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Guidance on the use of the term 'Quantified by Input' for Listed complementary medicines

8 June 2005

This document was developed in order to provide guidance on the appropriate criteria for permitting quantification by input as an alternative to performing an assay for the content of an active ingredient(s) in a complementary medicine during batch release testing.

Guidance development

Following acknowledgment of the need to provide guidance on this issue, a draft document was prepared by the Australian Regulatory Guidelines for Complementary Medicines (ARGCM) Consultation Group with input from the TGA. The draft document was made available for public comment and circulated to the industry associations requesting comment on behalf of their members.

The ARGCM Consultation Group reviewed the comments received from industry and amended the document to reflect necessary changes.

In August 2004, the guidance document was updated to include additional information for sponsors in regard to implementing the requirements for 'Quantified by Input'.

This revised version (May 2005) incorporates guidance for sponsors in regard to the use of validated limit tests.

'Quantified by Input'

The issue of use of the term 'Quantified by Input' on certificates of analysis has been raised by the TGA's Manufacturer Assessment Section (MAS) (formerly the GMP Audit and Licensing Section (GMPALS)) and referred to the Office of Complementary Medicines (OCM) for consideration. In addition, complementary medicine manufacturers have requested clarification over the requirement to assay certain ingredients in complementary medicines. These matters raise questions as to what are the circumstances under which the practice of 'quantified by input' is appropriate and what terminology should be used on certificates of analysis where this practice has been applied?

To ensure compliance with batch release specifications it is best practice to assay all batches of all finished products for the content of active ingredient(s). However, the TGA realises that this may be difficult with some complementary medicines. In recognition of this, the attached document sets out the conditions where manufacturers may not be required to perform an assay on an active ingredient (or a component in the active ingredient) in complementary medicine products.

Scope

This guidance does not extend to medicines other than complementary medicines nor is it applicable to other medicines containing a complementary medicine component.

Implementation

To allow sufficient time for manufacturers to change their recording systems, the implementation of the principles outlined in this guidance document will be phased in over a two-year period commencing on 1 January 2004. An additional one-year phase-in period will be allowed for the development of justifications for not assaying active ingredients in finished products.

Manufacturers who wish to quantify an active ingredient(s) in a finished product using 'quantified by input' are expected, as of 1 January 2004, to begin the development of a justification for not assaying the ingredient(s) in the finished product. They should not wait until the end of the phase-in period (1 January 2007) before developing a justification for not performing an assay. Consistent with the principles and guidance in this document and irrespective of the phase in period, some active ingredient testing must be performed on each batch of the finished product where a quantitative claim is made on the label. That is, there must be sufficient testing to provide assurance that the product is of intended quality (see Flow Chart).

The TGA acknowledges that justification, validation and implementation of an alternative procedure may take some time. Provided a manufacturer can demonstrate progress in developing a justification for using 'quantified by input' to a MAS auditor, or in a response to request from the TGA as part of its post-market surveillance program, then this would be considered an acceptable interim measure for not performing an assay. This approach would be particularly applicable for manufacturers with an extensive product range. Documentation should be available showing a schedule for introducing 'quantified by input' together with progress against the schedule.

In justifying the use of 'quantified by input' and for not undertaking an assay, the issue of what is a reasonable attempt at performing an assay is difficult to judge with objectivity. It may often be a subjective judgement as to whether the justification for not assaying is sufficient. Such cases will be resolved through discussion between the manufacturer and the TGA.


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Guidance on the use of the term 'Quantified by Input' for Listed complementary medicines

Scope:

This guidance document describes the criteria under which a manufacturer of a complementary medicine is not required to assay an active ingredient in a finished complementary medicine product. The document also provides the wording that a manufacturer should use on a certificate where an active ingredient has been 'Quantified by Input'. An active ingredient is defined in Section 52F of the Therapeutic Goods Act 1989 as "the therapeutically active component in a medicine's final formulation that is responsible for its physiological or pharmacological action." The guidance provided in this document does not override or replace the need to comply with all relevant statutory requirements. This guidance does not extend to medicines other than complementary medicines nor is it applicable to other medicines containing a complementary medicine component.

