Acceptable Daily Intakes (ADI) list on the net

The ADI List for agricultural and veterinary chemicals is now available through the TGA web site. The List is a compilation of Acceptable Daily Intakes for agricultural and veterinary chemicals used on food producing crops or animals.

An ADI is defined as the daily intake of a chemical which during an entire lifetime appears to be without appreciable risk to the health of the consumer on the basis of the known facts at the time. More detail on the process of establishment of ADIs has been published previously in TGA News (Issue 27, August 1998) and is also contained in the web document.

The ADI List can be accessed, as an Adobe Acrobat pdf file, through the TGA web site.

Chinese herbal medicines in Australian found to contain Aristolichia

On 30 July 1999, the TGA advised complementary healthcare practitioner organisations in Australia of two UK reports of end-stage renal failure associated with Aristolochia in Chinese herbal products labelled as containing Clematis.

The Office of Complementary Medicines (OCM) initiated a survey of products containing Clemati, on the Australian Register of Therapeutic Goods (ARTG) to determine if inadvertent substitution of Aristolochia for Clematis had occurred in products currently supplied to the Australian market. Two of fourteen samples provided as part of the survey and analysed by the TGA Laboratories were found to positively contain the herb Aristolochia. One was raw herbal material and the other a manufactured Clematis product.

All parties should be aware of TGA's position that Aristolochia has no safe application in therapeutic goods. Your attention is drawn to the public safety risk posed by extemporaneous dispensing of this herb. Readers are reminded that Aristolochia is included in Appendix C of the Standard for the Uniform Scheduling of Drugs and Poisons and is considered to be a substance of such danger to health that it is prohibited for sale, supply or use in Australia.

The TGA holds continuing safety concerns for products containing Clematis or Stephania (the latter herb was the subject of contamination by Aristolochia and resultant renal failures in Belgium in 1992). The TGA is investigating processes under the Therapeutic Goods Act 1989 for requiring sponsors of products on the ARTG which contain either Clematis or Stephania to hold valid analytical evidence to show that they do not inadvertently contain Aristolochia.

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CMEC news

Changes to the conditions of listing for goods containing guarana

Paullinia cupana (guarana) is a source of caffeine, but it appears many consumers are not aware of this fact. This may be particularly important for those who wish to avoid caffeine for health reasons. After reviewing the safety of guarana CMEC has recommended two label changes for therapeutic goods containing guarana. The importance of these label changes was recently reinforced by the release of a report by the West Australian Coroner, who had inquired into the death of a young woman following the consumption of a guarana product.

First, the presence of caffeine must be declared in the label. Second, the quantity of caffeine per dosage unit must be stated. Both must be present in a clear and legible format. If a product already has a statement on the label such as "Paullinia cupana y grams, equiv. caffeine x mg", this will be sufficient to meet TGA requirements, provided that it is presented in a clear and legible manner. The statement of quantity may be in the form "contains not more than x mg caffeine per dose".

By the end of 1999, all existing goods containing guarana must be recalled to wholesale level and overstickered with the required information, where necessary. By the end of March 2000 all products available at retail level must meet these requirements. New products must meet the requirements from the time of listing.

Sponsors are advised that, in this particular case only, overstickering can be carried out by companies that do not have a GMP license for labelling, provided that the overstickering is conducted in accordance with GMP principles. This will involve, as a matter of course, label/container reconciliations at the end of the process. Each sponsor will be required to certify to the TGA that they have completed the overstickering and that it has been in accordance with TGA requirements, including GMP principles. The TGA may conduct random audits to check compliance with these requirements.

Sponsors should note that the use of unlicensed manufacturers for additional statements/warnings imposed by TGA is not a standard practice and that each situation will be treated on a "case by case" basis.

Green lipped mussel and cancer

The New Zealand green lipped mussel (Perna canaliculus) has been the subject of recent interest as there have been claims that the mussel and the oil extracted from it can treat cancer. The TGA is not aware of any clinical evidence to show that green lipped mussel, or extracts derived from it, are of any value in the treatment of human cancer. Cancer patients should not rely on this substance for the treatment of their cancer and should seek medical advice before including it in their treatment regime.

There are a number of therapeutic goods available on the Australian market containing green lipped mussel and there is no evidence that sponsors of these products are responsible for these unfounded claims. Under the Therapeutic Goods Advertising Code, claims about cancer treatment or prevention are prohibited in advertisements directed to the public.

