Australian regulatory guidelines for complementary … · Web viewThe Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and Ageing,

Therapeutic Goods Administration

Part B: Listed complementary medicines

January 2013

Document title Page 2 of 67V1.0 Month 2012


About the Therapeutic Goods Administration (TGA)

The Therapeutic Goods Administration (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. 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 <www.tga.gov.au>.

Copyright© Commonwealth of Australia 2013This 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 <[email protected]>

ConfidentialityAll submissions received will be placed on the TGA’s Internet site, unless marked confidential. Any confidential material 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 TGA submission coversheet. For submission made by individuals, all personal details, other than your name, will be removed from your submission 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 your submission you must specifically request this in the space provided on the submission coversheet.

ARGCM Part B Page 3 of 67January 2013

mailto:[email protected]

http://www.tga.gov.au/


ContentsARGCM Part B: Listed complementary medicines 7

Listed therapeutic goods_____________________________________________________7

Medicines that can be listed on the ARTG__________________________________7

Ingredients approved for use in listed complementary medicines_____________________8

Legislative requirements for listed medicines____________________________9

Requirements of 26A of the Act___________________________________________________________9

Conditions of listing______________________________________________________________________14

Variations & sponsor’s rights to appeal against imposition of conditions of listing_16

Consent to supply goods that are not compliant with certain legislative requirements______________________________________________________________________________16

The listing process via the electronic listing facility___________________17

Listed medicine application lodgement via the electronic listing facility____________17

Validation system within the electronic listing facility________________________________17

Payment for applications_________________________________________________________________18

TGA processing of application___________________________________________________________18

Product variation____________________________________________________________20

Changes that result in ‘separate and distinct’ goods___________________________________20

Provisions for product amendment_____________________________________________________20

Changing information in the ARTG for ‘grandfathered’ products_____________________21

Post-market compliance____________________________________________________22

Listing compliance reviews______________________________________________________________22

Laboratory testing program_____________________________________________________________24

Good manufacturing practice inspections______________________________________________24

Product vigilance activities_______________________________________________________________24

Co-regulatory approach to control advertising_________________________________________25

Targeted and random surveillance in the marketplace________________________________25

Product recalls____________________________________________________________________________25

Attachment 1: Compositional guidelines for complementary medicine substances________________________________________________________27

Attachment 2: Data requirements for proprietary ingredients______28



Attachment 3: Data requirements for herbal materials_______________30

Attachment 4: Identification of herbal materials & extracts Q & A___31

Attachment 5: Guidance on equivalence of herbal extracts in complementary medicines_________________________________________________32

Attachment 6: Guidance on the use of modified unprocessed herbal materials in complementary medicines__________________________________33

Attachment 7a: Quality of listed complementary medicines__________34

Attachment 7b: Raw material specifications____________________________36

Attachment 7c: Impurities and incidental constituents_______________37

Attachment 7d: Finished product specifications________________________38

Attachment 7e: Finished product stability_______________________________47

Attachment 7f: Certificates of analysis for finished products_________48

Attachment 8: Medicine labels_____________________________________________50

Attachment 9a: Guidance on the use of the term ‘quantified by input’ for listed complementary medicines._____________________________________53

Attachment 9b: Questions and answers on the use of ‘quantified by input’___________________________________________________________________________59



Abbreviations

AAN Australian Approved Name (chemical)

ABN Australian Biological Name

ACCC Australian Competition and Consumer Commission

AFN Australian Food Name

AHN Approved Herbal Name

AHS Australian Herbal Substance Name

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

CHMP Committee for Medicinal Products for Human Use

CITES Convention on International Trade in Endangered Species of Wild Fauna and Flora

CG Compositional guidelines

EMA European Medicines Agency

Ph.Eur 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)

The Food Standards Code Australia New Zealand Food Standards Code

FSANZ Food Standards Australia New Zealand

GM Genetically modified

GMO Genetically modified organisms

GMP Good Manufacturing Practice

GT Gene Technology

The GT Act Gene Technology Act 2000

HCN Approved Herbal Component Name

HINC Herbal Ingredient Naming Committee

NICNAS National Industrial Chemicals Notification and Assessment Scheme

OGTR Office of the Gene Technology Regulator

OTC Over-The-Counter

Proprietary ingredient A confidential formulation about which information is not in the public domain

RASML Required Advisory Statements for Medicine Labels

RDI Recommended Dietary Intake



Abbreviations

SUSMP Standard for the Uniform Scheduling of Medicines and Poisons

The Act Therapeutic Goods Act 1989

The Advertising Code Therapeutic Goods Advertising Code 2007

The Regulations Therapeutic Goods Regulations 1990

TGA Therapeutic Goods Administration

TGOs Therapeutic Goods Orders

TGO 69 Therapeutic Goods Order No. 69 – General requirements for labels for medicines, as amended

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, as amended

TSE Transmissible Spongiform Encephalopathy

URPTG Uniform Recall Procedure for Therapeutic Goods

USP/NF United States Pharmacopoeia – National Formulary

WHO World Health Organization



ARGCM Part B: Listed complementary medicinesListed therapeutic goods

Medicines are either registered or listed on the Australian Register of Therapeutic Goods (ARTG) depending on their ingredients and the indications made for the medicine (refer to ARGCM Part A for an overview of the regulatory framework for listed and registered medicines).

Most, but not all, complementary medicines are listed, rather than registered, on the ARTG (however, note that not all listed medicines are complementary medicines).

Regulation 10 of the Therapeutic Goods Regulations 1990 (the Regulations) provides the therapeutic goods that should be either listed or registered on the ARTG. In relation to therapeutic goods that should be listed, Regulation 10b states:

Therapeutic goods, and classes of therapeutic goods, of a kind mentioned in Part 1 of Schedule 4 that are included in the Register are to be included in the part of the Register for listed goods.

Part of 1 Schedule 4 provides the types of therapeutic goods that should be listed on the ARTG, such as: sunscreens, medicated throat sprays, disinfectants, export only medicines, medicated space sprays, uncompounded medicine substances packed for retail sale, device kits and medicine kits. With respect to complementary medicine substances, Part 1 of Schedule 4 provides the following substances that can be included in listable goods:

certain vitamins

certain minerals

certain amino acids

certain herbal substances

substances included in Part 5 of Schedule 4 to the Regulations (e.g. fish oils)

mother tinctures; and

certain homoeopathic preparations.

Medicines that can be listed on the ARTG

To be listed on the ARTG, a medicine may only contain low risk ingredients that are eligible for use in listed medicines (see ‘Ingredients approved for use in listed complementary medicines’); must not contain substances that are prohibited imports for the purposes of the Customs Act 1901; must not contain substances that are included in a Schedule to the Poisons Standard or Appendix C of the Poisons Standard; and the medicine must not be required to be sterile. There are also additional restrictions on some herbal ingredients -see ‘Herbal ingredients permitted for use in listed medicines’.


http://www.tga.gov.au/industry/regulation-basics-medicines-classifications.htm

http://www.comlaw.gov.au/Details/F2012C00455


In addition, a listed medicine can only have indications (describing therapeutic use) for health maintenance, health enhancement or certain indications for non-serious, self-limiting conditions (for more information on indications for listed medicines refer to the draft 'Evidence required to support indications for listed medicines (excluding sunscreens and disinfectants)’.

Listed medicines are included on the ARTG using a streamlined electronic application and validation process – via the Electronic listing facility (ELF) which provides for early market access for low risk medicines.

Upon submission of a listing application, a sponsor must certify under section 26A of the Therapeutic Goods Act 1989 (the Act) that the therapeutic goods meet all applicable legislative requirements (see ‘Requirements of 26A of the Act’ below), which includes that the applicant holds information or evidence to support any claim that the applicant makes relating to the medicine.

Listed medicines are required to meet certain criteria in relation to safety and quality of manufacture, but the TGA does not evaluate their effectiveness prior to inclusion on the ARTG. However, after listing on the ARTG, a proportion of listed medicines are reviewed for compliance with regulatory requirements as part of the TGA’s random and targeted post-market monitoring activities (see ARGCM Part B ‘Post-market compliance’).

Ingredients approved for use in listed complementary medicines

Schedule 4 to the Regulations and listing notices made under subsection 9A(5) of the Act provide the types of ingredients that may be included in listed medicines.

The majority of ingredients that can be included in listed medicines are those that were included in therapeutic goods supplied in Australia before the Act came into operation in 1991. Since then, all new ingredients approved for use in listed medicines have undergone safety assessment by the TGA.

To be consistent with their low risk, regulatory limits/requirements may be placed on the use of certain ingredients in listed medicines. A searchable database of active and excipient ingredients is accessible via the TGA eBusiness Services (eBS) website.

If a person wishes to include an ingredient that is not currently approved for use in listed medicines, the substance must be evaluated by the TGA to ensure it is safe before such use is permitted (refer to ARGCM Part C).

Herbal Ingredients permitted for use in listed medicines

In relation to herbal ingredients, Division 1, Part 4 of Schedule 4 provides a list of herbal substances that are not permitted in listed medicines. Further, Division 2 of Schedule 4 provides a list of plant materials from which herbal substances may be derived for inclusion in listed therapeutic goods, provided they are compliant with certain qualifications.

An additional requirement for a herbal ingredient (to be eligible for inclusion in listed medicines) is that it meets the current definition of a herbal substance, as provided in Regulation 2 of the Regulations (refer to ARGCM Part A: Herbal medicines).

An isolated substance derived from a plant, or synthesised to mimic a naturally occurring plant constituent would not be permitted in listed medicines as a ‘herbal ingredient’. However, the isolated plant constituent may be eligible for use as a new substance if evaluated and approved by the TGA for use in listed medicines (refer to ARGCM Part C).


http://www.ebs.tga.gov.au/

http://www.tga.gov.au/industry/legislation-listing.htm

http://www.comlaw.gov.au/Details/F2012C00455

http://www.tga.gov.au/industry/ebs-elf-userguide.htm

http://www.tga.gov.au/industry/cm-evidence-claims.htm



Colouring ingredients

Colours used in oral products must be approved for such use. Refer to the document ‘Colourings permitted in medicines for oral use’.

Legislative requirements for listed medicines

Requirements of 26A of the Act

A medicine is listed on the ARTG on the basis of information provided by the applicant and a certification by the applicant that the goods (that are the subject of the application) are eligible for listing and meet the requirements of Section 26A of the Act. The Act allows for cancellation of a product from the ARTG if the goods are ineligible for listing and a sponsor’s certification is incorrect.

The applicant certifies (electronically via ELF) that the goods that are the subject of the application meet the requirements for each of the matters referred to in paragraphs 26A(2) (a)-(k) inclusive, and if applicable, paragraph 26A(3) of the Act, that is:

26A (2) The applicant must certify that:(a) the medicine is eligible for listing; and(b) the medicine is safe for the purposes for which it is to be used; and(c) the presentation of the medicine is not unacceptable; and(ca) the medicine does not contain an ingredient that is not specified in a determination under paragraph 26BB(1)(a); and (cb) if a determination under paragraph 26BB(1)(b) specifies requirements in relation to ingredients being contained in the medicine--none of the requirements have been contravened; and(d) the medicine conforms to every standard (if any) applicable to the medicine and to every requirement (if any) relating to advertising applicable under Part 5-1 or under the regulations; and(e) if the medicine has been manufactured in Australia--each step in the manufacture of the medicine has been carried out by a person who is the holder of a licence to carry out that step; and(f) the medicine complies with all prescribed quality or safety criteria that are applicable to the medicine; and(fa) the medicine's specifications comply with any requirements that are prescribed by the regulations for the purposes of this paragraph and that are applicable to the medicine; and(fb) the medicine's label:(i) complies with any requirements that are prescribed by the regulations for the purposes of this subparagraph and that are applicable to the medicine; and(ii) does not make a claim that is inconsistent with any claim made by the applicant in relation to the medicine in, or in connection with, the application; and(fc) the applicant holds information or evidence showing the medicine's specifications will be maintained under the conditions set out on the medicine's label until the medicine's expiry date; and(g) the medicine does not contain substances that are prohibited imports for the purposes of the Customs Act 190, and(h) all the manufacturers of the medicine are nominated as manufacturers in the application; and(i) the applicant has, with manufacturers of the medicine who are manufacturers of the prescribed kind, written agreements containing such matters as are prescribed; and(j) the applicant holds information or evidence to support any claim that the applicant makes relating to the medicine; and(k) the information included in or with the application is correct.26A(3) The applicant must certify that:Subject to subsection (7), if a step of manufacture of the medicine has been carried outside Australia, the Secretary must have certified, prior to the application being made, that the manufacturing and quality control procedures used in each step is acceptable.


http://www.tga.gov.au/industry/cm-colourings-oral-use.htm


TGA Note: In relation to subparagraphs 26A(2)(ca) and (cb) of the Act, these will come into effect when a determination has been made under the provisions of section 26BB of the Act.

Further clarification on the requirements, as per section 26A of the Act, is provided below.

