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Regulation impact statement: International harmonisation of ingredient names
Version 1, November 2015
2. The problem
Ingredients that are used in the formulation of medicines can be classified as either active (where they have a therapeutic effect) or excipient ingredients. The names of active ingredients in a medicine's formulation must be included on the medicine label4 and in the product's supporting documentation (for example pack inserts, promotional material, Product Information5 and Consumer Medicine Information documents). Only a select number of excipient ingredients are required to be included on a label or in information provided to a consumer.
Companies that supply or manufacture therapeutic goods in Australia also maintain internal supporting documentation on a product's formulation details (both active and excipient ingredients). This includes manufacturing and regulatory documentation, Drug Master Files and adverse event databases.
Approved terminology is needed to ensure that names of ingredients used in medicines are accurate and consistent. Consistency in naming helps people search for information about medicines, allows health professionals and the public to compare similar goods and avoids the risk of confusion between goods.
International Nonproprietary Names (INNs) are the global reference for medicine ingredient names. The INN system was developed by the World Health Organization (WHO) and is maintained by member states, including Australia. The list of INNs is updated twice a year6. Since 2002, TGA has adopted INNs, where available, as its primary reference for new ingredient names. However, there are ingredient names that were added to the TGA Business Services Ingredients Table prior to 2002 that are now not consistent with international naming practices.
Reference setting agencies (such as the WHO or the British Pharmacopoeia Commission) meet regularly to discuss the creation of new ingredient names or to update old names. These updates can include changes to the spelling or structure of existing ingredient names. Sometimes, new INNs are also created for long-existing substances that had previously been known by different names internationally. These types of changes have resulted in a number of ingredients on the Ingredients Table having different names than those now accepted as international best-practice.
In some cases, a new harmonised name was created on the Ingredients Table without removing the old name. This has resulted in more than one name for a specific substance and different products using different names for the same active ingredient. However, these differences are restricted to minor spelling variations.
Generally, the use of unharmonised, out-of-date or multiple ingredient names can create significant problems for the medicines industry, consumers and healthcare professionals. These problems include barriers to supplying a medicine in Australia, risks to consumer health and possible prescribing misadventure.
2.1.1 Medicines industry
The Australian pharmaceutical industry comprises bio-medical research, biotechnology firms, originator and generic medicines companies and service-related segments including wholesaling and distribution. In 2012-13, the Australian pharmaceutical industry reported a turnover of $23.4 billion7. With exports of $3.9 billion, pharmaceuticals were one of Australia's major manufactured exports that year8.
The medicines industry also includes companies that manufacture and supply complementary medicines, such as vitamins or minerals. In 2012, the complementary medicine industry revenue was estimated as $3.5 billion and expected to grow9.
Use of a unique Australian ingredient name creates an additional barrier to international trade for the Australian export industry. For example, the sponsor of a medicine in Australia may wish to also market that medicine internationally. Due to the lack of international harmonisation, the sponsor would need to perform additional steps to confirm that two ingredient names refer to the same substance. Although label and marketing materials are different for different countries, using a unique ingredient name results in additional labour time and complexity in developing this documentation. As raw materials may be sourced from multiple countries, manufacturing documentation may also need to be changed to align with Australian approved terminology. There would also be additional costs incurred in training staff to understand that both ingredient names refer to the same substance, and to maintain that training. These steps contribute to the barriers for Australian companies wishing to market products internationally.
Conversely, the need to use an out-of-date ingredient name in Australian medicine applications also imposes an additional burden on multinational companies wishing to market products in Australia. For example, a sponsor must ensure that the Drug Master File and product information documents submitted to the TGA as part of a medicine application use Australian approved terminology. If the ingredient name is different to the one used internationally, this imposes additional production costs on both the active ingredient manufacturer and the sponsor of the finished goods, which are then passed onto the Australian consumer.
2.1.2 Consumers and healthcare professionals
The use of out-of-date names means that Australian consumers and healthcare professionals may be unfamiliar with international medicine ingredient names. This not only restricts the ability of consumers to access important medicine information internationally, but can also make it more difficult for doctors and nurses to keep up with international updates on medicine safety, adverse event information and emerging issues.
Out-of-date ingredient nomenclature can result in significant legal or health problems for Australians travelling overseas. This includes situations where some countries have restrictions on certain medications being brought in by travellers or where Australian travellers may have allergies to certain ingredients. For example, visitors travelling to the UK are required to check whether the medicines they are travelling with are licenced for use in the UK; must carry medicines in a correctly labelled container and bring a letter from their doctor in case the medicine is queried by customs officers or additional supplies are required10. Consequently, using a unique or out-of-date Australian ingredient name increases the risks:
- of confusion for customs officers when travellers are entering or leaving a country, leading to delays and possible confiscation of medicines; and
- that additional supplies of a medicine may not be found while overseas.
