manner in which this is determined may differ.

In Australia, the Therapeutic Goods Act 1989 requires, with certain exceptions, that manufacturers of therapeutic goods hold a licence. It is an offence, carrying heavy penalties, to manufacture therapeutic goods for human use without a licence unless the manufacturer or goods are exempt from this requirement.

To obtain a licence to manufacture therapeutic goods, a manufacturer must demonstrate, during a factory audit, compliance with manufacturing principles. Overseas manufacturers of therapeutic goods supplied to Australia must provide evidence acceptable to the TGA that the goods are manufactured to a standard of GMP equivalent to that expected of Australian manufacturers of the same goods. If acceptable documentary GMP evidence cannot be provided, the TGA will undertake on-site audits in the same manner as that conducted for the Australian manufacturers. Further information can be found in the document 'Guidance on the GMP clearance of overseas medicine manufacturers', published on the TGA website.

In this context, and in recognition of the low risk nature of listable complementary medicines, a Guide to interpretation of the Australian Code of Good Manufacturing Practice for Medicinal Products (16 August 2002) applicable to the manufacture of complementary medicines was developed and has been available on the TGA website since 2003.

In addition to this, the 'QBI guidance document' has been available to industry since January 2007. The intention of this document was to assist manufacturers in identifying situations where there was difficulty in complying with the GMP requirement that all active ingredients in medicines be tested to confirm that the content complies with prescribed standards.

To further assist manufacturers of complementary medicines to apply the principles of QBI, a comparison of the requirements of the cGMP for different types of medicines is provided in Table 1 below.

Major GMP concessions to this section of the industry are in the areas of active material suppliers, process validation, finished product testing, air handling and equipment cleaning. Please note that the latter two points are strictly GMP issues and are not relevant to a discussion of QBI.

Shaded areas of the table indicate areas where concessions to the strict interpretation of the cGMP have been recognised by the TGA. For all relevant details, please consult the footnotes.

As can be seen, although active raw materials for complementary medicines are able to be obtained from suppliers who may not have a TGA GMP licence or a GMP clearance, acceptance testing of the material must be performed by a TGA licensed or approved manufacture. If a quantitive claim for an ingredient, or component in an ingredient, is made for a finished product, the assay of that ingredient, or component is considered a critical testa. Once this testing has been performed, the finished product manufacturer may be able to justify the application of QBI to that ingredient / component in the product. Conversely, a finished product manufacture may not QBI an ingredient / component in a medicine, for which a quantified claim is made in the finished product, if that ingredient / component has not been assayed in the raw material by a TGA licensed or approved manufacturer.

a For guidance on the determination of critical tests and sampling and testing protocols, please refer to the Technical Guidance on the Interpretation of Manufacturing Standards 'Sampling and Testing of Complementary Medicines' document developed by the Office of Manufacturing Quality, TGA.

Table 1: Comparison of GMP requirements for different types of medicines
GMP requirement Prescription Medicines - Sterile Prescription Medicines
Non-sterile
OTC Medicines Complementary Medicines
All APIs must be made by a manufacturer with a TGA licence or a valid clearance YES YES NO6 NO6
Supplier qualification of the API required YES1 YES1 YES1 YES7
Reduced sampling permitted for the API NO YES4 YES4 YES4
API and finished product specifications must be pre-approved by the TGA YES YES YES NO
Acceptance testing for the API must be carried out by a TGA licensed or approved manufacturer YES YES YES YES
Rotational testing of the API NO2 YES5 YES5 YES8
Testing of all active ingredients in each batch of medicine YES YES YES NO9
All tests included on the finished product specification to be carried out for each batch of medicine before release YES3 YES3 YES3 NO10
Manufacturing process must be prospectively validated for each product YES YES YES11 NO12

Notes:

  1. Usually involves on-site inspection by the finished product manufacturer or a competent party (e.g. sister company or the head office).
  2. In certain cases this may be allowed but would require pre-approval from TGA.
  3. In certain cases rotational testing may be carried out but this would require pre-approval from TGA.
  4. After appropriate validation of the manufacturer and supplier(s) of the API has been performed.
  5. Must be pre-approved by TGA; all critical tests must be performed for all deliveries; all other tests included in the specification must be performed at defined intervals.
  6. Single APIs may not always need to meet this requirement.
  7. A paper based evaluation (desk top audit) is accepted. An on-site inspection by the finished product manufacturer is not usually required.
  8. Does not require pre-approval from TGA; all critical tests must be performed for all deliveries; all other tests included in the specification must be performed at defined intervals.
  9. QBI is permitted when justified.
  10. QBI is permitted when justified; rotational testing may be applied without pre-approval.
  11. Some grouping of products may be allowed on a case by case basis.
  12. Validation can occur concurrently for groups of products.

Manufacturers are required, under the cGMP, to only purchase starting materials from approved suppliers and to test each material to confirm that it is of acceptable quality. However, once a particular supplier has been appropriately qualified and established an acceptable history of supply, the use of rotational testing may be justified. Technical guidance on the implementation of these principles is available in the Sampling and Testing of Complementary Medicines technical guidance document published on the TGA website by the TGA Office of Manufacturing Quality.

In some instances (e.g. fish oils, standardised herbal extracts), where starting materials are subject to rotational testing and an assay of a component is not scheduled to be performed, the material could be quantified by input with respect to the amount present in the finished product. This can only occur if no associated quantitative claim is made for the component in the medicine. For example, a standardised herbal extract that is used in the formulation of a medicine which does not make a quantitative claim for the standardised component, may be on a rotational testing program where the assay is not performed for every batch of material. In this instance, the herbal material would be noted on the certificate of analysis for the finished product as 'Quantified by input'.

The application of a rotational testing program to a finished product may occur for other reasons. For complementary medicines this can occur without prior approval from the TGA. Where the assay for the ingredient/component in the raw material has been performed by a TGA licensed or approved manufacturer, the manufacturer of the finished product may choose to perform the assay of the ingredient/component in the medicine on a rotational basis. In these cases, the Certificate of Analysis for that batch of medicine would include the statement 'Quantified by input - part of a rotational testing program', or words to that effect. Please note that sufficient testing to assure the quality of the medicine must be performed.

You will note that the headings of a number of paragraphs in the guidance document have been amended to include the word 'batch'. This change was made to provide consistency within the document and clarity with regard to the use of rotational testing.

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