The medicine is eligible for listing

Schedule 4 to the Regulations and listing notices made under subsection 9A(5) of the Act provides the types of medicines/medicine ingredients that are eligible for inclusion on the ARTG as listed medicines.

The medicine is safe for the purposes for which it is to be used

A listed complementary medicine can only: contain ingredients that have been assessed by the TGA to be of low risk; be manufactured in accordance with the principles of good manufacturing practice (GMP); and only carry indications for health maintenance and enhancement or certain indications for non-serious, self-limiting conditions.

Certain regulatory restrictions and/or controls may be imposed to ensure that the use of a listed medicine is consistent with low risk e.g.

label advisory statements

restrictions on dosage

route of administration

plant part or plant preparation; and/or

restriction of the form in which the substance can be presented.

Sponsors must ensure that they are fully aware of any condition or restriction affecting the use of ingredients in their products so that the product fully complies with all legislative requirements applicable in Australia.

Ingredients derived from animal materials may present a safety risk to consumers, as they may contain certain viruses and/or agents capable of transmitting transmissible spongiform encephalopathies (TSEs). Information on the TGA’s approach to minimising the risks associated with TSE is available at Supplementary requirements for therapeutic goods for minimising the risk of transmitting transmissible spongiform encephalopathies (TSEs). Pre-clearance of animal derived ingredients should be sought from TGA before making an application -refer to ‘Pre-clearance application for animal-derived ingredients’.

TGA Note: The TGA approach to minimising the risks associated with TSEs is currently under review.

The medicine presentation is acceptable

The Act provides the following definition:

‘presentation, in relation to therapeutic goods, means the way in which the goods are presented for supply, and includes matters relating to the name of the goods, the labelling and packaging of the goods and any advertising or other informational material associated with the goods.’


http://www.tga.gov.au/industry/cm-forms-animal-derived-ingredients.htm

http://www.tga.gov.au/industry/tse-supplementary-requirements.htm



http://www.tga.gov.au/industry/legislation-listing.htm


All aspects of the product are considered to comprise the ‘presentation’ including: the name; indications; directions for use; warning and cautionary statements; packaging; dosage form; logos; symbols and pictures on a medicine label.

The medicine label may not include any indication that is inconsistent with the information included in the ARTG for the medicine and must comply with applicable standards and advertising requirements (refer to Attachment 8 for more information regarding the requirements for medicine labels).

Section 3(5) of the Act and 3(A) of the Regulations state when the presentation of a good is considered unacceptable.

Section 3(5) of the ActFor the purposes of this Act, the presentation of therapeutic goods is unacceptable if it is capable of being misleading or confusing as to the content or proper use or identification of the goods and, without limiting the previous words in this subsection, the presentation of therapeutic goods is unacceptable:a) if it states or suggests that the goods have ingredients, components or characteristics that they do not have; orb) if a name applied to the goods is the same as the name applied to other therapeutic goods that are supplied in Australia where those other goods contain additional or different therapeutically active ingredients; orc) if the label of the goods does not declare the presence of a therapeutically active ingredient; or (ca) if the therapeutic goods are medicine included in a class of medicine prescribed by the regulations for the purposes of this paragraph—if the medicine’s label does not contain the advisory statements specified under subsection (5A) in relation to the medicine; ord) if a form of presentation of the goods may lead to unsafe use of the goods or suggests a purpose that is not in accordance with conditions applicable to the supply of the goods in Australia; ore) in prescribed cases.

Regulation 3A of the Regulations: Unacceptable presentations(1) For paragraph 3 (5) (e) of the Act, any labelling, packaging or presentation of therapeutic goods (including novelty dosage forms in the shape of animals, robots, cartoon characters or other similar objects) that is likely to result in those goods being mistaken for or confused with confectionery or toys is an unacceptable presentation of the goods.(2) For paragraph 3 (5) (e) of the Act, the presentation of therapeutic goods is unacceptable if the name applied to the goods is not sufficiently distinctive to allow for the identification of the goods for the purposes of recovery.

Generally, the presentation of therapeutic goods is unacceptable if it is capable of being misleading or confusing as to the content or proper use or identification of the goods. Examples of ‘unacceptable’ presentations include:

therapeutically active ingredients are present in the formulation but not declared as such on the label (and/or misleadingly declared as ‘excipients’ in the application)

statements are made attributing a therapeutic role to ingredients that have not been declared as active ingredients (i.e. excipient ingredients)

statements or pictures suggest that the product has uses or actions different from, or in addition to, the indications for use included on the ARTG

presentation of a product is in a form likely to result in its being confused with food (e.g. in confectionery-like novelty shapes and packaging)

product names are used that are likely to be misleading as to the composition of the medicine

the appropriate dosage for all age-groups in the likely target population is not stated (e.g. ‘adults’, ‘children 6-12 years’ etc., as appropriate)



the dosage form or directions are inappropriate for the target population (e.g. a capsule dosage form is not appropriate for infants)

warning or cautionary statements needed for proper usage of the product are omitted

a reformulated product uses the same name as a product previously supplied, without labelling that adequately informs the consumer that the reformulated product has different active ingredients from the product previously supplied

as a general guideline, label flashes such as ‘New formulation’ or ‘Now with …’ should not be used to describe any product, presentation or therapeutic indication / claim which has been available and promoted in Australia for more than 12 months

claims are made that a formulation is ‘hypo-allergenic’ or ‘non-irritant’, unless the sponsor holds supportive evidence from clinical tests that can be produced on request; and

claims are made that a product is ‘free from artificial colours’ if not true.

The medicine conforms to every standard applicable

Therapeutic goods must comply with applicable standards. Criminal or civil penalties can be imposed on persons who import, export, manufacture or supply goods that do not comply with applicable standards (unless a sponsor has consent to supply such a good under Section 14 of the Act – see ‘Consent to supply goods not compliant with certain legislative requirements’). The official standards for regulatory purposes in Australia are the British Pharmacopeia (BP), European Pharmacopoeia (Ph. Eur) and United States Pharmacopoeia – National Formulary (USP/NF) and Therapeutic Goods Orders (TGOs). The following TGOs are relevant to listed medicines:

Therapeutic Goods Order No. 69: General requirements for labels for medicines, as amended (TGO 69) (refer to Attachment 8: Medicine labels)

Therapeutic Goods Order No. 77: Microbiological standards for medicines (TGO77).

Therapeutic Goods Order No. 78: Standards for tablets and capsules (TGO 78); and

Therapeutic Goods Order No. 80: Child-resistant packaging requirements for medicines, as amended (TGO 80).

The medicine complies with manufacturing requirements

Australia has codes of good manufacturing practice (GMP) and quality system requirements for the manufacture of therapeutic goods, including complementary medicines. For more information refer to ‘Manufacturing therapeutic goods’.

In Australia, the Act requires, with certain exceptions, that manufacturers of therapeutic goods hold a licence. Where a product is imported, or if any steps in the manufacture of a listed medicine take place outside Australia, a delegate of the Secretary must have certified the acceptability of the overseas manufacturer’s GMP before the listing application is made. The information needed to establish the standard of an overseas manufacturer is available on the TGA website: ‘For overseas manufacturers’.

Sponsors must ensure that all the manufacturers of the medicine are included in the product ARTG entry. If a sponsor wishes to use a manufacturer that is not included in the ARTG entry, the entry must be amended to include the new manufacturer (see ARGCM Part B: ‘Product variation’).


http://www.tga.gov.au/industry/manuf-overseas.htm

http://www.tga.gov.au/industry/manuf.htm

http://www.tga.gov.au/industry/compliance-with-standards.htm


The medicine conforms to every requirement relating to advertising

Sponsors and advertisers should ensure that all advertising for the medicine complies with any applicable requirements of Part 5-1 of the Act and the Therapeutic goods advertising code 2007 (the Advertising Code). Australian based websites promoting use or supply of therapeutic products are also considered advertising and must comply with all aspects of the Advertising Code.

The medicine complies with all applicable prescribed quality or safety criteria

The sponsor is responsible for the quality of a listed complementary medicine (refer to Attachment 7a: Quality of listed medicines) and must hold information or evidence to demonstrate that the medicine complies with requirements and meets all specifications for the shelf life of the medicine, at the recommended storage conditions and the expiry date included on the label. Sponsors are required to certify under paragraph 26A(2)(fc) of the Act at the time of listing that they hold this information. A delegate of the Secretary can request information or documents about the quality of a listed medicine under paragraph 31(2) (ca) of the Act; and can cancel a listing if it appears to the delegate that the quality of the medicine is unacceptable.

The sponsor holds evidence to support indications made for the medicine

Consistent with their low risk, listed complementary medicines may only carry appropriate indications that are true, valid, not misleading and will not lead to their unsafe or inappropriate use.

At the time of listing, applicants of listed medicines certify under paragraph 26A(2)(j) of the Act that they hold information or evidence to support any claim that they will make about the medicine. Subsection 28(6) of the Act provides conditions of listing that a sponsor must hold evidence which supports the indications made for their medicine and must provide this evidence to the TGA if requested to do so. The evidence to support indications for listed complementary medicines are not subject to pre-market evaluation before listing; however, the TGA may undertake a compliance review of evidence held by sponsors as part of its random and targeted post-market monitoring activities- see ‘Listed complementary medicine compliance reviews’.

Evidence that may be used to support indications can be based on history of traditional use or scientific data. The draft 'Evidence required to support indications for listed medicines (excluding sunscreens and disinfectants)' specifies the type of evidence required to support indications made for listed medicines. Should an applicant wish to make a higher level indication than those permitted for listed medicines (refer to ARGCM Part A: Registered and listed medicines), then the product is required to be registered and undergo full pre-market evaluation by the TGA for quality, safety and efficacy. For further information on medicine registration refer to Part D of the ARGCM.

The information included in the application is correct

Applicants must ensure that the information contained in the application is correct. An incorrect certification against paragraph 26A(2)(k) of the Act could result in the product being cancelled from the ARTG under the provisions of paragraph 30(2)(ba) of the Act.




http://www.tga.gov.au/industry/cm-basics-regulation-compliance-reviews.htm


http://www.tga.gov.au/industry/legislation-tgac.htm



Conditions of listing

Statutory conditions of listing

There are a number of statutory conditions of listing that automatically apply when the medicine is listed on the ARTG. Failure to comply with a condition of listing may result in the cancellation of the medicine from the ARTG.

Section 28 of the Act provides the following statutory conditions of registration or listing.

(2B) If the Secretary includes therapeutic goods in the Register in relation to a person, the Secretary may, by notice in writing given to the person, impose conditions on the registration or listing of those goods.(3) The Secretary may, by notice in writing given to the person in relation to whom therapeutic goods are registered or listed, impose new conditions on the registration or listing or vary or remove conditions imposed under subsection (2B) or this subsection.(5) In addition to any conditions imposed under subsection (1), (2B) or (3), the registration or listing of therapeutic goods (the subject goods) is subject to the conditions that the person in relation to whom the subject goods are registered or listed will:(aa) not supply a batch of the subject goods in Australia, or export a batch of the subject goods from Australia, after the expiry date for the goods; and(ab) not, by any means, advertise the subject goods for an indication other than those accepted in relation to the inclusion of the goods in the Register; and(e) comply, in relation to the subject goods, with any reporting requirements that are prescribed; and(f) if a manufacturer who was not nominated as a manufacturer of the subject goods in the application for the registration or listing of the goods becomes a manufacturer of the goods—inform the Secretary in writing of that fact, no later than 10 working days after the manufacturer becomes a manufacturer of the goods; and(g) if premises that were not nominated as premises to be used in the manufacture of the subject goods in the application become premises used in the manufacture of the goods—inform the Secretary in writing of that fact, no later than 10 working days after the premises are first used for that purpose.(5A) In addition to any conditions imposed under subsection (1), (2B), (3) or (5), the listing of a medicine under section 26A is subject to a condition that the person in relation to whom the medicine is listed will deliver a reasonable number of samples of the medicine if the Secretary so requests:(a) within the period specified in the request; and(b) in accordance with any other requirements specified in the request.The period specified in the request must include at least 10 working days(5B) The listing of a medicine under section 26A is subject to a condition that:(a) each step in the manufacture of the medicine that is carried out in Australia is carried out by a person who is the holder of a licence to carry out that step or who is exempt from the operation of Part 3-3 in relation to that step; and(b) each step in the manufacture of the medicine that is carried out outside Australia is the subject of a certification in force under subsection 26A(3) or 28A(2).(5C) Subsection (5B) does not apply if the medicine is exempt from the operation of Part 3-3.(6) If:(a) in, or in connection with, an application for the listing of therapeutic goods, a claim is made by the applicant in relation to the goods; and(b) the claim is included in the Register in respect of the goods;the listing of the goods is subject to the following conditions:(c) a condition that the sponsor of the goods had, at the time when the claim was made, information or evidence that supported the claim and complied with the requirements (if any) of the regulations;(d) a condition that the sponsor retains the information or evidence at all times while the goods remain listed;(e) a condition that, at any time while the goods remain listed, the sponsor will, if asked to do so by the Secretary, give the information or evidence to the Secretary.