Principles:

The manufacture of complementary medicine products must be undertaken in a facility that is deemed by the TGA to have an acceptable level of Good Manufacturing Practice (GMP). Consistent with the TGA's risk-based approach to the regulation of medicines, it may be possible to justify some situations where the assay of an active ingredient in every batch of finished product is not necessary. In such situations, the content of active ingredient may be estimated from the amount dispensed during the manufacture of the product. This practice is termed 'Quantified by Input'. However, based on risk, it is not appropriate to apply this practice to all ingredients.

Ingredients that are associated with higher potential risk include those referred to in a schedule (see Note 1) of the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) or those restricted by inclusion in Schedule 4, Part 4, Divisions 1 and 2 or Schedule 4, Part 5, Division 2 of the Therapeutic Goods Regulations 1990 (the Regulations). Such ingredients should be assayed in the finished product (note that in some circumstances, where justified, rotational testing, or performance of a validated limit test, may be acceptable). For other ingredients, the practice of 'Quantified by Input' for an ingredient in a complementary medicine product may be acceptable, provided it can be justified on the principles outlined below (see Note 2).

Determining the requirement for assay of an active ingredient in a complementary medicine (refer to accompanying Flow Chart)

Based on the requirements described below, manufacturers can determine whether an active ingredient (or a component in an active ingredient) in a complementary medicine must be assayed in each batch of product.

A. Ingredients required to be assayed in a complementary medicine product:

Subject to the exceptions described in the accompanying Flow Chart, ingredients, or components in an ingredient, should be assayed in the finished product if they are:

  • referred to in a schedule of the SUSMP (see Note 1); or
  • restricted by inclusion in Schedule 4, Part 4, Divisions 1 and 2 or Schedule 4, Part 5, Division 2 of theRegulations .

Although the ingredient should be assayed in the finished product, rotational testing may be acceptable. The practice of rotational testing must be justified, and supported by documentation.

The use of a validated limit test may provide an acceptable level of assurance that a particular ingredient or component in an ingredient is present at a level which would exclude the product from inclusion in a schedule of the SUSMP or inclusion in Schedule 4, Part 4, Divisions 1 and 2 or Schedule 4, Part 5, Division 2 of the Regulations (see Note 3).

Where rotational testing is employed, the ingredient should be declared on the certificate for the finished product as 'Quantified by Input. This ingredient is part of a rotational assay program and was not assayed for this batch' (or words to this effect*).

* Any alternative wording must clearly indicate that an assay of the ingredient in the finished product has not been performed.

B. Ingredients that may not be required to be assayed in a batch of complementary medicine product:

Ingredients, or components in an ingredient, that are:

  • not referred to in a schedule of the SUSMP (see Note 1); or
  • not restricted by inclusion in Schedule 4, Part 4, Divisions 1 and 2 or Schedule 4, Part 5, Division 2 of the Regulations; or
  • not referred to quantitatively in the documentation for the raw material or for the product; may not have to be assayed in each batch of the finished product subject to the following:

Where a quantitative statement is made in the documentation for the product and the active ingredient supplier's competency to provide a valid assay result for the active ingredient has been verified (see Note 4), then the assay of the ingredient in the finished product need not be performed. Inclusion of this ingredient in a rotational testing program should be considered. However, at all times, sufficient testing should be carried out on each batch to provide assurance that the product is of intended quality.

Single active ingredient products should be tested using a validated assay technique. If there is no valid assay available for the active ingredient in the product, some form of identification testing should be undertaken and the ingredient marked as 'Quantified by Input'.

For products containing multiple active ingredients, at least one active ingredient (selected from those ingredients that have valid assays in the product) should be assayed. The remaining active ingredients can be assayed or marked as 'Quantified by Input' as required by the manufacturer's testing program.

