Therapeutic Goods Administration

Australian regulatory guidelines for complementary medicines
Part C: Evaluation of complementary medicine substances for use in listed medicines
April 2013
Draft for consultation
Document title / Page 1 of 53
V1.0 Month 2012

Therapeutic Goods Administration

About the Therapeutic Goods Administration (TGA)

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

Copyright

© Commonwealth of Australia 2013
This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <

Confidentiality

All submissions received will be placed on the TGA’s Internet site, unless marked confidential. Any confidentialmaterial contained within your submission should be provided under a separate cover and clearly marked“IN CONFIDENCE”. Reasons for a claim to confidentiality must be included in the space provided on the TGAsubmission coversheet.For submission made by individuals, all personal details, other than your name, will be removed from yoursubmission before it is published on the TGA’s Internet site.In addition, a list of parties making submissions will be published. If you do not wish to be identified with yoursubmission you must specifically request this in the space provided on the submission coversheet.

Contents

ARGCM Part C: Evaluation of complementary medicine substances for use in listed medicines

Overview

Eligibility for evaluation as a complementary medicine substance

Substances eligible for evaluation for use in listed complementary medicines

Overview of the evaluation process

Pre-submission meeting

Lodgement of application

Screening of application

Application accepted for evaluation

Application not accepted for evaluation

Evaluation

Consideration by a TGA advisory committee

Determination on the application

Implementation

Therapeutic Goods (Listing) notice

Information required for an application for evaluation of a complementary medicine substance

Simple and complex complementary medicine substances

Application

Quality

Safety

Attachment 1: Compositional guidelines for complementary medicine substances

TGA compositional guidelines

Generation of compositional guidelines

Publication of compositional guidelines on the TGA website

Procedure for amending compositional guidelines

General guidance for developing compositional guidelines for complementary medicine substances

Format for drafting compositional guidelines

Attachments 2 to 12

Attachments 2 to 12 are currently under review by the TGA

Attachment 13 Information required to demonstrate QUALITY of a complementary medicine substance for use in listed medicines

Introduction

Presentation of quality data in an application

General information on quality

Information on manufacture

Characterisation of complementary medicine substances

Specification

Analytical procedures

Validation of analytical procedures

Batch analyses

Justification of specification

Reference standards or materials

Container closure system

Attachment 14: Profile chromatograms

Profile development

Profile chromatogram interpretation

Attachment 15: Information required in an application to demonstrate SAFETY of a new complementary medicine substance

General data requirements

History and pattern of previous human use

Biological activity

Toxicology

Clinical trials

Adverse reactions

Ingredients of human or animal origin

Attachment 16: Choosing literature for evaluation and evaluating search strategies

Conducting the search

Recording the search strategy

Compiling the evidence

ARGCM Part C: Draft for consultation / Page 1 of 55
April 2013

Therapeutic Goods Administration

Abbreviations (applicable to Parts A, B , C and D of the ARGCM)
AAN / Australian Approved Name (chemical)
ABN / Australian Biological Name
ACCC / Australian Competition and Consumer Commission
ADI / Acceptable Daily Intake
AFN / Australian Food Name
AHN / Approved Herbal Name
AHS / Australian Herbal Substance
AAT / Administrative Appeals Tribunal
AQIS / Australian Quarantine Inspection Service
ARGB / Australian Regulatory Guidelines For Biologicals
ARGCM / Australian Regulatory Guidelines for Complementary Medicines
ARGMD / Australian Regulatory Guidelines for Medical Devices
ARGOM / Australian Regulatory Guidelines for Over-the-Counter Medicines
ARGPM / Australian Regulatory Guidelines for Prescription Medicines
ARTG / Australian Register of Therapeutic Goods
AUST L / A unique number assigned to products listed on the ARTG
AUST R / A unique number assigned to products registered on the ARTG
BP / British Pharmacopoeia
CAS
CHMP / Chemical Abstracts Service
Committee for Medicinal Products for Human Use
CITES / Convention on International Trade in Endangered Species of Wild Fauna and Flora
GC / Gas Chromatography
CG / Compositional guidelines
eBS
EMA / TGA eBusiness Services
European Medicines Agency
EP / European Pharmacopoeia
EPBC / Environment Protection and Biodiversity Conservation
EU / European Union
Evidence Requirements / Evidence required to support indications for listed medicines (excluding sunscreens and disinfectants)
FSANZ / Food Standards Australia New Zealand
GM / Genetically modified
GMO / Genetically modified organisms
GMP / Good Manufacturing Practice
GT / Gene Technology
HCN / Australian (Approved) Herbal Component Name
HINC / Herbal Ingredient Naming Committee
HPLC / High-performance liquid chromatography
IR / Infrared (IR) spectroscopy
ICH / International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
NICNAS / National Industrial Chemicals Notification and Assessment Scheme
OECD / Organisation for Economic Co-operation and Development
OGTR / Office of the Gene Technology Regulator
OTC / Over-The-Counter
Ph. Eur.
Proprietary ingredient / European Pharmacopoeia
A confidential formulation about which information is not in the public domain
RASML / Required Advisory Statements for Medicine Labels
RDI / Recommended Dietary Intake
SUSMP / Standard for the Uniform Scheduling of Medicines and Poisons
TGA / Therapeutic Goods Administration
TGAC / Therapeutic Goods Advertising Code 2007
TGOs / Therapeutic Goods Orders
TGO 69 / Therapeutic Goods Order No. 69 – General requirements for labels for medicines
TGO 77 / Therapeutic Goods Order No. 77 – Microbiological Standards for Medicines
TGO 78 / Therapeutic Goods Order No. 78 – Standards for Tablets and Capsules
TGO 80 / Therapeutic Goods Order No. 80 – Child-resistant Packaging Requirements for Medicines
The Act / Therapeutic Goods Act 1989
The Food Standards Code / Australia New Zealand Food Standards Code
The GT Act / Gene Technology Act 2000
The Regulations / Therapeutic Goods Regulations 1990
TLC / Thin layer chromatography
TSE / Transmissible Spongiform Encephalopathy
URPTG / Uniform Recall Procedure for Therapeutic Goods
USP / United States Pharmacopoeia – National Formulary
UV
WHO / ultraviolet
World Health Organization
ARGCM Part C: Draft for consultation / Page 1 of 55
April 2013