General additional conditions of listing

Section 28 of the Act provides legislative powers for the Secretary to impose, vary or remove additional conditions on listed therapeutic goods at the time the medicine is listed, or any time thereafter. The following general ‘Additional conditions of listing’ are imposed by the delegate of the Secretary at the time a medicine is listed on the ARTG and are notified to the sponsor in writing:

The sponsor shall keep records relating to this listed medicine as are necessary to: (a) Expedite recall if necessary of any batch of the listed medicine, (b) Identify the manufacturer(s) of each batch of the listed medicine. Where any part of or step in manufacture in Australia of the listed medicine is sub-contracted to a third party who is not the sponsor, copies of relevant Good manufacturing practice agreements relation to such manufacture shall be kept.

The sponsor shall retain records of the distribution of the listed medicine for a period of five years and shall provide the records or copies of the records to the Office of Complementary Medicines, Therapeutic Goods Administration, upon request.

The sponsor of the listed medicine must not, by any means, intentionally or recklessly advertise the medicine for an indication other than those accepted in relation to the inclusion of the medicine in the ARTG.

All reports of adverse reactions or similar experiences associated with the use or administration of the listed medicine shall be notified to the Head, Office of Product Review, Therapeutic Goods Administration, as soon as practicable after the sponsor of the goods becomes aware of those reports. Sponsors of listed medicines must retain records of such reports for a period of not less than 18 months from the day the Head, Office of Product Review is notified of the report or reports.

The sponsor shall not supply the listed medicine after the expiry date of the goods.

Where a listed medicine is distributed overseas as well as in Australia, product recall or any other regulatory action taken in relation to the medicine outside Australia which has or may have relevance to the quality, safety or efficacy of the goods distributed in Australia, must be notified to the National Manager Therapeutic Goods Administration, immediately the action or information is known to the sponsor.

Colouring agents used in listed medicine for ingestion, other than those listed for export only under section 25 of the Act 1989, shall be only those included in the list of 'Colourings permitted in medicines for oral use' as amended from time to time.

Substance specific conditions of listing

Specific conditions of listing may be imposed on a medicine in relation to specific ingredients included in the medicine. These conditions are imposed when the product is listed on the ARTG and are notified to the sponsor in writing. For example, the following condition of listing is imposed on listed complementary medicines that contain preparations of the herbal material, Ginkgo biloba leaf extract:

‘The Ginkgo biloba leaf extract used in the manufacture of this medicine must comply with the requirement of Identification Test B of the monograph Powdered Ginkgo Extract in the United States Pharmacopeia 32 - National Formulary 27 (USP32-NF27). This condition does not apply to powdered or dried leaf’.




Variations & sponsor’s rights to appeal against imposition of conditions of listing

Under subsections 28(2B) and 28(3) of the Act, while a medicine is listed on the ARTG, new conditions of listing may be imposed and/or existing conditions may be varied or removed, as determined by a Delegate of the Secretary. A sponsor may also request that a condition of listing be imposed or varied (an application fee may apply) - the Delegate of the Secretary will review the request and sponsors will be advised in writing of the decision.

The imposition or variation of a condition will take effect:

on the day on which the notice is given, if the notice states that the action is necessary to prevent imminent risk of death, serious illness or serious injury; or

in any other case, on the day specified in the notice, which will be a day not earlier than 28 days after the notice is given.

Sponsors are advised in writing of any conditions of listing and may appeal against a decision made under subsections 28(2B) and 28(3) of the Act to impose, vary or remove a condition of listing. There is a time limit for such an appeal and this interval, together with details of the process for an appeal, is advised in the letter from the TGA imposing the conditions (refer ARGCM Part A: ‘Appeal mechanisms’).

Consent to supply goods that are not compliant with certain legislative requirements

Sponsors are able to apply for consent to supply certain therapeutic goods that do not comply with some of the requirements set out in the therapeutic goods legislation. There are two main types of requests, as below.

Non-compliance with prescribed standards

Sponsors can apply to the TGA, in writing, under sections 14 and 14A of the Act, to request consent to supply goods that do not comply with a relevant standard (e.g. BP, Ph Eur, USP or TGOs). Requests should explain why the standard(s) cannot be met and provide details and reasons for proposed alternative(s). Such a request will incur an application fee.

The Delegate of the Secretary will review the request and sponsors will be advised in writing of the decision. Any consent that is provided by the Delegate may have conditions attached to that decision.

Decisions to ‘consent to supply goods that do not comply with a standard’ are required by the Act to be gazetted in the Commonwealth of Australia Gazette.

Request to use a restricted representation

Therapeutic goods advertisements cannot refer to a serious form of a disease, condition, ailment or defect as specified in the Advertising Code. These are known as restricted representations. In some cases, under the Act, the Secretary can permit the use of a restricted representation on the label or in information included in the package of the listed medicine. This permission is defined by Section 42DK(1) of the Act.

If the sponsor or advertiser wishes to publish or broadcast an advertisement containing a restricted representation, the sponsor must make an application under section 42DE of the Act. The application may be sent to the Director of the TGA’s advertising section.


http://www.tga.gov.au/industry/advertising-forms-restricted-representation.htm

http://www.tga.gov.au/about/fees.htm

http://www.tga.gov.au/about/fees-120701.htm


Permission must be obtained before using the representation in advertising therapeutic products to consumers.

Permission for use of restricted representations (on the label or in information included in the package of the listed medicine) is required by the Act to be gazetted in the Commonwealth of Australia Gazette or published on the TGA website.

For listed complementary medicines, approval to use a restricted representation is only likely to be granted if the goods are required to have a warning relating to a disease e.g. “this product should not be used by individuals with diabetes”.

The listing process via the electronic listing facility

Listed medicine application lodgement via the electronic listing facility

Applications to list medicines on the ARTG are done via the electronic listing facility (ELF), which is part of the TGA’s eBusiness services (eBS) framework.

Access to the ELF system is via a secure login on the eBS homepage and requires a user name and password. The electronic listing facility (ELF) user guide is available on the TGA website. In order to get access to ELF, applicants must first submit a client details form to obtain a ‘client identification number’. Having obtained a client identification number, an eBS access request form can be submitted. The TGA will establish access for the applicant to become the ‘E-business administrator’ for their company and then applications for user accounts for themselves and other personnel in their company can be made. For further information about obtaining a client identification number or gaining access to eBS, contact the TGA by phone: 1800 010 624 or email: [email protected].

Access to ELF allows for two types of user:

drafter – users who are drafters can carry out all functions relating to applications, excluding their final submission; and

submitter – users who are submitters can carry out all the same functions as a drafter and also submit completed, validated applications.

The ELF system allows users to:

create new draft applications

create draft applications from an existing ARTG entry

change certain information for current listings

submit completed applications to the TGA for processing

view previously submitted applications

view the details of medicines already listed on the ARTG

view the label checklist; and

view the latest news relating to ELF.

Validation system within the electronic listing facility


mailto:[email protected]

http://www.tga.gov.au/about/forms-client-details.htm

http://www.tga.gov.au/industry/ebs-elf-userguide.htm

https://www.ebs.tga.gov.au/


An application (to either list a new complementary medicine or update information on an existing listed medicine) must pass ELF validation before it can be submitted to the TGA. When the ‘validate’ button in ELF is initiated, the information in the application is compared against the rules and restrictions surrounding listed medicines.

Successful validation of an application does not mean that the product has been approved by the TGA nor does it mean that the product meets all the requirements for listing. The ELF system is a tool designed to allow electronic submission of an application for a listed medicine. The onus of responsibility is with the applicant to certify, upon submission, that the goods that are the subject of the application meet all the requirements of listing.

If the application fails validation, a validation report is generated providing the reasons for failure e.g. if a sponsor applies to list a medicine on the ARTG that requires a mandatory label advisory statement, which was not included in the application, the ELF system will ‘fail validation’ and prevent the sponsor from submitting the application to the TGA. The user will need to update the application accordingly before attempting to re-validate.

If the application passes validation, the status of the application will change from ‘draft’ to ‘passed validation’. Only applications that have the status of ‘passed validation’ can be submitted (via ELF) to the TGA. Note that if the application is not submitted at this time, the status of the application will revert from ‘passed validation’ to ‘draft’ and will be required to undergo re-validation before being able to be re-submitted.

Payment for applications

Fees for a listing application are non-refundable or transferable and must be paid within 14 days of the application being submitted to the TGA. If payment is not received, an email is sent to the applicant notifying them that the application has been rejected. Should the sponsor wish to proceed with the application, a new application will be required.

TGA processing of application

Once payment is processed, the application is released into the listing part of the TGA’s eBS system and assigned an AUST L number. Further processing includes:

initiation of the automated ELF random review selection process

an e-mail message is automatically sent to the sponsor informing them that the product has been successfully listed on the ARTG and providing the AUST L number

a ‘Certificate of medicine listing’ is generated for downloading by the sponsor; and

a ‘Conditions of listing’ letter is generated and sent to the sponsor by the TGA.

The product details will usually be viewable on the eBS website the day after the information has been written to the ARTG.

Diagram 1 shows the process for listing a medicine on the ARTG via the ELF.


http://www.tga.gov.au/about/fees.htm


Diagram 1: The process for listing a medicine on the ARTG via ELF


The application is rejected and sponsor is notified by email.

Response received from sponsor within allocated timeframe.

Product can be marketed.

TGA identification number (TGAIN) assigned to application and application written to ARTG.

AUST L number generated. ELF may randomly select product for a compliance review.

Application checked by the TGA and ‘Conditions of listing’ letter sent to sponsor.

If selected for random compliance review, the sponsor receives a letter requesting information (under Section 31 of the Act). The sponsor is usually given 20 working days to respond.

No

Product cancelled from ARTG (under provision of Section 30 (1C) of the Act.

Response evaluated by TGA. Further steps may include: no action; more information requested; or proposal to cancel product from ARTG.

Sponsor notified by email of application completion and provided the AUST L number. Certificate of listing available in eBS for downloading by the sponsor.

No

Application fees paid within 14 days of application.

Yes

Sponsor obtains a client ID number.Sponsor obtains a user ID and password to access ELF.Sponsor enters product details in ELF.Application passes validation in ELF (note this is not an approval process).Sponsor electronically signs a declaration whereby they certify (as per Part 26 A of the Act) that the application meets all conditions of listing.Sponsor submits application to the TGA.

Yes




Product variation

Following the inclusion of a product as a listed medicine on the ARTG, sponsors may need to update certain product details. Changes in manufacturer, changes in product ingredients or developing marketing strategies may require amendment of the product details of a medicine included listed on the ARTG.

Where the intended change does not create another product altogether i.e. a ‘separate and distinct’ therapeutic good (see below), there are provisions in the legislation for certain details to be amended in a medicines’ ARTG entry. However, if the intended change would create a ‘separate and distinct’ good sponsors are required to submit a new application to list the goods and a new AUST L number will be issued (unless the two medicines are eligible for ‘grouping’ under the Therapeutic Goods (Groups) Order- see ‘The Therapeutic Goods (Groups) Order’ below).

Changes that result in ‘separate and distinct’ goods

Section 16 (1A) of the Act outlines those criteria which make listed medicines (other than ‘export only’1 medicines) ‘separate and distinct’ from other therapeutic goods.

(1A) Medicines that are listable goods (other than export only medicines) are taken to be separate and distinct from other therapeutic goods if the medicines have:(a) different active ingredients; or(b) different quantities of active ingredients; or(c) a different dosage form; or(d) such other different characteristics as the regulations prescribe;

In relation to 16 (1A) (d) of the Act, ‘different characteristics’ for listed medicines (other than ‘export only’ medicines) are provided in Regulation 11:

(a) a different name; or(b) different indications; or(c) a different excipient; or(d) for medicines that contain any restricted ingredients:

(i) a different quantity of a restricted ingredient that is an excipient; or(ii) if the restriction on a restricted ingredient relates to its concentration in a relevant medicine — a different concentration of the restricted ingredient; or(iii) if the restriction on a restricted ingredient relates to its quantity in the recommended single or daily dose in a relevant medicine —

Provisions for product amendment

Where the intended change does not create a ‘separate and distinct’ good, a sponsor may request for certain details to be amended on a medicines’ ARTG entry and maintain the same AUST L number (please be aware that legislation is subject to change and should be regularly checked).

Minor changes to listed medicines on the ARTG (other than those listed for export only) are made via the ELF system. For further information, including the types of changes that incur a fee, refer to ‘Guidance on product changes in ELF 2’.

The ELF system has been designed to allow sponsors to make the same minor changes to multiple current listings under certain circumstances using the ‘Change multiple listings’ form in ELF. These changes are limited to: product names, common manufacturing steps;

1 as defined in subsection 3(1) of the Act


http://www.tga.gov.au/industry/ebs-elf-product-changes.htm


and manufacturers. Note that where the type of change incurs a fee, this fee is applicable to each medicine listing that is changed.

Variation under section 9D of the Act

A sponsor may request, in writing, to the TGA to vary certain information in the ARTG listing for a medicine. The allowable types of requests are set out in section 9D of the Act and include:

Correction of an entry if the entry contains information that is incomplete or incorrect - see subsection (9D(1) of the Act).