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New complementary medicine substances

Nine new complementary medicine substances can now be used as active ingredients in listable therapeutic goods. This brings to 19 the number of new actives permitted since the introduction in April this year of the gazettal process for notifying permitted new substances. The latest group of new substances are:

• Hydroxycitric acid and its sodium, potassium and calcium salts. This will be of benefit to sponsors who wish to use these substances but up until now have been restricted to using extracts of Garcinia species. However sponsors should be aware that the Complementary Medicines Evaluation Committee (CMEC) found no evidence to support any role for these substances in weight loss or weight maintenance in humans;
• Squalene, which is a lipid found commonly in shark liver oil;
• Alfalfa (Medicago sativa) fresh leaf extract (range 34:1 - 46:1 concentrate), provided that the extraction process does not concentrate the amino acid L-canavanine beyond levels present in the fresh herb;
• Kunzea ambigua oil. Sponsors should be aware that Kunzea ambigua, as an Australian native plant, is subject to export restrictions. Environment Australia can provide further details on these restrictions (see article on p8);
• Green lipped mussel (Perna canaliculus) - dried flesh and oil. The TGA has developed compositional specifications for these two substances for the guidance of sponsors. Copies of these specifications are available from the TGA Information Officer.

Changes to Schedule 4 of the Therapeutic Goods Regulations are imminent. These changes, once finalised, will also increase the range of substances that can be used as active ingredients in listable therapeutic goods. The changes are:

• The existing permission to use probiotic bacteria will be replaced with permission to use all members of the genera Lactobacillus and Bifidobacterium, with the exception of the species L. catenaformis, L. uli and B. dentium. Identification of the strain of bacteria used will be required when lodging listing applications, although strain names or numbers do not have to be declared on product labels.
• The current daily dose limit of 3 g for creatine, creatine monohydrate and creatine phosphate will be removed but a label warning statement will be required advising that professional advice should be sought before long-term use.
• Alfalfa (Medicago sativa), previously allowed only as an excipient, will now be allowed as an active ingredient in listable goods, provided that the extraction process does not concentrate the amino acid L-canavanine beyond levels present in the starting material.

Sustained release guidelines - draft for comment

The Office of Complementary Medicines has developed a draft policy statement on the listing of sustained release multivitamin, mineral and herbal products. The document is available on the TGA website or by contacting the TGA Information Officer. While the comment period closed on 19 December 1999, late comments may be considered.

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Pesticide regulators take part in a field trip to south-east Queensland

Monday 30th August - Friday 3rd September, 1999

A tour of south-east Queensland was organised by the Queensland Fruit and Vegetable Growers (QFVG) Association and the Queensland Department of Primary Industries (QDPI), to provide federal pesticide regulators with a better understanding of pesticide use in various agricultural crops in the region. A number of pesticide regulators took part in this field trip including one from the TGA.

The trip was useful, both as a means of improving liaison between the National Registration Scheme agencies and as a means of increasing communication with stakeholders, in this case, fruit and vegetable growers who rely on pesticides in the production of their crops.

Field trip participants
(photo courtesy of the Queensland Department of Primary Industry)

The major issue for discussion between pesticide users and regulators related to permits for off-label use of pesticides. These permits allow growers to use particular pesticides in so-called 'minor' crops, when they currently are only registered for use in a limited number of major crops. This led onto discussions about the need for the establishment of maximum residue limits (MRLs) in minor crops through the conduct of appropriate field trials, explanations of why such standards were necessary, and how these good agricultural practice standards relate to the health-based standard of the acceptable daily intake (ADI) for pesticide residues in food.

Growers raised a number of specific issues including (1) what they saw as unnecessary restrictions on some old pesticides recently re-reviewed under Australia's Existing Chemicals Review Program (ECRP) for agricultural and veterinary chemicals; (2) faster access to as-yet unregistered new chemical products available in some other countries; and (3) the need for farmers to have a range of pesticides available for a particular purpose so that they can use them in rotation, in order to prevent insect resistance arising from over-reliance on a particular pesticide.

Les Davies, Manager of the Chemical Review and International Harmonisation Section within the Chemicals and Non-Prescription Medicines Branch, took part in the trip on behalf of the TGA. His Section is responsible for toxicology and public health assessments of older pesticides, under Australia's Existing Chemicals Review Program.

Regulatory risk management symposium

Risk management is a formal approach to identifying and assessing the nature and probability of risks, monitoring and appropriately managing the risks, and communicating with people who may be affected by them. The Chemicals and Non-prescription Medicines Branch recently staged a symposium aimed at familiarising staff with risk management and how it can be applied in their activities, which include regulating medicines, pesticides, industrial chemicals and poisons. The two keynote speakers were Fiona Cumming (Director, Office of Complementary Medicines) and Peter Raphael (Executive Manager, Registration, National Registration Authority for Agricultural and Veterinary Chemicals).

The Symposium was opened by TGA's National Manager, Terry Slater, who emphasised that it is essential for TGA to manage risk effectively and consistently, given the nature of its relationship with industry and the public. As an example, he pointed out that TGA has recently assumed responsibility for the Office of the Gene Technology Regulator. Mr Slater warned that just one problem with genetically modified organisms could be enough to shape public perception in this important area. On the other hand, unnecessary regulation for low risk products could place Australian exports and industries at a competitive disadvantage.