Out-of-date nomenclature also affects residents returning, and tourists travelling, to Australia. For example, phenobarbital (INN) is known as phenobarbitone in Australia. There are restrictions on the importation of barbituates into Australia, where illegal importation may attract criminal sanctions, including imprisonment and/or fines up to $825,00011. Using out-of-date nomenclature requires Australian Customs officers to be aware of numerous names for an ingredient, increasing the risk of confusion and potentially resulting in avoidable border control problems.
TGA receives thousands of queries every year from travellers wishing to bring medicines for personal use into Australia. In 2013 the personal importation of medicines was the second most common query to the TGA Public Contact Team. In some of these queries, travellers have experienced border control problems, as they have been unaware of restrictions placed on their medicines, even though they have searched for information based on a specific ingredient name.
Healthcare professional representative groups have raised concerns that the use of more than one name for an ingredient can cause confusion in prescribing, increasing the risks of mis-dosing. For example, double-dosing can occur where a patient takes a product that uses one name for an ingredient as well another product containing the same ingredient under a different name. These risks of double-dosing are especially high for patients who visit more than one medical practitioner. There is limited evidence to show that these types of errors have occurred in Australia as a result of the current availability of more than one name for an ingredient; however, the consequences of such an error are severe and preventable. For example, 'lignocaine' is an ingredient used as an anaesthetic. 'Lignocaine' is an old British Pharmacopoeia (BP) name and is the approved name in Australia, however its INN (which has since been adopted by the BP) is 'lidocaine'. If not prescribed or administered correctly, this substance can have a severe effect on a patient's health12.
The importance of clear and consistent ingredient naming was demonstrated in May 2013 when the Pharmaceutical Benefits Scheme (PBS) adopted new medicine terminology for prescribing and dispensing systems. The update included a change to the order of active ingredients in multi-ingredient products on dispensing software. This resulted in the order of ingredients for some products within the software not aligning with the order of ingredients on the relevant product labels. Pharmacists reported numerous dispensing errors in the three days following the data release13, prompting a reversal of the data update.
2.2 Why is action needed?
2.2.1 Requirement to use approved ingredient names
TGA is responsible for regulating a range of therapeutic goods, including medicines and medical devices. Therapeutic goods must be entered in the Australian Register of Therapeutic Goods (ARTG) before they can be lawfully supplied in or exported from Australia, unless exempt from or otherwise authorised by TGA. The ARTG is an electronic system that relies on consistent ingredient terminology; consequently, TGA maintains approved terminology for use in therapeutic goods.
Regulation 2 of the Therapeutic Goods Regulations 199014 (the Regulations) defines the list of approved ingredient names maintained by TGA. This list of ingredient names includes those for chemical substances (Australian Approved Names [AANs] and Australian Biological Names [ABNs]) as well as names for herbal substances.
Approved ingredient names are published in the Ingredients Table on the TGA Business Services website15. These approved ingredient names are then used:
- when applications for registration and listing (including for export) of medicines are made to TGA
- in records of medicine formulations included in the ARTG
- on labels for medicines16
- in Product Information and Consumer Medicine Information17 documents and
- other product documentation (such as advertising) where use of approved terminology is required.
If an ingredient name has been changed internationally, affected sponsors contact TGA to request its inclusion in the Ingredients Table as an approved name. Until this occurs, the international name cannot be used in Australian medicine labels or product information.
Although each country has specific labelling requirements, by changing ingredient names to INNs and updated pharmacopoeia names, Australian companies can benefit by more easily creating marketing and product information materials.
2.2.2 Improving information access and exchange
International harmonisation of ingredient names can help Australians who wish to find out more information on their medicines. The Internet is an increasingly common source of health-related information for consumers. Aligning Australian ingredient names with their international names will reduce confusion and help Australians more easily access international medicines information.
Australian consumers and healthcare professionals who travel internationally are also expected to benefit from harmonisation. Increasing consumers' familiarity with international ingredient names can reduce the risk of confusion when seeking medical advice/assistance in other countries, when explaining allergies to specific substances and when seeking legal advice on bringing personal medicines into a country. The harmonisation of active ingredient names could reduce the risk of adverse health or legal consequences for Australian travellers.