Variation of the entry where the only effect would be to either reduce the class of persons for whom the medicine is suitable; or to add a warning, or precaution that does not include any comparison of the medicine with any other therapeutic goods by reference to quality, safety or efficacy (9D(2) of the Act).

Other variations relating the medicine where the Secretary (or Delegate) is satisfied that the variation does not indicate any reduction in the quality, safety or efficacy of the goods for the purposes for which they are to be used (9D(3) of the Act).

The Therapeutic Goods (Groups) Order

As stated above, if a sponsor’s request for variation of a listing entry for a medicine would result in the varied medicine being ‘separate and distinct’ from the existing medicine, then the varied medicine is regarded as a new medicine and must be listed separately. However, in certain circumstances, the new medicine may be listed on the ARTG with the same AUSTL number as the existing medicine (however, individual products within the group are considered separate and distinct products under section 16(1) and (1A) of the Act). This process is called ‘grouping’.

Eligibility for ‘grouping’ is determined by an Order made under section 16 of the Act – currently the Therapeutic Goods (Groups) Order No. 1 of 2001 (Groups Order). The usual fee for an application for new listing applies, but there is only one annual charge for the two grouped medicines.

The circumstances in which two or more therapeutic goods can be ‘grouped’ are set out in the Groups Order and include, for example, where a new medicine is listed by a sponsor that is intended to replace an existing medicine and differs from that medicine by only one of the following:

particular kinds of excipients

indications and/or directions for use; or

product name.

Changing information in the ARTG for ‘grandfathered’ products

‘Grandfathered products’ are those products that were available in Australia prior to the Act coming into effect. When products were ‘grandfathered’ on the ARTG, some entries may not have included indications. In such cases, the following statement is included in the ARTG record:

‘This product accepted for registration/listing as ‘currently supplied’ at the time of commencement of the Act. Indications held in ARTG paper records’.



If a sponsor of a ‘grandfathered’ listed medicine wants to change information in the ARTG for their medicine, the same rules as for other listed medicines apply.

Post-market compliance

The TGA has a comprehensive risk-based system for post market compliance activities which provides timely identification and appropriate regulatory responses to problems associated with the formulation, manufacture, labelling and advertising of medicines. Information on the TGA's approach to managing compliance risk is available at TGA regulatory framework.

The objectives of the TGA’s post-market program for listed complementary medicines are to:

provide assurance of the safety of complementary medicines through a risk-based program of post market monitoring and surveillance

provide consumer confidence in the safety, quality and efficacy of complementary medicines; and

ensure industry compliance with regulatory standards for complementary medicines.

The measures used within the TGA to meet these objectives include:

targeted and random desk-based compliance reviews of listed complementary medicines

targeted and random laboratory testing of medicines and ingredients

inspections of manufacturers to ensure compliance with good manufacturing practice

product vigilance activities

effective co-regulatory approach to control product advertising

targeted and random surveillance of the products in the market place; and

an effective, responsive and timely product recall procedure.

The compliance review of a listed complementary medicine involves:

assessing information about the product against the relevant legislative requirements, including, where relevant, the certifications given by the sponsor at the time the product was listed; and

taking appropriate actions when a breach of the legislative requirements is identified.

A listed complementary medicine may be subject to a number of compliance reviews while it remains on the ARTG.

Listing compliance reviews

A proportion of newly listed medicines are randomly selected by computer, based on a mathematical model, for compliance review. Compliance reviews initiated from this source are referred to as ‘random reviews’.

The TGA also conducts ‘targeted reviews’ when a listed complementary medicine is identified with potential non-compliance issues. These potential non-compliance issues


http://www.tga.gov.au/about/tga-regulatory-framework.htm

http://www.tga.gov.au/about/tga-regulatory-framework.htm


may be brought to the TGA’s attention by internal or external sources. Internal sources may include regular screening of new ARTG entries and information gathered from previous compliance reviews. External sources may include: the public, media, health care professionals, industry, international alerts and information from other regulatory agencies.

Random reviews

If a recently listed medicine is randomly selected at the time of listing for a compliance review, the following information will usually be requested from the sponsor under the provisions of section 31(2) of the Act:

actual label(s) used for the product as it is supplied in Australia

finished product specifications

a certificate of analysis for the last released batch (i.e. a statement about results of testing of the product and how they compare with established acceptance criteria)

a summary of the evidence held by the sponsor that supports the indications and claims made in relation to the product (detailed evidence may be requested during the review, if required); and

copies of completed TSE (transmissible spongiform encephalopathy) questionnaire/s and supporting data, if applicable to ingredients.

The TGA may also view Australian websites for the purpose of considering whether advertising for the product complies with the Advertising Code.

Targeted reviews

If a listed complementary medicine with potential-non compliance issues is chosen for a targeted review, the review may be conducted upon information provided in a complaint or referral (if appropriate), information from other sources and/or information included on the ARTG. A request for information by notice under section 31(2) of the Act may also be required. In addition to the type of information that can be sought for the purposes of a random review (as outlined above), the information requested under section 31 (2) of the Act for a targeted review may include (but is not limited to):

raw material specifications and certificates of analysis

methodology and results in relation to a specific test

copies of permits and/or licences allowing the importation of the medicine if it contains substances that are prohibited imports for the purposes of the Customs Act 1901

details of manufacturing process

promotional and advertising material; and/or

detailed evidence (i.e. full copies of all references ) used to support the indications and claims made in relation to the product.

For more information on the random and targeted compliance reviews, including possible regulatory actions and appeal rights, refer to Listed complementary medicine compliance reviews.






Safety and efficacy reviews

Further to the compliance reviews described above, specific safety and efficacy reviews in response to issues arising in the market place may be carried out for:

ingredients

individual medicines; and

medicine groups.

Laboratory testing program

The TGA undertakes a laboratory testing program which complements the desk-based compliance reviews of listed complementary medicines and evaluation of registered medicines, as well as other post market regulatory activities. The laboratory testing program prioritises therapeutic goods considered to carry a higher risk, while still allowing for responsive testing for issues arising in the marketplace e.g. adverse events and complaints about specific medicines.

The testing program involves the selection of both random and targeted samples for analysis. Samples for the testing program are obtained from manufacturers, wholesalers, pharmacies, hospitals, retail outlets or consumers.

For more information on the laboratory testing program, refer to The Office of Laboratories and Scientific Services (OLSS) activities.

Good manufacturing practice inspections

Manufacturers of therapeutic goods supplied in Australia are subject to regular inspections by the TGA’s Office of Manufacturing Quality. Details of the requirements for the manufacture of listed medicines are specified in the ‘PIC/S guide for good manufacturing practice for medicinal products’. For more information regarding the GMP inspection of medicine manufacturers please refer to ‘Audit of medicine manufacturers’.

Product vigilance activities

The TGA monitors therapeutic products in the market using a range of product vigilance tools to collect and evaluate information relating to the benefits and risks associated with their use. For more information on Australia's processes refer to ‘Therapeutic product vigilance’.

Adverse reaction reporting

The Act and Regulations requires sponsors of all therapeutic goods currently included on the ARTG to report to the TGA adverse reactions that they become aware of for their medicines. The TGA has developed the ‘Australian requirements and recommendations for pharmacovigilance responsibilities of medicine sponsors’ which outlines specific reporting requirements for sponsors of Australian medicines.

The TGA also relies on the public, healthcare professionals and industry to report problems with therapeutic goods so that potential and actual safety concerns can be identified and action taken where required. Refer to ‘Reporting problems’ on the TGA website for the various mechanisms by which adverse reactions and events can be reported.


http://www.tga.gov.au/safety/problem.htm#medicine

http://www.tga.gov.au/safety/australian-pharmacovigilance-sponsors-00.htm

http://www.tga.gov.au/safety/australian-pharmacovigilance-sponsors-00.htm

http://www.tga.gov.au/safety/tga-therapeutic-product-vigilance.htm

http://www.tga.gov.au/safety/tga-therapeutic-product-vigilance.htm

http://www.tga.gov.au/industry/manuf-medicines-audit.htm

http://www.tga.gov.au/industry/manuf-pics-gmp-medicines.htm


http://www.tga.gov.au/about/tga-structure-olss-activities.htm

http://www.tga.gov.au/about/tga-structure-olss-activities.htm


Co-regulatory approach to control advertising

In Australia all advertisements and generic information provided about therapeutic goods directed to the public must comply with provisions of the Act, the Regulations and the Advertising Code. The advertising of therapeutic goods is controlled by a combination of statutory measures administered by the TGA and self-regulation through Codes of Practice administered by the relevant therapeutic goods industry associations.

Further information, on Australia's co-regulatory system of advertising for therapeutic goods, including details of the Therapeutic Goods Advertising Code Council (TGACC), the Complaints Resolution Panel (CRP) and the Complaints Register, may be obtained from the TGACC internet site.

Targeted and random surveillance in the marketplace

The TGA is responsible for on-going surveillance, enforcement and related activities, including investigations into illegal and counterfeit therapeutic goods. Investigations by the TGA may be initiated on the basis of a:

complaint by the public or a healthcare practitioner

referral from a section within the TGA

referral from another Australian agency, such as the Australian Quarantine and Inspection Service, Food Standards Australia New Zealand or Australian Customs; or

referral from an international agency.

Product recalls

A product recall is the removal of therapeutic goods from supply on the Australian market. Recall of any distributed goods may be required for a number of reasons relating to their quality, efficacy or safety e.g. a recall can occur because of problems such as: labelling or packaging errors; contamination issues; or an increase in unexpected side effects etc.

Further information on recalls of therapeutic goods is provided on the TGA website: About recalls.


http://www.tga.gov.au/safety/recalls-about.htm

http://www.tga.gov.au/safety/recalls-about.htm

http://www.tgacc.com.au/


Attachments are common to all parts of the ARGCM (A, B, C & D). Note that the list of attachments and the content will be updated as each part of the ARGCM is released for consultation.



Attachment 1: Compositional guidelines for complementary medicine substances

The purpose of the information contained in a compositional guideline is to provide detailed characterisation of the starting material. For simple complementary substances, this is generally straightforward and may be only a simple extension of the specifications. For complex complementary substances, the compositional information is generally more detailed and contains a significant amount of additional qualitative and quantitative information.

Compositional guidelines are available on the TGA website.

Guidance on compositional guidelines for complementary substances is being developed by the TGA and will be released as part of the consultation process for ‘ARGCM Part C: Evaluation of complementary medicine substances’.


http://www.tga.gov.au/industry/cm-cg.htm


Attachment 2: Data requirements for proprietary ingredients

TGA Note: The information in this Attachment has been revised following feedback from the consultation process for ARGCM Part A.

While there is no safety assessment or evaluation of a proprietary ingredient formulation or ingredients at the time of application, consideration is given to the suitability of the ingredients in the formulation for inclusion in a therapeutic good.

For a proprietary ingredient to be eligible for inclusion in listed complementary medicines, all ingredients (except flavours, fragrances or inks) included in the proprietary ingredient’s formulation must be permitted for use in listed medicines.

Where a listed complementary medicine is the subject of a listing compliance review, the TGA may request additional information on the proprietary ingredient, given that the formulation details for a proprietary ingredient are supplied in isolation of the finished product formulation.

If an ingredient in the proprietary ingredient formulation is not permitted for use in listed medicines (and the proprietary ingredient is not a flavour, fragrance or ink) the ingredient must be evaluated, either as a new substance in listed medicines (see ARGCM Part C) or as part of the evaluation process for a registered medicine, before it can be included in a proprietary ingredient.

While in the proprietary ingredient notification process the advising of a manufacturer is optional, where the manufacture of an ingredient is considered a significant step in the manufacture of the finished product (e.g. a tablet granulation, a tablet coating, an active / excipient pre-mix, or a vehicle for a topical product), evidence of licensing or approval of the manufacturer may be required.

Where a proprietary ingredient is not considered a significant step in the manufacture of the finished product (e.g. most colours, printing inks, flavours and fragrances, and proprietary ingredients whose sole purpose is as a source of the preservative system for the finished product) evidence of Good Manufacturing Practice (GMP) is not required

Information to be included in a notification of a new proprietary ingredient for use in listed medicines

The following information is required to be submitted in the notification of a new proprietary ingredient for use in listed medicines:

1. The purpose of the proprietary ingredient e.g. colour, flavour, fragrance, ink, coating solution, preservative or active pre-mix.

2. The names of all ingredients, in an approved name format consistent with the Australian approved terminology for medicines (e.g. ‘Approved herbal name (AHN)’).

3. The quantitative composition of all ingredients, expressed as a concentration of the total proprietary ingredient.



An exception to points 2 and 3 above are proprietary ingredients used as fragrances and flavours where the declaration of quantitative composition and use of Australian approved terminology, while preferable, is not mandatory.

In addition to the requirements above, specific requirements for different types of proprietary ingredients include:

Colours

Proprietary ingredients used as colours in oral listed medicines are required to contain only colours currently approved for use in oral medicines.

