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Q&A: Draft Guidance on the use of the term 'Quantified by Input' for Listed complementary medicines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This document is part of the consultation Draft Guidance on the use of the term 'Quantified by Input' for Listed complementary medicines and should be read in the context of that consultation.

The following Questions and Answers on the use of "Quantified by Input" (QBI) must be read in conjunction with the Draft Guidance on the Use of the Term Quantified by Input for Complementary Medicines, the relevant parts of the Australian Regulatory Guidelines for Complementary Medicines (ARGCM) and the references cited therein.

The Questions and Answers that follow are intended to provide additional guidance to sponsors and manufacturers of complementary medicines. The approach taken by TGA to permit the quantification of low risk ingredients in a finished complementary medicine, by input, recognises the technical difficulties that may be associated with quantifying certain ingredients in multi-ingredient products.

A sponsor of a medicine has ultimate responsibility for the product. An authorised person1, in releasing the product for supply, must ensure (among other requirements) that the product label, manufacturing formula, and specifications are consistent with the entry in the Australian Register of Therapeutic Goods (ARTG). Sponsors should refer to the Guide to interpretation of the Australian Code of Good Manufacturing Practice for Medicinal Products (16 August 2002) applicable to the manufacture of complementary medicines.

1 Authorised person(s): Person(s) recognised by the TGA as part of manufacturing licensing as having the necessary basic scientific and technical background and experience to release each batch of product for supply and to certify that it is in accordance with the requirements of the marketing authorisation. The Authorised person may be a consultant licensed by the TGA to release product for supply.

1. Should a new formulation (product) be produced that uses QBI for an ingredient, or a component in an ingredient, in the product without a QBI justification having been completed prior to launch?

NO: Clause 4.13(e) of the Australian Code of Good Manufacturing Practice for Medicinal Products (16 August 2002) requires, inter alia, that prior to release for supply, a finished product must meet the specified qualitative and quantitative limits. In the case of complementary medicines, this may be accomplished by QBI (see Guide to interpretation of the Australian Code of Good Manufacturing Practice for Medicinal Products (16 August 2002) applicable to the manufacture of complementary medicines). It is important, when developing a new product, to ensure that justification of the use of QBI for any component, or ingredient, is included as part of development, including verification of a starting material supplier's competency to provide a valid assay result.

2. In the case of a finished product containing a herbal extract, where no quantitative claim is being made for a component in the extract:

  1. Is it appropriate to state on the Certificate of Analysis, "Not assayed. Quantified by Input"? and
  2. Do I have to do a profile test for QBI release?
  1. YES: provided the ingredient or component of the ingredient is not referenced in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP), or not otherwise restricted.
  2. ii. NO: profile testing is considered to be an identity test and identity tests are not relevant to QBI. The identity of each ingredient should be assured before it is used in manufacture.

3. A generic test method has been validated for a particular active ingredient in a defined group of products, but has not been fully validated for the assay of the ingredient in a new product. The method gives expected and reproducible results for the active in batches of the new product. Can the result of the assay of the active be included on a Certificate of Analysis for that batch of the finished product, or should the ingredient be declared as QBI because the test method has not been fully validated for the active in this product?

NO: the analytical result cannot be included on the Certificate of Analysis for that batch. Validation needs to be performed to confirm the validity of the test method when applied to the new product. See guidance document Finished Product (Medicine) Analytical Procedure Validation. A QBI statement may only be used for the ingredient if it meets QBI guidance criteria. That is, there is written justification that a validated assay method is not available for the ingredient or component in the finished product. Otherwise a validated analytical test method must be applied.

It should be possible to validate an analytical method for a group of products, provided the grouping justification is scientifically sound and defendable. In this case the justification should be documented. The information may be reviewed by an auditor during a GMP audit or by the Post Market Review Section (PMRS) of the Office of Complementary Medicines (OCM) during a review.

Note: It is expected that each laboratory will have a Standard Operating Procedure (SOP) for assay validation. This could include reference to the TGA or other validation guidance document. Laboratories are expected to follow their SOP to develop a valid assay method.

4. (a) In terms of equipment, level of knowledge and cost, how much effort should be made to develop a valid assay for an active in a finished product2?

There are a range of techniques that most laboratories would be expected to have available or have access to. These techniques would be expected be consistent with those generally used for quality assurance in pharmacopoeial monographs. The use of novel or highly specialised technologies is not expected for testing complementary medicines.

It is expected that analysts will have a full working knowledge of the equipment and its capabilities, and the operators in a company should be able to develop new methods using the equipment. Preferably, there should be a SOP for the development of new assay methods which includes searching the relevant literature. For example, when using an HPLC assay method, if appropriate markers, reference compounds and columns are reasonably available, then these should be used. It would not be acceptable to justify the use of QBI because the HPLC conditions could not be varied sufficiently to produce a valid assay.