Peter Raphael illustrated how the NRA's approach to risk management was determined by the legislative framework within which it operates. The NRA has to ensure that ag/vet chemical products are not likely to pose any undue hazard to occupational or public health, are not likely to have an unintended effect on the environment, and will not unduly prejudice trade and commerce.

The Office of Complementary Medicines has responsibilities that include regulating nutritional supplements and herbal preparations, which Dr Cumming described as being intermediate between foods, (which have a low therapeutic efficacy and low perceived risk) and prescription medicines, which have demonstrated efficacy but may be of higher risk. New substances for inclusion in complementary medicines are therefore assessed for safety, quality, and where appropriate for efficacy.

Dr Cumming stressed that it was incumbent on regulators to monitor public health, and that risk communication was of paramount importance. This could be achieved through use of product label warning statements or, if needed, a more widely based public education campaign to increase awareness of risk, and educate about the true nature of risk. She added that it is necessary to ensure that decision-making processes are open and transparent. Effective risk communication was a two-way process, in which regulators had to be accessible, responsive to new information, and actively seeking input so that the community has a sense of ownership.

Graham Peachey, Director, Chemicals and Non-Prescription Medicines Branch;
Fiona Cumming, Director, Office of Complementary Medicines;
Peter Raphael, Executive Manager, Registration, National Registration Authority for Agricultural and Veterinary Chemicals

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Streamlining of export arrangements

Review

The regulation of therapeutic goods for export has been reviewed by consultants, Tom Hayes and Associates. The Review examined regulations applying to therapeutic goods (not devices) and proposed options for positive and practical change to the current regime to remove unnecessary impediments while maintaining appropriate standards.

The Report has been circulated to industry associations and implementation of recommendations discussed at a joint TGA/Industry meeting.

Industry/TGA Project Groups

Implementation is being linked to a number of administrative efficiencies with the objective of enhancing the timeliness of the TGA export process.

Two joint TGA/Industry export certification project teams have been established to tackle specific problems and develop solutions:

• one to examine issues relating to non-prescription and listable medicines, including complementary medicines, and exempt products; and
• the other to look at issues relating to prescription medicines.

TGA Co-ordination

A TGA Exports Review Reference Group, chaired by the Director of the Chemicals and Non-Prescription Medicines Branch, Mr Graham Peachey, has been established to oversight a Workprogram flowing from the Review and the joint project groups.

Proposed improvements

The Export Certification Review Implementation Workprogram has been developed with the objective of:

• providing a clear, documented and transparent policy framework for Australia's export certification procedures;
• ensuring appropriate application of the WHO Export Pharmaceutical Certification Scheme as recommended by the Hayes Review;
• implementing administrative efficiencies designed to enhance the timeliness of the export certification process; and
• enhancing the understanding of importing countries of Australia's regulatory provisions.

Consultation will take place around the Workprogram, key elements of which include:

• a TGA export certification policy;
• revised Certificates of Pharmaceutical Product (CPPs) for registrable and "solely for export" goods to allow for a limited number of standardised comments that provide information about the circumstances of the product;
• a revised export listing form for blood products;
• proposed new export certificates for listable medicines, including complementary medicines, and exempt products;
• incorporation of the prior informed consent procedure into the CPP;
• staged introduction of electronic lodgement of export certification applications. First for "listed medicines approved for supply in Australia", and later for CPPs;
• liaison with Department of Foreign Affairs and Trade to streamline the authentication interface for export certification documents;
• consultation with Department of Industry, Science and Resources on the development of educational programs around export promotion including TGA export procedures; and,
• establishment of an Export Desk to advise and refer sponsors with export problems and concerns.

Time is of the essence...

Top tips to avoid delays in obtaining a Certificate of Pharmaceutical Product (CPP)

• Please read the Guide to Application for Certification of a Pharmaceutical Product before completing the application form. Make sure the form has been completed correctly, appropriate boxes have been ticked and all questions are answered.
• Check all information, including formulation, to ensure it matches with information on the Australian Register of Therapeutic Goods (ARTG). If not, please contact the ARTG and/or relevant areas to have the discrepancies rectified before applying for a CPP. Changes to the CPP application after it has been submitted result in delays in CPP issue.
• Australian Approved Names (AANs) must be used for all ingredients other than proprietary ingredients
• Herbal extracts should use Approved Herbal Names, plant parts, type of extract (soft, dry, liquid etc), ratios, solvents and percentages used as well as dry/fresh herb equivalents as appropriate.
• Metric units must be used to express quantities.
• If more than one manufacturer is to be included in the Certificate, please provide details in a Schedule, as the Certificate accommodates details of only one manufacturer.
• Schedules must be numbered consecutively. Formulation details as Schedule 1 is mandatory but subsequent schedule numbers are not linked to specific information. (The Guide's example on Schedule numbering is provided only for guidance.)
• Each Schedule should contain a signed and dated declaration that the information provided is current and correct.
• Remember to tick the relevant box next to the declaration on page 4 of the application form to indicate which declaration applies to the product.