Flavours, fragrances and inks

A limit applies to the concentration allowed in listed medicines for proprietary ingredients that are flavours, fragrances and inks, as provided in the table below:

Proprietary ingredient type Maximum concentration permitted in listed medicines

Flavours 5%

Fragrances 1%

Inks 0.1%

Active pre-mixes

Proprietary ingredients that are classified as active pre-mixes must contain at least one active ingredient and an excipient ingredient.



Attachment 3: Data requirements for herbal materials

Guidance on data requirements for herbal medicines is being developed by the TGA and will be released as part of the consultation process for ‘ARGCM Part C: Evaluation of complementary medicine substances’.



Attachment 4: Identification of herbal materials & extracts Q & A

<http://www.tga.gov.au/industry/cm-identification-herbal-extracts.htm>


http://www.tga.gov.au/industry/cm-identification-herbal-extracts.htm


Attachment 5: Guidance on equivalence of herbal extracts in complementary medicines

<http://www.tga.gov.au/industry/cm-herbal-extracts-equivalence.htm>


http://www.tga.gov.au/industry/cm-herbal-extracts-equivalence.htm


Attachment 6: Guidance on the use of modified unprocessed herbal materials in complementary medicines

<http://www.tga.gov.au/industry/cm-herbal-modified-unprocessed.htm>


http://www.tga.gov.au/industry/cm-herbal-modified-unprocessed.htm


Attachment 7a: Quality of listed complementary medicines

It is a requirement under the Act (26A subsection 5B) that each step in the manufacture of a medicine in Australia is carried out by a licensed manufacturer (unless the therapeutic good is exempt from this requirement). For more information refer to ‘Manufacturing therapeutic goods’. It is an offence, carrying heavy penalties, to manufacture therapeutic goods for human use without a licence unless the manufacturer or goods are exempt. The manufacturer’s licence carries details of the types of manufacture permitted under the licence.

Where a product is imported, each nominated overseas manufacturer must demonstrate an acceptable standard of good manufacturing practice (GMP) as would be required of an Australian manufacturer. Pre-clearance of overseas manufacturers is mandatory for listed complementary medicines. The information needed to establish the standard of an overseas manufacturer is available on the TGA website: ‘For overseas manufacturers’.

Australia has a code of good manufacturing practice and quality system requirements for the manufacture of therapeutic goods, including complementary medicines. Each code/quality system sets out requirements relating to quality management, personnel, premises and equipment, documentation, production, quality control, contract manufacture and analysis, complaints and product recall and self inspection. The observance of these requirements is necessary through all stages of manufacture to consistently provide a high level of assurance of the quality, safety, and efficacy of therapeutic goods. Compliance with the code of good manufacturing practice and quality system requirements in Australia is determined by carrying out regular on-site inspections.

Some complementary medicines are comprised of relatively simple ingredients (e.g. amino acids, mineral salts, vitamins) and the quality parameters applying to such products are essentially the same as for other medicines. Special considerations are required for those complementary medicines that contain complex ingredients that are difficult to characterise and/or certain combinations of multiple active ingredients.

Sponsors should be aware of the following documents that provide specific guidance for complementary medicines:

Annex 7 of the ‘Guide to good manufacturing practice for medicinal products’ provides specific guidance on the manufacture of herbal medicinal products.

‘Supplier qualification’ provides the steps by which supplier qualification may be achieved.

‘Identification of herbal materials and extracts’ provides common questions and answers relating to identification of herbal materials. The overarching principle for the identification of herbal starting materials is traceability to a primary source or certified herb and testing must discriminate between related species and/or potential adulterants/substitutes that are likely to be present.

Sampling and testing of complementary medicines covers the sampling and testing requirements for raw materials used in the manufacture of intermediate, bulk or finished complementary medicine products. It also describes a plan for reduced sampling and testing once an approved supplier has been qualified.


http://www.tga.gov.au/industry/cm-identification-herbal-extracts.htm

http://www.tga.gov.au/industry/manuf-twg.htm#supplier


http://www.tga.gov.au/industry/manuf-medicines-cgmp.htm

http://www.tga.gov.au/industry/manuf-overseas.htm




The guideline ‘Starting material analytical procedure validation for complementary medicines’ describes the minimum approach acceptable to achieve validation of the test procedures used for starting materials for use in complementary medicines. In determining the minimum validation activities to be applied to a test procedure, a risk-based assessment should be undertaken; different approaches may be acceptable but must be documented and able to be justified. Additional validation activities may also be undertaken at the discretion of the sponsor.

The document ‘Equivalence of herbal extracts in complementary medicines’ assists sponsors of medicines containing herbal extracts to determine how and when a herbal extract may be considered 'equivalent' to an ingredient currently included in a therapeutic good and when it may be used as a substitute without causing the product to be considered a different therapeutic good.

‘Use of modified unprocessed herbal materials in complementary medicines’ assists sponsors in identifying situations where the composition of an unprocessed herbal material has been modified to the extent that it is significantly different from the original material approved for use in listed or registered medicines.

‘On-going stability testing for listed complementary medicines’ provides guidance on the development of a stability protocol for 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.

‘Stability testing of listed complementary medicines’ provides common questions and answers on stability testing.

‘Product quality review for listed complementary medicines’ provides guidance on product quality reviews, which are part of GMP requirements.

The guideline ‘Process validation for listed complementary medicines’ provides guidance to ensure that the validation process used is effective in producing a quality medicinal product.

The TGA has also adopted a number of European guidelines which are provided on the TGA website. Of particular relevance to listed medicines are:

‘Guideline on stability testing: stability testing of existing active substances and related finished products’.

‘Note for guidance on quality of herbal medicinal products’ has been adopted by the TGA and provides guidance to achieve consistent quality for products of herbal origin.

‘Note for guidance on specifications: test procedures and acceptance criteria for herbal drugs, herbal drug preparations and herbal medicinal products’ has been adopted by the TGA and provides general principles for setting and justification of a uniform set of specifications for products of herbal origin.


http://www.tga.gov.au/industry/pm-euguidelines-adopted-ocm.htm



http://www.tga.gov.au/industry/pm-euguidelines-adopted-quality.htm

http://www.tga.gov.au/industry/pm-euguidelines-adopted-quality.htm

http://www.tga.gov.au/industry/pm-euguidelines-adopted.htm

http://www.tga.gov.au/industry/manuf-twg.htm#cm


http://www.tga.gov.au/industry/cm-stabillity-testing-qa.htm


http://www.tga.gov.au/industry/cm-herbal-modified.htm

http://www.tga.gov.au/industry/cm-herbal-extracts.htm

http://www.tga.gov.au/industry/cm-analytical-procedure-starting.htm

http://www.tga.gov.au/industry/cm-analytical-procedure-starting.htm


Attachment 7b: Raw material specifications

Guidance on raw material specifications is being developed by the TGA and will be released as part of the consultation process for ‘ARGCM Part C: Evaluation of complementary medicine substances’.



Attachment 7c: Impurities and incidental constituents

Guidance on ‘impurities and incidental constituents’ is being developed by the TGA and will be released as part of the consultation process for ‘ARGCM Part C: New complementary substance for use in listed medicines.



Attachment 7d: Finished product specifications

TGA note: The information below is relevant to Listed complementary medicines (ARGCM Part B). When Parts C and D are revised, the content will be expanded to provide any additional, specific information relevant to registered complementary medicines and new substances for use in listed medicines.

The finished product specification is a description of the product formulation and the set of tests and limits that are applied to the finished medicinal product in order to ensure that every batch is of satisfactory and consistent quality at release and throughout its shelf life. The specifications should monitor all parameters (generally by physicochemical testing) in which variations would be likely to affect the safety or efficacy of the product e.g. storage conditions.

The specifications against which a finished product is tested before release for sale are referred to as the ‘batch release specifications’. The specifications against which a finished product is tested to ensure satisfactory quality throughout its shelf life are referred to as the ‘expiry specifications’. Products tested by the TGA are tested for compliance with the limits in the expiry specifications.

The European guideline ‘Note for guidance on specifications: test procedures and acceptance criteria for herbal drugs, herbal drug preparations and herbal medicinal products’ has been adopted by the TGA and provides general principles for setting and justification of a uniform set of specifications for products of herbal origin.

Where a finished product meets the definition of a monograph in the BP, Ph. Eur. or USP/NF, this is the minimum standard that must be applied in its entirety, otherwise a consent of a Delegate is required (refer to ARGCM Part B ‘Consent to supply goods that are not compliant with certain legislative requirements’).

Note that the BP, Ph. Eur. or USP/NF specifications are expiry specifications. The requirements of applicable general monographs of the BP, Ph. Eur. or USP/NF must also be met unless consent is granted/ provided by the TGA. Examples of these general monographs are those entitled ‘Herbal Drugs’, ‘Herbal Drug Preparations’ and ‘Herbal Extracts’. Note that the most recent edition of any cited pharmacopoeial monograph or standard should be used, or a justification for not doing so included.

Data requirements

Batch formulation

A batch formula should include all of the components that will be used in the manufacture of the finished product and their amounts on a per batch basis (including any overages).

Description of manufacturing process and process controls

Manufacturing steps for listed medicines typically include the manufacture of the dosage form, packaging and labelling, chemical and physical testing, microbiological testing and release for supply. Details of the manufacturing process for the finished product should be available for each manufacturing site and should include information about solvents used, even if they are evaporated from the product during manufacture.








Tests, methods and limits

A table of the tests, test methods and limits should be held by the manufacturer and provided to the sponsor (e.g. assay (GC): 95 to 105 per cent). For dissolution tests, brief details of the apparatus, medium and limit should be available e.g. dissolution (paddle at 50rpm, 900mL of water, 75% (Q) at 30 minutes).

The specifications must include the requirements listed in any TGO and in the BP, Ph. Eur or USP/NF general monograph applicable. If there is no BP, Ph. Eur. or USP/NF monograph specific to the product, the specifications must include all of the requirements in the BP, Ph. Eur. or USP/NF general monographs (for dosage forms).

Batch release and expiry specifications for all ingredients including excipients

Where the product is subject to a monograph in the BP, Ph. Eur. or USP/NF, the expiry specifications must include all of the tests and limits in that monograph. It is a legal requirement for finished products that have a monograph in the BP, Ph. Eur. or USP/NF to comply with the requirements of that monograph unless another appropriate method has been validated. Note that this refers to the current editions of each pharmacopoeia.

A summary list that gives details of both the batch release and expiry specifications should be included. Where the expiry specifications differ from the batch release specifications, this should be noted. It is unusual for batch release specifications and expiry specifications to be identical. If this is the case, it should be specifically noted. The specification code number and date should also be included.

The batch release limits must be chosen so as to guarantee that all batches will comply with the expiry specifications throughout the product’s shelf life. At a minimum, the expiry specifications should include all of the tests that are included in the batch release specifications. Tighter limits are usually applied to critical parameters at batch release, to allow for possible changes to the product during storage (e.g. decomposition of the active ingredient).

Proprietary ingredients

The specifications applied to proprietary ingredients should be appropriate to the type of ingredient, and its function and proportion in the finished product. For an ingredient blend that contains the active substance, it may be appropriate to have tests for the identification and content of the active ingredient, and impurity tests.

Colouring ingredients

The document ‘Colourings permitted in medicines for oral use’ is available on the TGA website. While topical products may include colours other than those listed in this document, the specifications for colourings used in topical products should be comparable with those permitted for oral use.

In the absence of a BP, Ph. Eur. or USP/NF Monographs, colours shall conform either to the specifications in the FAO / WHO Compendium of Food Additive Specifications (as published by the Joint Food and Agriculture Organization (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) on its website), or to those defined in the European Commission Directive 95/45/EC (on specific purity criteria concerning colour for use in foodstuffs – as amended from time to time).

Batch-to-batch variations in the amount of ingredients




The reasons for a proposed range or ranges in the quantities of any ingredients should be recorded.

For some active ingredients, such as herbal substances, the weight of the active raw material used in a batch of the formulated product may vary according to the content of a standardised component. Details of the actual weight of active raw material used for each batch of finished product must be recorded.

Losses of active ingredient may occur during the manufacturing process or during storage, as a result of the instability of the substance. An overage is where the amount of an ingredient added during manufacture is greater than that nominated on the product label. Overages may be used to ensure compliance with expiry specifications. The use of overages must be justifiable- the use of an overage to compensate for poor analytical methodology or poor stability performance is not usually considered sufficient justification. Manufacturers should ensure that batch release assay values (where performed) reflect any overages used in the product.

Expiry limits for active ingredients are included in Therapeutic Goods Order 78 (TGO 78). An exemption is required where use of an overage leads to specifications that are broader than that allowed by the BP/TGO 78.

It is recognised that it may be necessary to vary the quantities of certain excipients from batch to batch in order to achieve acceptable results during the manufacturing process. For immediate release complementary medicines, Table 1 provides the permissible changes to the nominal amounts of certain excipients.