2.2.3 Clear ingredient naming
Australian terminology policy requires that the name used for an ingredient provides enough information to uniquely identify the substance. This can include information such as the substance's hydration state, the specific salt, or its stereochemistry (physical properties like stereoisomers, chiral states, etc.). By ensuring that only one name is used to specify an ingredient, the TGA supports the National Medicines Policy's objective for Quality Use of Medicines18 by reducing confusion when selecting, prescribing or using medicines.
Quality use of medicines means that consumers and healthcare professionals select health management options wisely; choose suitable medicines if a medicine is considered necessary; and use that medicine safely and effectively. Using one name for an active ingredient reduces the risk of consumers accidentally double-dosing (taking a product that uses one name as well as a product with the same substance under a different name). Healthcare professionals would also not have to remember multiple names, reducing the risk of prescribing errors and severe health effects.
More specific names can also assist in the efficient evaluation and registration of new medicines. For example, an application for a product containing 10 mg/mL of apomorphine hydrochloride19 under the current TGA naming approach refers to 10 mg/mL of apomorphine hydrochloride hemihydrate (which would contain more water, which is not therapeutically relevant, and less of the active component). However, as international conventions assume a substance is anhydrous (dry) if it does not include a hydration state, the sponsor may have intended to apply for 10 mg/mL of apomorphine hydrochloride anhydrous. This ambiguity then leads to the need for additional questioning and clarification from the sponsor.
2.2.4 Improving functionality of the Ingredients Table and the ARTG
Some ingredients require the inclusion of a hyphen to accurately describe the structure of the substance (for example dl-alpha-tocopherol). Within the Ingredients Table, removal of hyphens from words previously inverted for searchability purposes (e.g. 'insulin — bovine'), will assist in reducing confusion with names that include hyphens necessary for their chemical structure. Removing multiple names for the same substance will also help in TGA's reporting activities, by making sure that the reports capture all products containing a specific substance.
The use of more than one name for an ingredient causes flow on problems to both TGA and external databases. The National e-Health Transition Authority (NeHTA), the Australian Government and state and territory governments are electronically connecting the points of care so that health information can be shared securely. NeHTA uses ARTG data to develop the Australian Medicines Terminology, a naming convention for describing medicines on prescribing, dispensing and ordering software across Australia. Due in part to inconsistencies on the ARTG, NeHTA systems have had to develop their own consistent naming which may be different from ingredient names on medicine labels. However, improving consistency within the ARTG will flow onto NeHTA systems and help reduce the potential for serious prescribing and administration errors.
2.3 What is proposed to change?
2.3.1 Summary of proposal released for consultation
The TGA compiled a list of active and excipient ingredient names that may need changing to harmonise with a more appropriate international reference and/or to align with TGA naming policies20. This review also included errors identified for correction (such as duplications and typographical errors). Table 1 summarises the types of changes proposed.
|Change type||Source of change|
Direct harmonisation with an INN.
This includes the harmonisation of both the parent substance name as well as any derivatives.
|Changing a non-pharmacopoeia reference to a pharmacopoeia reference or INN.||International harmonisation|
|Inclusion of hydration state where appropriate. For example, inclusion of 'monohydrate' ('anhydrous' is the default, and does not need to be stated).||International Non-proprietary Names Modified (INNM)21, Section IV, Paragraph 14, page 8.|
Where appropriate, using 'f' instead of 'ph', 't' instead of 'th' and 'e' instead of 'ae' or 'oe', 'i' instead of 'y', and avoiding the use of 'h' and 'k', e.g.:
mesylate to mesilate
oestrogen to estrogen
cholecalciferol to colecalciferol
Guidelines on the Use of INNs for Pharmaceutical Substances, Annex 2, Paragraph 7.
(INNM, Section II, Paragraph 7 gives examples)
|Use of 'macrogol' terminology for synthetic polymers (rather than 'PEG')||INNM, Section IX, Paragraph 27, page 13.|
|Avoiding the use of isolated numbers, letters or hyphens (unless required for chemical structure).||Guidelines on the Use of INNs for Pharmaceutical Substances, Annex 2, Paragraph 6.|
|Using one name to refer to one substance and avoiding names that are in 'common' use (e.g. no use of brand names; a separate entry is required for each hydration state).||Guidelines on the Use of INNs for Pharmaceutical Substances, Annex 2, Paragraph 1.|
|Correct word order for salts and other derivatives||INNM|
Use of common name for metals instead of Latin (e.g. use of 'iron' rather than 'ferrous').
Addition of oxidation state for a metal in a metallic compound where more than one oxidation state is possible but only a single oxidation state is present (e.g. iron (II) aspartate).