2 The TGA is working with industry to develop a list of ingredients, components and matrices where experience has established that a validated assay is not feasible.

4. (b) In the interim, can QBI be used?

NO: this is not acceptable practice for either an existing or new product (see also 1. above).

As the question of whether or not QBI is appropriate for a particular ingredient should be part of product development, the relevant decisions should be made before generation of a Certificate of Analysis. Therefore, written justification for use of QBI should be developed and included with product specifications. Although this involves the manufacturer, the sponsor is still ultimately responsible for the product and is required to obtain such details from the manufacturer prior to commencement of supply.

5. Does the QBI guideline apply to both Listed (AUST L) and Registered (AUST R) complementary medicines?

QBI generally applies to Listed complementary medicines. However, the use of QBI for a Registered complementary medicine could form part of the TGA registration application / evaluation process where, in certain instances, the principles may be able to be applied.

6. In some situations, the use of QBI for an ingredient, or a component in an ingredient, is subject to a validated limit test3 (see footnote 2 in the Flowchart). However, the limit test has not yet been validated for the product containing the ingredient/component. What must be done4?

The limit test must be validated before QBI can be used.

3 A 'limit test' is a semi-quantitative assay for an analyte in a product. It should be developed with suitable specificity, precision and accuracy, but it is not expected to provide an exact value.

4 The TGA is working with industry to develop a list of ingredients, components and matrices where a validated limit test has been established.

7. (a) Can QBI be used if a manufacturer states that they cannot perform a validated limit test on a restricted component in the finished product?

YES: if the level of the restricted component in the herbal extract has been tested by a TGA licensed or approved manufacturer AND the level has been shown to be acceptably low. In all cases, some testing must be performed on each batch of the finished product. That is, sufficient testing should be carried out to provide assurance that importantly, the medicine is safe, and of intended quality.

7. (b) Can QBI be used if a manufacturer states that they cannot perform a validated assay of the standardised component of a herbal extract in a finished product?

YES: if the potency of a standardised component has been tested by a TGA licensed or approved manufacturer. In all cases, some testing must be performed on each batch of the finished product. That is, sufficient testing should be carried out to provide assurance that importantly, the medicine is safe, and of intended quality.

8. My manufacturer is using a herbal extract that is standardised to a particular component. However, I am not relying on that component in my claim substantiation, nor is it included on the product label or in my Electronic Listing Facility application. Do I have to assay the component if no quantitative claim is being made?

NO: it is not subject to QBI requirements, because no claim is included in the Australian Register of Therapeutic Goods (ARTG) or made on the label for the standardised component in the herbal extract that is used in the finished product.

9. In the case of an ingredient that is not subject to restrictions, may I choose whether to quantify the ingredient by input or to include the ingredient as part of a rotational testing program?

NO: rotational testing and QBI are based on separate principles. If a valid assay is available for the ingredient in the finished product, this testing must be performed. It is possible that a rotational testing program maybe implemented, with appropriate justification. In this case, for specific batches, the ingredient may be noted on the certificate of analysis as 'Quantified by input - part of a rotational testing program'. Conversely, if a valid assay is NOT available, and other relevant criteria are met, the ingredient may be able to be 'Quantified by input' in the finished product. The use of QBI is based on the inability to assay the ingredient at all.

10. When using rotational testing, can the testing laboratory (or the sponsor) select a particular active(s) to be tested from all eligible actives that might be rotationally tested?

NO: rotational testing is the performance of specified tests on pre-selected batches and/or at predetermined intervals, rather than on a batch-to-batch basis. A predetermined rotational testing program for all relevant actives should be applied. This is undertaken with the understanding that those batches not being tested still must meet all acceptance criteria established for that product. It is inappropriate to always test the same active(s) from a list of rotationally tested actives. Under a rotational testing program, manufacturers and/or sponsors can require additional testing of an active for any reason, for any batch, containing that active.

11. What is meant by a validated assay method and a valid assay result?

A valid assay result is one that has been obtained using a validated assay method. As a minimum, a validated assay method for an active ingredient in a finished product is one that meets the requirements of the TGA's Finished Product (Medicine) Analytical Procedure Validation guideline.

A valid assay result may be in or out of specification. Batches out of specification may be acceptable in certain circumstances - where they are in accordance with the ARTG record of the product and all deviations and 'out of specification' results have been satisfactorily addressed. This is auditable.

12. Is there standard template that can be used for a QBI justification statement?

NO: but there are certain essential elements that should be included in QBI justification documentation. Documentation should be appropriately authorised. As a minimum, the following information should be included:

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