Table 1. Changes permitted to the nominal amounts of certain excipients

Excipient type Acceptable range around the nominal formulation

pH-adjusting ingredients qs*

Volume-adjusting fluids qs

Quantity of ingredients whose function is to contribute to viscosity +/- 10%

Colour in tablet coating (but not in body of tablet) qs

Solvent in granulating fluid qs

Granulating fluid (fixed composition) +/- 10%

Disintegrant (even if the excipient serves more than one role in the formulation)

up to +25%

Coating solution qs

Talc and water-soluble lubricants and glidants -25% to +100%

Water-insoluble lubricants and glidants, except talc (e.g. magnesium stearate, stearic acid)

+/- 25%

Filler (bulking agent) in hard gelatin capsules +/- 10%

Polishing agents qs

Carriers and potency adjusting ingredients for materials of biological and herbal origin

+/- 10%

Filler (bulking agent) in tablets and soft gelatin capsules to account for the changes in the item above

+/- 10%

*qs – quantum satis or ‘as required’

Control of critical steps and intermediates

Tests and acceptance criteria that are applied to critical steps or intermediates in the manufacture of the finished product should be documented; for example, manufacturing acceptance criteria for a tablet granulation or in-process controls for pH during mixing of a syrup.



Information required for a finished product specification

Product details

name of product

product code

date of specification

revision or version number

name and signature of the appropriate company official

description of physical appearance

detail of physical tests performed (and limits) including total weight, weight variation, tests and limits, disintegration tests and limits

a description of the dosage form including any special character (e.g. modified release); and

packaging type and closure

recommended storage conditions

recommended shelf-life

details of the full formulation including all active and all excipient ingredients (including coatings and capsule shell ingredients)

the type of container and closure for the product, including the materials used; and

a table of the ingredients in the product and their purpose in the formulation (e.g. active, disintegrant, antimicrobial preservative). Note this table should provide greater detail than just the product formulation. It should include overages, if any, and a reference to the quality standard for each of the ingredients (e.g. compendial monograph reference or manufacturer’s specifications number); and

Information required for every ingredient in the product should include:

the Australian approved name (AAN)

the quality standard and / or grade

any overages used

the nominal (label claim) amount; and

clear identification as to whether the amount of substance is expressed in terms of the salt/complex, or base. If the label claim is not in the same terms, the amount in terms of the label statement should also be stated.

Additional information required for each active ingredient in the product

Information on the active ingredient should be sufficient to adequately characterise the active ingredient and demonstrate that the active ingredient used in the complementary medicine will be of appropriate and consistent quality.

The types and level of detail of information depend on the nature of the active ingredient. The following information should be provided:



what is analysed in each batch (marker vitamin for a multi-vitamin product)

what is analysed on rotation, and the frequency

what is not analysed at all, and how the ingredient’s presence is verified in such cases

describe briefly the analytical procedure (HPLC, AA, TLC) applied to each ingredient in the final product; and

unless covered in a separate document; both the expiry and release limits – upper and lower.

Where the active ingredient is difficult to characterise quantitatively, such as some complex herbal extracts, it may be difficult to adequately control the active ingredient through quantitative specifications. In this case, a combination of specifications and the detailed method of manufacture may be required to adequately characterise the substance.

Additional information required for herbal ingredients in the product is:

botanical species and plant part

if an extract, the amount of the extract, the extraction ratio, extracting solvent and diluting medium and the equivalent amount of dried plant; and

if direct compression tableting materials are used, then, as with herbal extracts, describe the amount of material used, its equivalence to active substance, and describe the diluent.

For additional guidance on herbal ingredients, see Attachment 3 ‘Data Requirements for herbal materials and Attachment 9a: ‘Guidance on the term ‘quantified by input’ for listed complementary medicines’.

Residual solvents

It is necessary to consider the total amount of residual solvents that may be present in the finished product. This includes solvent residues resulting from the manufacture of the finished product.

Depending on the amounts and types of solvent residues, it may be appropriate to include a test and limits for residual solvents in the finished-product specifications. Tests and limits in the specifications, or justification for not including them, should be based on the BP Appendix VIIIL – Residual Solvents.

If the control of residual solvents in the finished-product specifications is deemed to be unnecessary, then the basis for this decision should be justified and available to the TGA.

Microbiological requirements

Note that medicines required to be sterile cannot be included on the ARTG as listed medicines.

All non-sterile dosage forms should include limits for microbial content in the finished product batch release and expiry specifications. The Therapeutic Goods Order No. 77 – Microbiological Standards for Medicines (TGO 77) specifies the minimum microbiological requirements with which a medicine must comply throughout its shelf life.

Microbial specifications for solid oral or dry powder products may not be necessary if it can be demonstrated during product development that the product is at a very low risk of contamination and microbial growth.


http://www.tga.gov.au/industry/legislation-tgo.htm

http://www.tga.gov.au/industry/legislation-tgo.htm


It is not a requirement that every batch of a product (with a low risk of contamination) be tested at batch release. Once it has been demonstrated, by testing a number of routine production batches to establish a product history, that the manufacturing processes do not permit contamination by excessive numbers of microorganisms, testing may be reduced to once every 6 to 12 months or some other selected basis (e.g. every tenth batch).

However, products likely to support microbial growth such as products with significant water content (e.g. creams, gels and oral liquids) should include tests and limits for microbial content in both the batch release and expiry specifications.

For products containing an antimicrobial preservative(s), expiry specifications should include tests to ensure the efficacy of preservatives. Given that the effectiveness of many preservatives is pH dependent, the specifications for such products should usually include the pH range within which preservative efficacy will be ensured. The expiry limits for the preservative should be supported by preservative efficacy testing that is performed during stability testing.

Analytical procedures and validation

Details should be available for all analytical methods used in the specifications, together with validation data that demonstrate (among other things) accuracy, precision, specificity (e.g. freedom from interference by excipients, degradation products and other likely impurities), and linearity.

Guidance on validating analytical test methods can be found in ‘Process validation for listed complementary medicine’. Complete validation data are not required for methods described in a TGA recognised monograph or standard. However, data must be available to show there is no excipient interference and the equipment used must be suitable for the purpose.

Justification of finished product specifications

The suitability of the tests, limits and test methods for the finished product should include reference to the results of the method validation studies and the ability of the specifications to guarantee the quality and consistency of the finished product. A justification for any unusual features in the finished-product specifications should be detailed.

The limits applied at batch release should be available and justified in terms of their ability to ensure that the product will remain within the expiry specification throughout the product shelf life. For example, if the batch release and expiry limits for assay are identical, the implication is that there will be no loss of the active ingredient throughout the shelf life. Any changes or unusual variability in the results obtained in the stability studies require justification in this respect.

The reasons for proposed range(s) in the quantities of any ingredients should be able to be justified. Validation data should be provided in support of any unusually wide range(s).

Container information

A description of the container and closure system should be provided, including the materials used. The suitability of the container should be justified in terms of its compatibility with the product and its capacity to protect the product from mechanical damage, moisture and light.

In the case of commonly used types of pharmaceutical package, it may be sufficient to simply describe the packaging. If the packaging material is unusual, then detailed information should be provided on the composition of the material, together with an


http://www.tga.gov.au/industry/manuf-twg.htm#validation

http://www.tga.gov.au/industry/manuf-twg.htm#validation


assessment of the potential for undesirable material to be leached from the packaging into the medicine.

Child-resistant closures

‘TGO 80 – Child-Resistant Packaging Requirements for Medicines’ applies to medicines containing any of the substances specified in the First Schedule to the Order, as well as other medicines that imply, through their presentation, that the packaging is child-resistant. Presentations considered to indicate child-resistant packaging include closures with the push-down and turn graphics, typically used on child-resistant caps, and label statements referring to the closure as being child-safe or designed to prevent access by children.

TGO 80 specifies requirements relating to the use of child-resistant packaging (CRP) for medicines which may present a significant risk of toxicity to children if accidentally ingested and also specifies the performance requirements that packaging must meet in order to be considered child-resistant.

Tamper-evident packaging

Tamper-evident packaging of therapeutic goods that may be vulnerable to tampering (either deliberate or accidental) is important in ensuring consumer safety and the integrity of the goods.

‘The code of practice for the tamper-evident packaging (TEP) of therapeutic goods’ refers to therapeutic goods that are unscheduled or in Schedule 2 or 3 of the SUSMP and are administered transdermally, orally or come into contact with mucous membranes. Sponsors may choose to apply TEP to therapeutic products.

Dose measuring device

Where the packaging includes or refers to a dose measuring device, the device should be shown to comply with the test and limits of the BP Appendix XIIL – Uniformity of Weight (Mass) of Delivered Doses from Multi-dose Containers. This is to ensure that the device consistently delivers an accurate amount of oral dosage forms such as granules, powders and liquids.

Dose measuring devices included with a container may be required to be included on the ARTG as a device. Refer to the ‘Australian regulatory guidelines for medical devices’ for further information.

Dose dispensing from a container

Where the packaging dispenses a dose from a container, other relevant standards may be applicable. For example, oral drops must comply with the test for dose and uniformity of dose of oral drops included in the BP monograph for Oral Liquids.

Information for tablets and capsules

If the product is in tablet or capsule form, sponsors should ensure that it complies with the applicable TGO or general monographs of the BP, Ph. Eur. and USP/NF. Where this is the case, the finished-product specifications must include details of any test required (e.g. disintegration), referencing the test limits and test method defined in the Order or monograph.

Dissolution may be an indicator for bioavailability and is considered an important part of quality control for solid, oral-dosage forms. Sponsors of all solid dosage forms where feasible, are encouraged to employ dissolution testing. Disintegration testing is not


http://www.tga.gov.au/industry/devices-argmd.htm

http://www.tga.gov.au/industry/packaging-tamper-evident-cop.htm


required where dissolution testing has been performed. TGO 78 specifies the tablets and capsules for which dissolution testing must be included in the specifications. Further information on dissolution requirements for specific dosage forms can be found in USP ‘Drug Release’ and ‘Disintegration and Dissolution of Dietary Supplements’.

If there is a BP monograph for the product, but it does not include a dissolution test, and there is also a USP/NF monograph for the product that does include a dissolution test, sponsors are encouraged to include the USP/NF dissolution test in the finished-product specifications.

If there are no pharmacopoeial monographs for the product, or a related product, that includes a dissolution test, the development of a dissolution test at the time of product development is encouraged. Once developed, dissolution testing is a valuable tool in validating changes to the product post-listing.

The results of dissolution testing from stability studies should be used in setting the dissolution limits for expiry. Note that the inclusion of a dissolution test in the finished product specifications means that the product must meet the limits throughout its shelf life, but it does not necessarily mean that every batch must be tested at release.

Modified release products should include dissolution testing data in the finished product specification. If sponsors wish to employ a non-pharmacopoeial dissolution test, a justification for the proposed test and limit should be available.

Information for Modified-release products

Modified-release products are dosage forms that have been formulated to release the active ingredient(s) at a different rate or to release the active ingredient(s) in a different region of the body compared to a conventional counterpart.

They include products that have been developed for exceptionally rapid release of the active ingredients. Examples of when modified-release dosage forms may be appropriate include:

the active ingredient is absorbed and eliminated rapidly (e.g. it has a half-life of less than 6 to 8 hours) and has a correspondingly rapid loss of effectiveness

the site of absorption is not restricted to a particular part of the gastrointestinal tract

the product is intended for use in conditions of sufficient duration to warrant the use of a sustained-release formulation; or

the product has to provide therapeutically effective doses of the active ingredient throughout the dosage interval.

Information about different types of modified-release tablets and capsules is given in Therapeutic Goods Order No. 78 (TGO 78) General Standard for Tablets and Capsules.

Modified-release formulations should be supported by evidence to demonstrate that the product meets controlled-release claims. Data should include a justification for the modified-release formulation based on physiological, clinical and/or bioavailability data. In vitro and animal studies may be used as supporting data.



Attachment 7e: Finished product stability

Guidance on finished product stability is being developed by the TGA and will be released as part of the consultation process for ‘ARGCM Part D: Registered complementary medicines’.



Attachment 7f: Certificates of analysis for finished products

A certificate of analysis (used for ‘release for supply’ purposes) is a document certified as a truthful statement of the tests and test results for an individual, manufactured batch of a particular finished product.

The certificate should provide the following information:

the primary manufacturer

the product name

the date of the certificate and the date of the testing

the batch number of the product

the tests and the test results

the acceptable test specifications; these are the test limit or the range of results for each test with which the batch must comply before release for supply; and

the signature of the appropriate company official.

The range of tests applied to a product is at the discretion of the manufacturer and will depend on a number of factors including the type(s) of active ingredients and the pharmaceutical dosage form. Reference should be made to standard pharmacopoeial texts for guidance on tests and test methods. Some products are also subject to requirements under Therapeutic Goods Orders (TGOs). For example, a herbal tablet formulation should include tests for at least:

identity tests for the presence of actives

disintegration time

uniformity of weight

assay of actives (if possible); and

tests for contaminants (if the starting materials are not tested for these individually) such as microbiological contaminants, heavy metals and foreign matter.