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Topical OTC products - when is efficacy data required?

Registered OTC medicines are evaluated in terms of quality, safety and efficacy. Some topical OTC medicines have a long history of use in many different formulations and their efficacy is well accepted. Examples include salicylic acid for treatment of warts and benzoyl peroxide for treatment of acne. Efficacy data is generally not required to support the registration of these products.

The Medicines Evaluation Committee (MEC) has identified other groups of topical products where the efficacy and/or safety of the product is influenced by the formulation. In these cases, a change in non-active ingredients may affect the extent of penetration of the active substance and therefore efficacy data is usually required before the product is recommended for approval. Because OTC medicines are so diverse, the committee has advised a flexible approach in which the need for data should be determined on a case-by-case basis. This article is intended to assist sponsors of topical OTC products in knowing when efficacy and/or safety data is likely to be required, based on previous decisions of the MEC.

The following categories of OTCs have been identified by the MEC as being formulation-dependent in terms of efficacy and/or safety:

• Head lice preparations
• Topical aciclovir for treatment of cold sores
• Topical minoxidil
• Topical NSAIDs
• Antibacterial hand washes, surgical scrubs and antiseptics (other than for the 'first aid' treatment of minor wounds)
• Antidandruff shampoos containing imidazole antifungals as active ingredients

In some instances, the committee has accepted in-vitro data but in other instances, data from clinical trials was required. For this reason, sponsors are advised to contact the OTC Medicines Evaluation Section for advice on how similar products have been dealt with by the MEC in the past. In some cases it may be necessary to refer an enquiry to the MEC for specific advice on a particular product. To date, all applications for topical NSAIDs and aciclovir have been required to be supported by efficacy data in the form of clinical studies.

The key point is that the TGA will adopt a flexible approach to data requirements and place all reasonable submissions before the MEC for review. However, sponsors would be wise to take account of previous decisions and information can be obtained by contacting the OTC Medicines Evaluation Section.

Traditional medicines and wildlife conservation

What is the issue?

Many of the world's animals and plants are threatened because of human activity such as destruction of habitat, hunting, poaching and the uncontrolled trade in wildlife and wildlife parts. One factor driving this trade is the demand for animal and plant derivatives for use in traditional medicines. Some of these species, like the tiger and rhinoceros, are now in great danger of extinction.

Other protected species which are used in medicines include bear, turtle, seahorse, wild American ginseng, aloe, many orchids and musk deer.

Ending the illegal trade in protected wildlife and wildlife parts, though not the only answer, will help prevent their further decline. The government, traditional medicine practitioners, importers and users need to continue to work together to address this threat and promote medically acceptable alternatives to the use of these species.

Australia's wildlife trade laws

Since 1973, 145 countries, including Australia, have ratified the Convention on the International Trade in Endangered Species of Wild Fauna and Flora (CITES). CITES requires countries to place controls on the export and import of species which are listed as protected. Where trade is allowed, export and import permits must be issued before the trade occurs. Australia implements its CITES obligations through the Wildlife Protection (Regulation of Exports and Imports) Act 1982. The Act also strictly regulates the export of Australian native wildlife and the import of all live animals.

It is illegal to trade commercially in any part of, or product derived from, any wild endangered animal or plant. Controls on the trade in threatened species are generally less strict but an export permit and an import permit are always required. The export of most Australian plants, and products derived from them, is also regulated

Importing and exporting includes sending or receiving items by mail or courier, and carrying items in personal luggage. The Wildlife Protection Act controls also cover possession of protected wildlife and wildlife products.

Traditional Medicines and the Wildlife Protection Act

On 6 May 1999 an amendment to the Wildlife Protection Act came into effect strengthening controls on the import of products, including traditional medicines, containing or represented (for example, by their packaging and labelling) to contain endangered species (including any part of, or product derived from them). The amendment ensures that all products containing or represented to contain an endangered species, for example tiger or rhino, are treated as if they do, in fact, contain the ingredient.

It is not the intention of the amendment to prohibit the general use of images of wildlife as a marketing tool.

The amendment was required to implement resolutions agreed to by all CITES member countries. Other countries have already introduced these measures and they are supported within Australia by a wide range of traditional medicine associations, environmental and conservation groups, leaders of the Chinese community and all parties in the Federal Parliament.

If you import wildlife parts or medicines containing wildlife into Australia, be sure that none of the ingredients are from protected species and that none of your medicines contain or represent that they contain, protected species derivatives. For further details on how to comply with wildlife export/import regulations contact Environment Australia <http://www.ea.gov.au>.