Therapeutic Goods Administration

ARGCM PartC: Evaluation of complementary medicine substancesfor use in listed medicines

Overview

Listed medicines are included on the Australian Register of Therapeutic Goods(ARTG) via a streamlined electronic listing facility which is part of the TGA's eBusiness services (eBS) framework. The process for listing products allows for early market access for low risk complementary medicines.

Unlike registered medicines, there is no evaluation prior to the medicine being listed on the (ARTG).The TGA therefore uses a variety of mechanisms to assure the safety and quality of the ingredients used, as well as the resultant medicines. One of these mechanisms is that listed medicines may only contain ingredients that have been evaluated and approved by the TGA as being of low risk.

A searchable database of active and excipient ingredients is accessible via the TGA eBusiness Services (eBS) website. If an applicant wishes to use a complementary medicine substance in a listed medicine that is not currently a permitted ingredient, the substance is required to be evaluated by the TGA.

/ The primary reason for the evaluation of a substance is to determine whether it is of appropriate quality and safety to be permitted for use as an ingredient in listed complementary medicines.

An application for evaluation may be submitted for:

  • a complementary medicine substance that is not currently a permitted ingredient; or
  • a proposed new role or a change to a regulatory requirement of use for a permitted ingredient, for example: a proposal for an ingredient permitted for use as an excipient to be used as an active ingredient.

A request for evaluation of a substance (to allow its use as an ingredient in complementary medicines) is considered under Regulation 16GA ofthe Therapeutic Goods Regulations 1990 (the Regulations). A prescribed fee is required to be paid by the applicant.

If the substance on evaluation is found to be suitable for use as an active ingredient, a notice is made by the Minister for the purposes of subsection 9A(5) of the Therapeutic Goods Act 1989 (the Act) (the Listing Notice) requiring that specified therapeutic goods containing the active ingredient be included in the part of the ARTG forlisted goods. The effect of the Listing Notice is that the particular active ingredient specified in the notice can be used as an ingredient of a listed good for inclusion in the ARTG and that prior to those goods being lawfully supplied in Australia, the goods will be required to be included in the part of the ARTG for listed goods. The notice ceases to have effect once the Regulations are amended (to require that any of those goods be included in the part of the ARTG for listed goods or registered goods). In addition, prior to that notice being made, the active ingredient must be an ingredient generally covered by the list in Schedule 14 of the Regulations (designated active ingredients) and not covered by any prohibition set out under Schedule 4 of the Regulations or under the Act.

If the substance is permitted for use in listed medicines as an excipient ingredient, it is included in the eBS and available for use without the requirement for publication of a Listing Notice.

/ Once permitted for use in listed medicines, an ingredient may be used in a listed medicine by any sponsor.

Quality and safety are the main parameters considered when evaluating a substance for suitability for use as an ingredient in listed medicines.The same evaluation process applies for substances proposed for use as active or excipient ingredients.

Quality aspects (for example: chemical identity, manufacturing process, process controls and stability) are evaluated for the purpose of characterising (identifying the physical and chemical properties of) the substance. Where there is a default standard for the substance, the quality of the substance is assessed against that standard.Where there is no specific default standard applicable to the substance a TGA compositional guideline is required.

/ The default standards recognised under the Act are relevant statements in monographs in any of the following: the British Pharmacopoeia (BP), European Pharmacopoeia (Ph. Eur.) or the United States Pharmacopeia – National Formulary(USP).
A compositional guideline is a summary of descriptions, tests and appropriate acceptance criteria (which are numerical limits, ranges or other criteria) that define the characteristics and specify the composition of an ingredient permitted for use in listed medicines.