Quantified by input

Guidance on the use of the term ‘quantified by input’ for listed complementary medicines’ (Attachment 9A) describes the criteria under which a manufacturer is not required to analyse an ingredient in a finished product. It also details the wording that should be used on a certificate of analysis, where an actual ingredient has been ‘quantified by input’.

Variations in content of some active ingredients

For some active ingredients, such as herbal substances, the weight of the active raw material used in a batch of the formulated product may vary according to the content of a standardised component. Details of the actual weight of active raw material used for each batch of finished product must be held.



Overages of active ingredients

Overages may be used during manufacture. An overage is where the amount of an ingredient added during manufacture is greater than that nominated on the product label. Overages may be used to ensure compliance with end-of-shelf-life specifications. Losses of active ingredient may occur during the manufacturing process or during storage, as a result of the instability of the substance. For regulatory compliance purposes, TGO 78 includes expiry limits for active ingredients.

Manufacturers should ensure that batch release assay values (where performed) reflect any overages used in the product.

Details and justification for overages must be available. An exemption is required where use of an overage leads to specifications that are broader than that allowed by the BP/TGO 78.

The use of an overage to compensate for poor analytical methodology or poor stability performance is not usually considered sufficient justification.

NB: Overages are not to be included in the formulation details section of an ELF application

Routine variations in excipients

It is recognised that it may be necessary to vary the quantities of certain excipients from batch to batch in order to achieve acceptable results during the manufacturing process. Consistent with the requirements for non-prescription medicines, the following changes to the nominal amounts of certain excipients may be made. Note that this applies to only immediate release complementary medicines (See Table 1 Attachment 7C.)



Attachment 8: Medicine labels

TGO 69 provides the following definition:

‘label’ means a display of printed information upon, or securely affixed to, the container and any primary pack containing the goods’

A product’s ‘label’ includes the label attached to the container (e.g. bottle, tube, sachet or blister pack) and the primary pack (e.g. carton). Sponsors must ensure the product label and any printed information supplied (e.g. a package insert) complies with all relevant legislation and advertising requirements and also, is appropriate for the claimed therapeutic use in the targeted population group e.g. an illustration of an infant would be inappropriate for a product with a dose range starting at 6 years.

Medicine labelling must comply with the following:

The ‘Therapeutic Goods Order No 69- General requirements for labels of medicines’ (TGO 69) (and amendments TGO 69A, TGO 69B and TGO 69C) provides the requirements for medicine labels including how information should be displayed, e.g. active ingredient, dose, directions for use, expiry date, batch number etc.

Part 5-1 (Advertising and generic information) of the Act and the Advertising Code outline the advertising requirements for therapeutic goods so that the marketing of a product promotes quality use and does not mislead or deceive the consumer.

The ‘Required advisory statements for medicine labels’ (RASML) provides a list of mandatory advisory statements that, under TGO 69, must be included on a medicine label.

Any conditions of listing (see ‘Conditions of listing’ ARGCM Part B).

Language on medicine labels

The information on the labels should be written in clear and easily understood English. Text in languages other than English may be included on labels, provided that all mandatory information is on the label in English. A certified declaration may be required, during a listing compliance review of the product, to confirm that the meaning in the other language text is the same as that given in the English text.

Ingredient details on medicine labels

The TGO 69 and Part 2 of Schedule 2 to the Regulations require that labels include the name and quantity of all active ingredients, any preservative in a topical product and the names of specified excipients. All information on medicine labels should use Australian approved terminology (refer to ARGCM Part A and the TGA’s approved terminology for medicines). If sponsors wish to include details of other ingredients (that are not required to be declared) on a label, the following conditions apply:

The selective disclosure of an individual excipient on a medicine label is generally not acceptable (with the exception of cosmetic components in a sunscreen), as this could imply that the excipient has a therapeutic activity. For example, it is not acceptable to make a statement, ‘contains vitamin C’ when the product contains a sub-therapeutic dose of ascorbyl palmitate (vitamin C) as an antioxidant excipient.


http://www.tga.gov.au/industry/medicines-approved-terminology.htm

http://www.tga.gov.au/industry/medicines-approved-terminology.htm


It is acceptable to declare on a medicine label excipients that are known to cause adverse effects in some individuals (however, in most cases, this is already a requirement under the First Schedule to TGO 69).

Quantitative or qualitative statements on the medicine label of all excipient ingredients in the product are permitted.

Directions for use and dosage on medicine labels

TGO 69 requires that labels state the product’s method, dose and frequency of administration. Non-specific directions such as ‘take as required’ are generally not appropriate. Directions for use must clearly identify the dose for each target population for which the product is intended i.e. adult and child doses. If the product is not intended for use in children, the label should specify that the dose is an adult dose (e.g. ‘adult dose: 10 mL’). Where the labelling gives doses for children over a specified age, the label should include a statement such as ‘Do not give to children under 12 years’ or ‘Not recommended for children under 12 years’.

Where a product has multiple indications and the different indications require different doses (as supported by the evidence held by the sponsor), the directions for use should specify the particular recommended daily dose for each indication.

Labelling should recommend use of metric measuring devices to accurately measure doses. Where the recommended doses cannot be measured using a readily available metric measuring device, a suitable measuring device should be provided in or as part of the pack. References to culinary ‘spoonful’ (e.g. teaspoon, dessertspoon, tablespoon etc.) are not acceptable.

Warning statements and required representations on medicine labels

The TGO 69 and Part 2 of Schedule 2 of the Regulations require warning statements and required representations, where these apply to the medicine, to be included on the medicine label. Some warning statements have specific requirements in relation to the text appearance and position on labels.

Many warning statements relate to safe use of the medicine (e.g. where an incorrect route or method of administration may be hazardous) and sponsors should be aware that failure to include them on a medicine label could result in product recall.

Some indications require mandatory warning statements on the label. For example, products with the indication ‘relief of the symptoms of colds’ require two warnings to be included on the label, in addition to directions for use:

‘If symptoms persist consult your healthcare practitioner’ (or words to that effect); and

‘Adults only’ or ‘Not to be used in children under two years of age without medical advice’ (or words to that effect).

Negative disclosure statements on medicine labels

A product label may include a statement that the product does not contain a substance known to cause adverse effects in some individuals (e.g. ‘gluten free’, ‘alcohol free’) provided the statement is true.

If the label includes a statement that the product does not contain a substance, sponsors should ensure that the substance is not contained in any ingredient in the product



formulation. For products containing proprietary ingredients, sponsors must check with the manufacturer of the ingredient to ensure the integrity of the label statement.

Inclusion of a statement that the product contains no sugar is acceptable provided sucrose, glucose, fructose and other sugars with a cariogenic potential or the potential to affect diabetics are not included in the formulation. In addition, the formulation of the active ingredient(s) (in addition to excipients) should be carefully examined to ensure that carriers etc. do not contain sugars with a cariogenic potential.

Distinctiveness of labels and reference to other products

To reduce the possibility of confusion among consumers, the name and presentation of a new product should be clearly distinguishable from other products.

A sponsor may refer to another product (within their product range) on the medicine label, provided that their other product is included on the ARTG (or exempt from the requirement to be included on the ARTG).

Product labels for listed medicines are not submitted to the TGA at the time of listing via ELF and are therefore not approved by the TGA. However, medicine labels may be reviewed as part of the TGA’s random and targeted compliance reviews (see ARGCM Part B: ‘Listing compliance reviews’).



Attachment 9a: Guidance on the use of the term ‘quantified by input’ for listed complementary medicines.

This guidance document should be read in conjunction with the Attachment 9B ‘Questions & answers on the use of ‘quantified by input’.

Background

Under good manufacturing practice (GMP), for medicinal products it is a requirement that all active ingredients in medicines be tested to confirm that the content complies with prescribed standards. However, it is recognised that in some circumstances this may not be possible or practical to achieve. Where it is established that such medicines are manufactured in accordance with the principles of the GMP, and other criteria are met, quantitative testing of the active ingredient in the finished product may be omitted and the ingredient in the product ‘Quantified by input’ (QBI).

Scope

This guidance document describes the criteria under which a manufacturer of a listed complementary medicine would not be required to assay an active ingredient in a finished complementary medicine product. The document also provides wording that a manufacturer could use on a certificate where an active ingredient (see note 1) has been QBI. Please note that 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.

It is intended that this document be used by manufacturers, in consultation with the relevant sponsor, as part of product development. It is most relevant where a quantitative claim (see note 2) is made for a particular active ingredient in a complementary medicine. However, in certain circumstances, these principles may also be applied to excipients and/or components in ingredients that are considered to be ‘restricted ingredients’ (see note 3). Diagram 1 provides a flow chart that outlines the assessment process that should be applied.

Principles

Consistent with the Therapeutic Goods Administration’s (TGA) risk-based approach to the regulation of medicines, it may be possible to justify certain situations where it is not necessary to assay an active ingredient in every batch of finished product. In such situations, the content of an active ingredient may be estimated from the amount dispensed during the manufacture of the product. This practice is termed ‘Quantified by input’ (QBI). However, based on risk to consumers, it is not appropriate to apply this practice to all ingredients. The application of the principles of QBI to a particular active ingredient in a product is based on the following factors:

1. The manufacture of the complementary medicine product must be undertaken in a facility that is deemed by the TGA to be GMP complaint.

2. The ingredient in the medicine is approved for use in listed medicines. For ingredients that have quantity-based restrictions, it is expected that an assay in the finished product would be performed. However in some specific



circumstances, where justified, rotational testing or the performance of a validated limit test may be acceptable.

Where a manufacturer does not intend to assay an active ingredient in a batch of a complementary medicine, this decision must be supported by written justification. The justification may be reviewed at a TGA GMP inspection of the manufacturer or by the TGA during a listing compliance review. In justifying the use of QBI and therefore not undertaking an assay, the issue of what constitutes 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. In such cases discussion with the TGA may help to resolve the issue.

Assessing the suitability of an active ingredient in a batch of a listed complementary medicine for quantifying by input:

When determining whether the content of an active ingredient/component in a listed complementary medicine could be QBI, the following points need to be addressed:

the intent to make quantitative claims for the ingredient in the finished product

any restrictions applicable to the ingredient or any component in the ingredient, e.g. referred (see Note 4) to in the Standard for the Uniform Scheduling of Drugs and Medicines(SUSMP) or 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)

the performance of any relevant quantitative testing (assay) of the active raw material by a TGA licensed or approved manufacturer; and

the availability of a validated assay method for the ingredient/component in the finished product.

Many ingredients of biological origin used in complementary medicines are not single component ingredients (e.g. shark cartilage, non-standardised herbal extracts). In these situations, where the ingredient/component is not subject to any restrictions and no associated quantitative claims are made in the finished product, the ingredient may be quantified by input. The words ‘Not assayed, quantified by input’, or words to that effect, may be used on the certificate of analysis of the finished product.

In cases where the active ingredient consists of a single component, or where a quantitative claim is made for any component within an ingredient, it is usually expected that the ingredient/component would be assayed in the finished product. This is particularly important when, to ensure the safety of the medicine, an ingredient/ component is subject to restrictions in any relevant legislative instrument.

However, in certain situations it may be justifiable to QBI such ingredient/components, including those that are restricted, and not assay the finished product. This could occur as part of a rotational testing program (see Note 5), where, for certain batches of medicine, the assay of a specified ingredient/component would not be performed. In these cases, a statement such as: ‘Quantified by input. This ingredient is part of a rotational testing program and was not assayed in this batch’ may be used on the certificate of analysis of the finished product.

Further, the use of a validated limit test (see Note 6) may be able to be justified. The use of such a test may provide an acceptable level of assurance that the ingredient/component is present at a level which would exclude the medicine from a schedule of the SUSMP or restriction as defined in the Regulations.



In other instances, the formulation of the medicine may be of such complexity that a validated assay method for the ingredient in the finished product is unavailable or is difficult to achieve. To be able to apply the principles of QBI to the manufacture of these medicines, the potency of the ingredient/component must have been established by a TGA licensed or approved manufacturer prior to inclusion in the formulation. Once this has been done, the words ‘Not assayed. Quantified by input’ may be used for the ingredient/component on the certificate of analysis of the finished product.

For multi-active medicines (e.g. multivitamin/mineral complexes) it may be justifiable to use QBI for ingredients for which a validated assay method for testing the finished product is available. If the quality and safety of the medicine is assured through other testing, the assay of certain ingredients may be put on a rotational testing program. Again, this can only be applied if the potency of the ingredient/component has been established by a TGA licensed or approved manufacturer prior to inclusion in the formulation. Once this has been done, the words ‘Not assayed, quantified by input’ or ‘Quantified by input. This ingredient is part of a rotational testing program and was not assayed in this batch’ may be used for the ingredient/component on the certificate of analysis of the finished product.

Implementation

Consistent with the principles and guidance in this document, 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 Diagram 1: Flow chart for determining the requirement for assay of an active ingredient).


Any ingredient or component subject to a restriction or referred to in the SUSDP should be assayed in the finished product. Rotational testing may be acceptable where supported by documentation. 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’.

The words ‘Not assayed, quantified by input’ (or words to this effect) may be used on certificates for the finished product

Has the potency of the active ingredient/component been tested by a TGA licensed or approved manufacturer?