TGA naming policy22 - the use of common names is more readily understood by consumers.
The addition of the oxidation state better identifies the ingredient.
TGA noted that some of the identified ingredients were of high clinical significance and a change to their name would be associated with additional risks23. Dual-labelling was proposed for these ingredients to help transition to the new name and minimise the risk of the wrong medicine being used. Dual-labelling would require both the old name and the new name to be included on the label. Including two names on a label for the same ingredient is not uncommon for some medicines; the labels of many complementary and over-the-counter medicines include the approved ingredient name as well as its synonym (usually a more 'common' name) in brackets.
Forty ingredient name changes are proposed for dual-labelling due to their higher clinical risk. Dual-labelling would be mandated for a period of time, after which a sponsor could start using the new name as the sole ingredient name.
2.3.2 Post consultation considerations
A summary of the issues raised during consultation is under Section 6 - Consultation. Among other feedback, stakeholders identified some discrepancies in the list of ingredients and requested that the order of dual-labelling be changed (new name first, followed by the old name). As a result, a number of additional entries were added24 to the harmonisation list and some proposed changes to ingredient names removed or amended.
The review of stakeholder comments identified that the substance 'adrenaline' (proposed to be changed to 'epinephrine' following a period of dual-labelling) is known by both names in some countries. For example, the BP name for adrenaline is now 'adrenaline (epinephrine)'. Therefore, in the United Kingdom, adrenaline products are labelled as 'adrenaline (epinephrine)' with no intent to change to 'epinephrine' as the sole name.
Stakeholders also identified significant risks associated with changing the name 'adrenaline' to 'epinephrine', especially around its potential to be mistaken for 'ephedrine'. For example, following a shortage of adrenaline syringe labels in an operating theatre in the UK, epinephrine labels were ordered. Twice in one day, anaesthetists who used ephedrine for treating hypotension labelled their syringes 'epinephrine'25.
The revised proposal for adrenaline is to include both the old and new name with no end date, to best align with international practice. This proposal also extends to adrenaline derivatives:
- 'adrenaline (epinephrine) acid tartrate'
- 'adrenaline (epinephrine) hydrochloride'
- 'noradrenaline (norepinephrine)'
- 'noradrenaline (norepinephrine) acid tartrate monohydrate'
Final list for harmonisation
Following consideration of stakeholder comments, a final full list of 478 ingredient names is proposed for harmonisation. This list includes 269 active ingredients and 263 excipient ingredients26. The list also includes the 40 ingredients proposed for dual-labelling.
- In accordance with the Therapeutic Goods Order No. 69 (TGO69) - General requirements for labels for medicines
- Section 7D of the Therapeutic Goods Act 1989
- WHO | What's in a name?
- Australian Pharmaceuticals Industry Data Card 2014 (pdf,461kb)
- Pharmaceuticals Industry Profile
- Understanding Complementary Medicine
- Visit Britain - Medical and health information
- Importing Barbituates (pdf,141kb)
- For example, lignocaine is used to treat life-threatening ventricular arrhythmias and if not administered correctly can result in patient death - see lignocaine HCl approved product information documentation <http://www.ebs.tga.gov.au>
- Confidential industry report - August 2013
- Therapeutic Goods Regulations 1990
- TGA Business Services
- Unless exempt, medicines are required to comply with the Therapeutic Goods Order No. 69 (TGO69) - General requirements for labels for medicines. Inclusion of excipient ingredients on a label depends on the type of product (i.e. for injection, for ophthalmic use).
- PI/CMI search facility
- Quality Use of Medicines
- Used to treat Parkinson's disease
- Outlined in the TGA approved terminology for medicines
- Metal ingredients either use Latin names (such as 'cuprous' or 'cupric' for copper and 'ferrous' or 'ferric' for iron) or English common names. There is also no specific INN guidance on how to name metallic substances, and both common and Latin names for metals appear in INNs.
- This risk was calculated based on the combination of the prescription only status of the medicine and the degree of change in the ingredient name (i.e. prescription only medicines that only changed one letter in their ingredient name were not considered to be of 'high clinical risk').
- The ingredients that were added to the list were either duplicate or parent entries of those already identified in the consultation paper. For example, 'Lignocaine hydrochloride' was included in the list for consultation, however, the parent ingredient entry 'lignocaine' was accidentally omitted.
- James, H. R. 'Ephedrine/epinephrine drug label confusion', Anaesthesia, 1998, Vol 53, issue 5. <http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2044.1998.04771.x/pdf (pdf,280kb)>
- 54 of the 263 excipient ingredients are also present as active ingredients in some products.