The safety evaluation determines whether the toxicological profile of the substance meets the requirements for the purpose for which it is to be used and is, therefore, considered safe to be used as an ingredient in listed medicines.

Although efficacy of a substance is not assessed, the evaluation process includes consideration of the proposed therapeutic use (indications) of medicines (containing the proposed ingredient) in order to determine if the proposed ingredient is safe at the dose and duration of exposurerequired for therapeutic effect. For example, when evaluating a substance that is proposed to be used as an ingredient indicated for long-term use, the TGA will consider whether submitted safety studies are of sufficient duration. In addition, clinical and other efficacy data, while not evaluated from an efficacy perspective, often include information on adverse events that is useful in the safety evaluation.

/ A sponsor is required to certify (under 26A of the Act) that they hold evidence to support the indications and claims made for their medicine. The sponsor of the medicine must provide this evidence to the TGA, if requested to do so.The medicine may be cancelled from the ARTG if any of the sponsor’s certification under specified provisions of section 26A of the Act is found to be incorrect.

Eligibility for evaluation as a complementary medicine substance

Substances eligible for evaluation for use in listed complementary medicines

Schedule 14 to the Regulations provides a list of designated active ingredientsfor complementary medicines:

Designated active ingredients

  1. an amino acid
  2. charcoal
  3. a choline salt
  4. an essential oil
  5. plant or herbal material (or a synthetically produced substitute for material of that kind), including plant fibres, enzymes, algae, fungi, cellulose and derivatives of cellulose and chlorophyll
  6. a homeopathic preparation
  7. a microorganism, whole or extracted, except a vaccine
  8. a mineral including a mineral salt and a naturally occurring mineral
  9. a mucopolysaccharide
  10. non human animal material (or a synthetically produced substitute for material of that kind) including dried material, bone and cartilage, fats and oils and other extracts or concentrates
  11. a lipid, including an essential fatty acid or phospholipid
  12. a substance produced by or obtained from bees, including royal jelly, bee pollen and propolis
  13. a sugar, polysaccharide or carbohydrate
  14. a vitamin or provitamin

If a substance is of the type listed in Schedule 14 to the Regulations, it may be eligible for evaluation for use in listed complementary medicines providing:

  • the substance is not a prohibited import
  • if the substance is of herbal origin, it must not be included in Division 1, Part 4 of Schedule 4 to the Regulations (herbal substances not permitted in listed medicines) or be subject to a restriction under Division 2, Part 4 of Schedule 4 to the Regulations; and
  • the substance, or a constituent of the substance, is not subject to the conditions of a Schedule (or applicable Appendix) to the Standard for the Uniform Scheduling of Medicines and Poisons (the SUSMP).

Some substances are subject to the conditions of a Schedule (or applicable Appendix) to the SUSMP only when present at a certain quantity in a finished product. If such a limit applies to a substance for which an application has been received, that limit is applicable to its use as an ingredient in listed medicines.

If the proposed new substance is currently not in a Schedule to the SUSMP, but the substance, or a constituent of the substance, has a potential safety concern that may meet the criteria for inclusion in a Schedule, the applicant should seek advice from the TGA prior to submitting an application.

If an applicant considers the scheduling of a substance should be reconsidered, they can submit an Application to amend the Poisons Standard.

/ The proposed use of the substance is considered in the TGA evaluation of the substance. As such, a listed medicine including the ingredient must not be required to be sterile and can only carry indications permitted for listed medicines.

Overview of the evaluation process

Applications for evaluation of substances pass through the following phases:

  • pre submission meeting (recommended)
  • lodgement and payment of fees
  • screening of application
  • evaluation
  • if required, consideration by a TGA advisory committee
  • determination; and
  • implementation.

/ There is currently no statutory time frame for the evaluation of complementary medicine substances. The complexity of the substance, the completeness and the quality of the data submitted in the application will all influence the length of time required for evaluation.

Chart 1 illustrates the stages through which an application for the evaluation of a new complementary substance progresses within the TGA.

Chart 1: Flow chart of process for evaluation of a new complementary medicine substance within the TGA.

Pre-submission meeting

The TGA encourages applicants to arrange a meeting with the TGA prior to submitting an application for evaluation of a complementary substance. Applicants should contact the TGA to arrange meeting details. There is no fee associated with a pre-submission meeting.Refer to the Australian Regulatory Guidelines on Prescription Medicines Attachment 5: ‘Conduct of meetings between TGA and sponsors’.

The purpose of the meeting is to ensure that the applicant is aware of the data required for a submission to be accepted for evaluation. If it is determined at the meeting that the proposed dossieris likely to be critically deficient, the applicant has the opportunity to address these deficiencies prior to submitting the application to the TGA.

Lodgement of application

Submit a completed ‘Application for evaluation of a new complementary medicine substance form’, two copies of the dossier (at least one of which must be in a PDF electronic format able to be searched and copied) and the evaluation fee. Fees are subject to change, and applicants should refer to Summary of fees and charges available on the TGA website.