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 effect). 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 or component in the finished product?

The ingredient should be assayed in each batch of the finished product.

Ingredient or component can be quoted on the certificate for the finished product as ‘Not assayed, quantified by input (or words to this effect). Rotational testing for this ingredient/component 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 the ingredient, or any component in the ingredient, referred to in a schedule of the SUSDP or otherwise restricted?

No e.g. herbal extractTextTextText

Yes e.g. standardised herbal extracts

Yes

No

Yes

No

NoTextTextText

Yes e.g vitaminTextTextText

Is the active ingredient primarily a single component ingredient?

Is a quantitative claim made for any component in the documentation for the product?

No e.g. shark cartilage with no equivalency statements or a simple herbal extract stated as being equivalent to the fresh herb.

YesTextTextText


Diagram 1: Flow chart for determining the requirement for assay of an active ingredient



Refer to notes 7, 8 and 9 when considering this flowchart

Notes

Note 1: An ‘active ingredient’ is the therapeutically active component in a medicine’s final formulation which is responsible for its physiological or pharmacological action (as defined in Section 52F of the Act).

Note: 2: A ‘quantitative claim’ is a claim made for a medicine which states that a particular quantity of an ingredient, or component in an ingredient, is present in the medicine.

Note 3: An ingredient, or component within an ingredient, is considered to be ‘restricted’ where there is a quantity or concentration based restriction referred to in a legislative instrument such as the SUSMP, Schedule 4 of the Regulations, a condition of listing, etc (see definition of ‘restricted ingredient’ below).

11(2) A substance is a restricted ingredient if:(a) it is an ingredient in a relevant medicine; and(b) for that medicine to be, or to remain, eligible for listing, the permissible quantity or concentration of the substance in the medicine is restricted by operation of any of the following:(i) Schedule 4;(ii) the Poisons Standard;(iii) a condition imposed under section 28 of the Act;(iv) a standard under section 10 of the Act;(v) the Required Advisory Statements for Medicine Labels document;(vi) any other provision in these Regulations or in the Act that deals with eligibility of medicines for listing.11(3) In this regulation:relevant medicine means a medicine that is listable goods or listed goods and that is not an export only medicine.

Where a quantity based restriction may apply to an ingredient or component it is generally not appropriate for that ingredient to be QBI because of the on-going need to confirm that the medicine meets the quantity based restriction and remains safe. This means that any ingredient referred to or mentioned in any of the legislative instruments may generally not be QBI, irrespective of whether or not the quantity based restriction applies.

Note 4: A substance may be ‘referred’ to or mentioned in the SUSMP, but it may not be ‘included’ in a Schedule. That is, it may not be subject to the requirement of the SUSMP entry because the quantity/concentration of the ingredient is below that specified in the entry. It should be noted that, by definition, a listed medicine cannot contain any substance that is included in a Schedule.

For example, Vitamin D preparations are referred to in the SUSMP for internal human therapeutic use, although preparations containing 25 micrograms or less of vitamin D per recommended daily dose are not subject to restrictions in the SUSDP. Therefore:

medicines which contain vitamin D at levels that provide a daily dose of more than 25 micrograms are included in Schedule 4 and cannot be used in Listed medicines; and

for Listed medicines which provide 25 micrograms or less of Vitamin D, a Vitamin D assay of the finished product must be performed.

In instances where reference to an ingredient in a legislative instrument only relates to a requirement for a warning statement (e.g. Hypericum perforatum in Schedule 4, Part 4, Division 2 of the Regulations), that ingredient may, subject to the principles of this document, be eligible for quantification by input. Please note that this would not be the case if the warning statements are quantity dependent.



Note 5: Rotational testing is the performance of specified tests on pre-selected batches and/or at predetermined intervals, rather than on a batch-to-batch basis with the understanding that those batches not fully tested must still meet all acceptance criteria established for that product. This represents a less than full schedule of testing and should be supported by written justification. This justification may be reviewed at a TGA GMP inspection of the manufacturer or by the OCM.

Note 6: A ‘limit test’ is a semi-quantitative assay for a component in a product. It generally provides a pass/fail result for the component. 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 is present in a product at levels consistent with low risk and, subject to the principles of this document, be eligible for quantification by input. In instances where restrictions in the SUSDP or in Schedule 4 of the Regulations apply to an amount of an ingredient/ component 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.

Note 7: QBI does not replace the need to comply with relevant statutory requirements.

Note 8: Any alternative wording must clearly indicate that an assay of the ingredient in the finished product has not been performed.

Note 9: The use of a validated limit test to establish that an ingredient, or component in an ingredient, is not subject to a quantity based restriction, may provide suitable justification to permit the ingredient to be quantified by input.



Attachment 9b: Questions and answers on the use of ‘quantified by input’

The approach taken by TGA (to permit the quantification by input of low risk ingredients in a finished complementary medicine) recognises the technical difficulties that may be associated with quantifying certain ingredients in multi-ingredient products.

The sponsor of a medicine has ultimate responsibility for the product. However, the certifying of a product to be in compliance with its marketing authorisation is considered a step of manufacture. This step, also known as ‘Release for supply’ requires a suitably licenced to manufacturer (within Australia) or that the sponsor hold a suitably annotated GMP clearance on behalf of an overseas manufacturer. Some third parties, such as consultants, may hold a licence to manufacture therapeutic goods which is limited to the step of ‘Release for supply’. In releasing the product for supply, the site authorised to perform that step 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).

1. Could a new formulation (product) be produced that uses QBI for an ingredient, or a component in an ingredient, in the product without a QBI justification having been completed prior to launch?

NO: It is important, when developing a new product, to ensure that justification of the use of QBI for any component, or ingredient, is included as part of development, including verification of a starting material supplier's competency to provide a valid assay result.

2. In the case of a finished product containing a herbal extract, where no quantitative claim is being made for a component in the extract:

i. Is it appropriate to state on the Certificate of Analysis, ‘Not assayed, quantified by input’?

YES: Provided the ingredient or component of the ingredient is not referenced in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP), or not otherwise restricted.

ii. Do I have to do a profile test for QBI release?

NO: Profile testing is considered to be an identity test and identity tests are not relevant to QBI. The identity of each ingredient should be assured before it is used in manufacture.

3. A generic test method has been validated for a particular active ingredient in a defined group of products, but has not been fully validated for the assay of the ingredient in a new product. The method gives expected and reproducible results for the active in batches of the new product.

i. Can the result of the assay of the active be included on a certificate of analysis for that batch of the finished product?

NO: The analytical result cannot be included on the certificate of analysis for that batch. Validation needs to be performed to confirm the validity of the test method when applied to the new product. See guidance document ‘Finished product (medicine) analytical procedure validation’.


http://www.tga.gov.au/industry/cm-analytical-procedure-finished.htm





ii. Should the ingredient be declared as QBI because the test method has not been fully validated for the active in this product?

NO: A QBI statement may only be used for the ingredient if it meets QBI guidance criteria. That is, there is written justification that a validated assay method is not available for the ingredient or component in the finished product. Otherwise a validated analytical test method must be applied.

It should be possible to validate an analytical method for a group of products, provided the grouping justification is scientifically sound and defendable. In this case the justification should be documented. The information may be reviewed by an inspector during a GMP inspection or by the TGA during a listing compliance review.

Note: It is expected that each laboratory will have a standard operating procedure for assay validation. This could include reference to the TGA or other validation guidance document. Laboratories are expected to follow their standard operating procedure to develop a valid assay method.

4. (a) In terms of equipment, level of knowledge and cost, how much effort should be made to develop a valid assay for an active in a finished product?

There are a range of techniques that most laboratories would be expected to have available or have access to. These techniques would be expected be consistent with those generally used for quality assurance in pharmacopoeial monographs. The use of novel or highly specialised technologies is not expected for testing complementary medicines.

It is expected that analysts will have a full working knowledge of the equipment and its capabilities, and the operators in a company should be able to develop new methods using the equipment. Preferably, there should be a standard operating procedure for the development of new assay methods which includes searching the relevant literature. For example, when using a high-performance liquid chromatography (HPLC) assay method, if appropriate markers, reference compounds and columns are reasonably available, then these should be used. It would not be acceptable to justify the use of QBI because the HPLC conditions could not be varied sufficiently to produce a valid assay.

4. (b) While a valid assay is being developed, in the interim can QBI be used?

NO: This is not acceptable practice for either an existing or new product (see also question 1 above).

As the question of whether or not QBI is appropriate for a particular ingredient should be part of product development, the relevant decisions should be made before generation of a certificate of analysis. Therefore, written justification for use of QBI should be developed and included with product specifications. Although this involves the manufacturer, the sponsor is still ultimately responsible for the product and is required to obtain such details from the manufacturer prior to commencement of supply.

5. Does the QBI guideline apply to both listed (AUST L) and registered (AUST R) complementary medicines?

QBI generally applies to listed complementary medicines. However, the use of QBI for a registered complementary medicine could form part of the TGA registration application/ evaluation process where, in certain instances, the principles may be able to be applied.



6. In some situations, the use of QBI for an ingredient, or a component in an ingredient, is subject to a validated limit test*. If the limit test has not yet been validated for the product containing the ingredient/component can QBI be used?

No: The limit test must be validated before QBI can be used.

*A 'limit test' is a semi-quantitative assay for an analyte in a product. It should be developed with suitable specificity, precision and accuracy, but it is not expected to provide an exact value.

7. Can QBI be used if a manufacturer states that they cannot perform a validated limit test:

(a) on a restricted component in the finished product?

YES: If the level of the restricted component in the herbal extract has been tested by a TGA licensed or approved manufacturer AND the level has been shown to be acceptably low. In all cases, some testing must be performed on each batch of the finished product. That is, sufficient testing should be carried out to provide assurance that importantly, the medicine is safe, and of intended quality.

(b) of the standardised component of a herbal extract in a finished product?

YES: If the potency of a standardised component has been tested by a TGA licensed or approved manufacturer. In all cases, some testing must be performed on each batch of the finished product. That is, sufficient testing should be carried out to provide assurance that importantly, the medicine is safe, and of intended quality.

8. My manufacturer is using a herbal extract that is standardised to a particular component. However, I am not relying on that component in my claim substantiation, nor is it included on the product label or in my electronic listing facility application. Do I have to assay the component if no quantitative claim is being made?

NO: It is not subject to QBI requirements, because no claim is included in the Australian Register of Therapeutic Goods (ARTG) or made on the label for the standardised component in the herbal extract that is used in the finished product.

9. In the case of an ingredient that is not subject to restrictions, may I choose whether to quantify the ingredient by input or to include the ingredient as part of a rotational testing program?

NO: Rotational testing and QBI are based on separate principles. If a valid assay is available for the ingredient in the finished product, this testing must be performed. It is possible that a rotational testing program may be implemented, with appropriate justification. In this case, for specific batches, the ingredient may be noted on the certificate of analysis as 'Quantified by input - part of a rotational testing program'. Conversely, if a valid assay is NOT available, and other relevant criteria are met, the ingredient may be able to be 'Quantified by input' in the finished product. The use of QBI is based on the inability to assay the ingredient at all.

10. When using rotational testing, can the testing laboratory (or the sponsor) select a particular active(s) to be tested from all eligible actives that might be rotationally tested?

NO: Rotational testing is the performance of specified tests on pre-selected batches and/or at predetermined intervals, rather than on a batch-to-batch basis. A predetermined rotational testing program for all relevant actives should be applied. This is undertaken with the understanding that those batches not being tested still must meet all acceptance



criteria established for that product. It is inappropriate to always test the same active(s) from a list of rotationally tested actives. Under a rotational testing program, manufacturers and/or sponsors can require additional testing of an active for any reason, for any batch, containing that active.

11. What is meant by a validated assay method and a valid assay result?

As a minimum, a validated assay method for an active ingredient in a finished product is one that meets the requirements of the TGA's ‘Finished product (medicine) analytical procedure validations for complementary medicines’ guideline'. A valid assay result is one that has been obtained using a validated assay method.

A valid assay result may be in or out of specification. Batches out of specification may be acceptable in certain circumstances - where they are in accordance with the ARTG record of the product and all deviations and 'out of specification' results have been satisfactorily addressed. These activities and their records are subject to inspection by the TGA.

12. Is there standard template that can be used for a QBI justification statement?

NO: There are certain essential elements that should be included in QBI justification documentation. Documentation should be appropriately authorised. As a minimum, the following information should be included:

the identity of the product (AUST L)

the sponsor and manufacturer

the ingredient(s) that have been QBI; and

justification of why QBI has been used, consistent with the criteria detailed in Attachment 9a: Guidance on the use of the term ‘quantified by input for complementary medicines.




Therapeutic Goods AdministrationPO Box 100 Woden ACT 2606 Australia

Email: [email protected] Phone: 1800 020 653 Fax: 02 6232 8605www.tga.gov.au

Draft ARGCM Part B R12/1074080

http://www.tga.gov.au/

Documents

Australian regulatory guidelines for complementary … · Web viewThe Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and Ageing,