If the above conditions are satisfied, then the ingredient 'Quantified by Input' should be marked or referenced on the certificate as appropriate as:

'Not assayed. Quantified by Input' or 'Quantified by Input. This ingredient is part of a rotational assay program and was not assayed in this batch' (or words to this effect*).

Where a quantitative statement is made in the documentation for the product, the supplier's assay value for the active ingredient has NOT been verified and a valid assay for the ingredient in the finished product is not available, then an assay of the ingredient should be performed at input by the manufacturer of the finished product before the practice of 'Quantified by Input' can be used.

In this situation, the ingredient 'Quantified by Input' should be marked or referenced on the certificate as:

'Not assayed. Quantified by Input' (or words to this effect*).

If the supplier's assay value for the active ingredient has NOT been verified, and a valid assay for the ingredient in the finished product is available, then the ingredient should be assayed in the finished product.

* Any alternative wording must clearly indicate that an assay of the ingredient in the finished product has not been performed.

Implementation:

To allow sufficient time for manufacturers to change their recording systems, the implementation of the principles outlined in this guidance document will be phased in over a two-year period commencing on 1 January 2004. An additional one-year phase-in period will be allowed for the development of justifications for not assaying active ingredients in finished products (see Note 5).

Notes:

Note 1: The word 'referred' means mentioned in a schedule and not simply restricted by a schedule unless the reference is to an ingredient or component of an ingredient that is fully excluded from the scope of the statement in the schedule. For example, Vitamin D preparations are referred to in the SUSMP for internal human therapeutic use, although Vitamin D preparations containing 25 micrograms or less of Vitamin D per recommended daily dose are not subject to restrictions in the SUSMP. Therefore Vitamin D is required to be assayed in the finished product unless otherwise justified (see A - 'Ingredients required to be assayed in a complementary medicine product', above).

In instances where reference to an ingredient in a schedule of the SUSMP or in Schedule 4, Part 4, Divisions 1 and 2 or Schedule 4, Part 5, Division 2 of the Regulations only relates to a requirement for a warning statement (e.g. Hypericum perforatum in Schedule 4, Part 4, Division 2 of the Regulations; pyridoxine in schedule 4 of the SUSMP), that ingredient may, subject to the principles of this document, be eligible for quantitation by input (see B - 'Ingredients that may not be required to be assayed in a batch of complementary medicine product' above).

Note 2: Where a manufacturer intends not to assay an active ingredient in a batch of a complementary medicine it must be supported by written justification. This justification may be reviewed at a TGA GMP audit of the manufacturer or by the Office of Complementary Medicines (OCM).

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

The use of a validated limit test may provide an acceptable level of assurance that a particular ingredient or component in an ingredient is present in a product at levels consistent with low risk and, subject to the principles of this document, be eligible for quantitation by input. In instances where restrictions in the SUSMP or in Schedule 4 of the Regulations apply to an amount of a ingredient or component of an ingredient in a recommended daily dose, the application of a limit test will require knowledge of the recommended dose. In instances where this is not known, manufacturers should liaise with the product's sponsor to ascertain this information. For example, folic acid is included in schedule 2 of the SUSMP unless present at 500 microgram or less in the recommended daily dose.

Note 4: For the purpose of validating the active ingredient supplier's assay result, the manufacturer of the finished product must hold documentary evidence that the assay values supplied with raw materials have been verified. This would normally involve testing several delivery lots as part of a vendor certification program. Delivery lots of such raw materials may or may not be assayed upon receipt depending on the quality program in place at the time of receipt. However, an assay result of the raw material must be available within the quality program used by the manufacturer. For further information on this subject, please refer to the Australian Code of Good Manufacturing Practice for Medicinal Products – Questions & Answers page on the TGA website.

Note 5: Manufacturers who wish to quantify an active ingredient(s) in a finished product using 'Quantified by Input' are expected, as of 1 Jan 2004, to begin the development of a justification for not assaying the ingredient(s) in the finished product. They should not wait until the end of the phase-in period (1 January 2007) before developing a justification for not performing an assay. Consistent with the principles and guidance in this document and irrespective of the phase in period, some testing must be performed on each batch of the finished product where a quantitative claim is made on the label. That is, there must be sufficient testing to provide assurance that the product is of intended quality (see Flow Chart).

