Stability testing of Listed complementary medicines

Questions & answers

1 April 2004

The following sections must be read in conjunction with the relevant parts of the Australian Regulatory Guidelines for Complementary Medicines (ARGCM) and 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 in relation to stability testing of herbal and certain other Listed complementary medicines, recognises the differences between these types of therapeutic products and pharmaceutical products that usually contain a single, chemically defined, active. The approach also recognises the technical difficulties that may be associated with stability testing of complex multi-ingredient complementary medicines.

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.

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The sponsor of the goods is responsible for these matters. The sponsor must ensure that stability data exists to support the shelf life. The shelf life must be based on scientific data. TGA may check the data through the usual regulatory mechanisms.

Stability testing is necessary to ensure the product is of acceptable quality throughout its entire storage period. In order to do this, it is necessary to monitor compliance of the product with a suitable quality specification throughout the shelf life. It is not acceptable to only test at the time of expiry, for example, on a retention sample (even though the results of this type of testing may provide useful information about the overall stability of the product).

Most often, the content of active ingredients and/or components and relevant physical properties of the product are monitored during storage under defined conditions using methods capable of detecting deterioration or degradation. Consult the Australian Regulatory Guidelines for Complementary Medicines (ARGCM) Part II Section 5.2.10 for detailed information.

Ideally, all those with a label claim should be monitored. However, this may not always be achievable. Refer to Q4 below.
It may not be possible to check the stability of all active ingredients in a multi-ingredient complementary medicine. In such cases, studies which force the sample to degrade, for example, with heat, to allow identification of changes taking place that may then be used as stability indicators for the product. With adequate experience of product formulations and their stability, it may be possible to group ingredients and to selectively monitor for a smaller number of ingredients.

Provided it can be justified, stability studies on mineral salts and their derivatives that are included as active ingredients may not be required. However, organo derivatives of minerals, such as selenomethionine and chromium picolinate are not as stable as inorganic salts and should be treated as labile ingredients.

NB. Where the efficacy is believed to be associated with an element in a particular oxidation state, for example, ferrous salts, evidence should be held to show that the element remains in this oxidation state during the shelf life of the product.

Only methods that are validated as being stability indicating ie. ones that are capable of detecting changes in the composition or properties of the product. These are usually chemical and physical/organoleptic.

Yes. The TGA recognises the technical difficulties that may be associated with stability testing of complex multi-ingredient complementary medicines.

Accordingly, the shelf life of a Listed complementary medicine may be determined by reference to stability studies performed on a similar product. A sponsor using this option must hold evidence to justify the applicability of the data from a similar product. In using data from another product, stability data for the comparator must have been obtained using a protocol consistent with the principles elaborated in the Australian Regulatory Guidelines for Complementary Medicines (ARGCM) Part II Section 5.2.10. However, stability data for the product in its market packaging should also be obtained as part of a manufacturer's on-going stability program (see Q13 below).

If at the time of Listing the product on the ARTG, complete stability data are not available the sponsor may make a judgement on an interim or abbreviated shelf life. The judgement must be supported by evidence and may be used until the results of stability testing are available.
In the case of non-standardised herbal products containing a herbal ingredient(s) where there is no identified active component(s), it may be acceptable to monitor physical changes. For example, physical appearance, disintegration time, as well as changes to the overall chromatographic profile of the product (see ARGCM Part III Section 4.7 Profile Chromatograms and Part II Section 5.2.10 Finished Product Stability).

Generally, a 'change' to a herbal ingredient would be one in which a component changes by more than 10 percent. However, in some cases, such as epoxides in essential oils, this magnitude would be excessive. Sponsors are responsible for determining the content of their finished product specification. The specifications may be based on, but not limited, to those given in official standards (eg. BP, TGO's).

NB. In the case of Listed products containing herbal ingredients that are standardised to a particular component, it is necessary to monitor the component throughout the stability trial. A change of more than 10 percent in the standardardised component is undesirable and requires justification. In addition, the chromatographic profile and any other relevant tests should be monitored (as for non-standardised herbal products above).

The sponsor must decide on the significance of any changes in the chromatographic profile, to the quality, safety or efficacy of the product and take appropriate action.
A minimum of two production batches should be used. Pilot scale batches can be substituted as an interim measure. Accelerated stability testing is acceptable. However, full term data at the nominated storage temperature should be collected.
Sponsors must ensure that there is data or justification to support the stability of the product when there are changes in manufacturer, supply of ingredients, manufacturing process, etc.

It is assumed the chromatographic procedure has been fully validated. This will minimise any system variations. However changes in, for example, equipment performance and chromatographic column characteristics can still occur and for this reason it would be advisable to store a sample of the product under conditions that will minimise degradation (eg. in a refrigerator), and use this as a comparator at the different time stations during the trial. Where thin layer chromatography (TLC) is used, it may be possible to collect and store a digital image of the chromatographic plate at the start of the trial and use this as a reference throughout the remainder of the trial. Once again, however, the TLC procedure should be fully validated to ensure consistency between time stations.

Further information is included in the Australian Regulatory Guidelines for Complementary Medicines (ARGCM) / Australian Regulatory Guidelines for OTC Medicines (ARGOM) guidance documents.