The TGA acknowledges that justification, validation and implementation of an alternative procedure may take some time. Provided a manufacturer can demonstrate progress in developing a justification for using 'Quantified by Input' to a MAS auditor, or in a response to request from the TGA as part of its post-market surveillance program, then this would be considered an acceptable interim measure for not performing an assay. This approach would be particularly applicable for manufacturers with an extensive product range. Documentation should be available showing a schedule for introducing 'Quantified by Input' together with progress against the schedule.

In justifying the use of 'Quantified by Input' and for not undertaking an assay, the issue of what is a reasonable attempt at performing an assay is difficult to judge with objectivity. It may often be a subjective judgement as to whether the justification for not assaying is sufficient. Such cases will be resolved through discussion between the manufacturer and the TGA

Flow Chart: Determining the requirement for assay of an active ingredient in a complementary medicine

(this does not replace the need to comply with relevant statutory requirements)

Is the active ingredient primarily a single component ingredient?
YES
e.g. a vitamin







NO
e.g. herbal extract
Is a quantitative claim made for any ingredient in the documentation for the product?
YES
e.g. standardised herbal extracts


NO
e.g. shark cartilage with no equivalency statements or a simple herbal extract stated as being equivalent to the fresh herb
Is the ingredient, or a component in the ingredient, referred to in a schedule of the SUSMP or otherwise restricted by its inclusion in Schedule 4, Part 4, Divisions 1 and 2 or Schedule 4, Part 5, Division 2 of the Regulations? The words 'Not assayed. Quantified by Input' (or words to this effect1) may be used on certificates for the finished product.
YES
NO
The ingredient or component should be assayed in the finished product2. Rotational testing may be acceptable where supported by documentation. In such cases, with suitable justification, the ingredient can be quoted on the certificate for the finished product as Quantified by Input. This ingredient is part of a rotational assay program and was not assayed for this batch' (or words to this effect1). Has the supplier's competency to provide a valid assay result for the ingredient been verified?
YES
  NO
Ingredient can be quoted on the certificate for the finished product as 'Not assayed. Quantified by Input' (or words to this effect1). Rotational testing for this ingredient should be considered. In all cases, some testing must be performed on each batch of the finished product. That is, sufficient testing to provide assurance that the product is of intended quality should be carried out. Is a valid assay available for the ingredient in the finished product?
YES
  NO







The ingredient should be assayed in each batch of the finished product.
   
The finished product manufacturer should assay the ingredient at input. The ingredient should be quoted on the certificate for the finished product as 'Not assayed. Quantified by Input' (or words to this effect1). In all cases, some testing must be performed on each batch of the finished product. That is, sufficient testing to provide assurance that the product is of intended quality should be carried out.
  1. Any alternative wording must clearly indicate that an assay of the ingredient in the finished product has not been performed.
  2. The use of a validated limit test to establish that an ingredient, or component in an ingredient, is not subject to inclusion in a schedule of the SUSMP or in Schedule 4, Part 4, Divisions 1 and 2 or Schedule 4, Part 5, Division 2 of the Regulations, may provide suitable justification to permit the ingredient to be 'Quantified by Input'.

About the Therapeutic Goods Administration (TGA)

  • The TGA is part of the Australian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices.
  • The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary.
  • The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices.
  • The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. The TGA investigates reports received by it to determine any necessary regulatory action.
  • To report a problem with a medicine or medical device, please see the information on the TGA website.

Copyright

© Commonwealth of Australia 2005

This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any process without prior written permission from the Commonwealth. Requests and inquiries concerning reproduction and rights should be addressed to the Commonwealth Copyright Administration, Attorney General's Department, National Circuit, Barton ACT 2600 or posted at http://www.ag.gov.au/cca

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