Drug Approval System of

Australia

Drafted Version

(Expected to be revised)

May 2016

APEC Harmonization Center

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Abbreviation

ACPM: Advisory Committee on Prescription Medicines

ACSOM: Advisory Committee on the Safety of Medicines

ADEC (Australian Drug Evaluation Committee)

ADR: Adverse Drug Reaction

API: Active Pharmaceutical Ingredient

CoA: Certificate of Analysis

CPP: Certificate of a Pharmaceutical Product

CRO: Contract Research Organization

CTD: Common Technical Document

DMF: Drug Master File

EMA: European Medicine Agency

GCP: Good Clinical Practice

GLP: Good Laboratory Practice

GMP: Good Manufacturing Practice

ICH: International Conference on Harmonisation

ICH-CTD: ICH Common Technical Dossier

IND: Investigational New Drug Application

MoH: Ministry of Health

NCE: New Chemical Entity

NDA: New Drug Application

NDP: New Drug Product

OTC: Over-the-counter

SMF: Site Master File

VMP: Validation Master Plan

Notice

1. Due to the purpose of this document, most of the information was quoted directly

from the website or related guidelines of each country’s drug regulatory agencies,

and reviewed by the agencies.

2. This document is limited only to pharmaceutical products, not applicable to

biological and herbal products.

3. When referring to the contents of this document, check the up-to-date

information including related laws and regulations, and revision of guidelines.

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Table of Contents

I. Drug Regulatory Agency ·································································· 5

1. Therapeutic Goods Administration······················································· 5

1.1 Organization ·········································································· 5

1.2 Task···················································································· 5

1.3 Website················································································ 5

II. Related Laws ··············································································· 6

1. Therapeutic Goods Act 1989 ····························································· 6

III. Classification of Pharmaceutical Products ·········································· 7

1. New drug ···················································································· 7

2. Generic drug ················································································ 7

3. Orphan drug ················································································· 8

3.1 Orphan drug designation······························································ 8

IV. Drug Approval System ·································································· 9

1. Investigational new drug application ···················································· 9

1.1 Overview ··············································································· 9

1.2 Procedure ·············································································· 10

1.3 Review period ········································································ 11

1.4 Required dossiers ···································································· 11

2. New drug application approval·························································· 12

2.1 Procedure ·············································································· 12

2.2 Pre-submission meetings···························································· 14

2.3 Review period ········································································ 15

2.4 Required dossiers ···································································· 15

3. Generic drug approval application ····················································· 19

3.1 Procedure ··············································································19

3.2 Review period ········································································ 20

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3.3 Required dossiers ···································································· 20

3.4 Patent-approval linkage system····················································· 22

4. Orphan drugs ·············································································· 23

4.1 Designator ············································································· 23

4.2 Designation procedure ······························································· 23

4.3 Required dossiers for designation ·················································· 24

4.4 Review period········································································· 25

4.5 Required dossiers ···································································· 25

4.6 Incentives ············································································· 26

5. Priority review ············································································· 27

V. Others ······················································································· 28

1. Good Manufacturing Practice ··························································· 28

1.1 GMP conformity assessment of oversea manufacturing product (including

drug substance)······································································· 28

1.2 Overview of the GMP clearance process for overseas

manufacturer·········································································· 28

1.3 Maintenance of a clearance·························································· 36

1.4 Flowchart for GMP clearance······················································· 36

2. Drug Master File ·········································································· 38

2.1 Overview ·············································································· 38

3. Labeling and package inserts···························································· 39

3.1 Overview ·············································································· 39

4. Certificate of a Pharmaceutical Product ··············································· 39

5. Manufacturing Licenses ································································· 40

5.1 Requirements for manufacturers ··················································· 40

6. Fees ························································································· 40

6.1 Prescription medicines ······························································ 40

6.2 Non-prescription medicines ························································ 41

6.3 Good manufacturing practice ······················································· 42

VI. References ················································································ 43

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List of Figures

Figure 1. Type of clinical trial in Australia

Figure 2. Workflow 1 non-generic application in Australia

Figure 3. Workflow 2 generic application in Australia

Figure 4. Generic Drugs Work Flow Chart and Review Period in Australia

Figure 5. Flow chart for GMP clearance

List of Tables

Table 1. Clinical trials and fee in Australia

Table 2. Generic drug approval procedure in Australia

Table 3. CTD Module for generics in Australia

Table 4. Required assessment type

Table 5. Documentary evidence requirements

Table 6. TGA's target timeframes for GMP Clearance applications

Table 7. Registration fees for prescription medicines in Australia

Table 8. Administrative charge for prescription medicines in Australia

Table 9. Annual charges for prescription medicines in Australia

Table 10. Registration of non-prescription medicines including complementary

medicines in Australia

Table 11. Overseas manufacturers GMP clearance fees in Australia

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I. Drug Regulatory Agency

1. Therapeutic Goods Administration

1.1 Organization1

TGA is a part of the Australian Government Department of Health. The TGA’s Brancheds

are arranged into three major Divisions- Market Authorisation Division, Monitoring and

Compliance Division and Regulatory Support Division. The National Manager of TGA is a

member of the Department of Health’s Executive Committee and is supported by a Principal

Medical Adviser and a Principal Legal Adviser.

1.2 Task2

1) Head offices

Market Authorisation Division: is responsible for undertaking evaluations of

applications to approve new therapeutic products for supply in Australia. Senior

managers in the Division make decisions whether to approve or reject market

authorisation of medicines, medical devices and blood and tissues that are imported,

exported, manufactured and supplied in Australia.

Monitoring and Compliance Division: is responsible for ongoing monitoring of

therapeutic products approved for supply in Australia to ensure they meet the

necessary standards throughout their lifecycle.

Regulatory Support Division: provides whole-of-agency regulatory support

services that enable the TGA to undertake its regulatory responsibilities. This

includes the legal, finance, information technology and information management,

parliamentary, planning and education and human resource management services.

2) Review centers

Medicines Authorisation Branch - responsible for approving prescription and non-

prescription medicines

Complementary Medicines Branch

Devices Authorisation Branch

1.3 Website

www.tga.gov.au

1 http://www.tga.gov.au/tga-structure

2 http://www.tga.gov.au/tga-structure#mad

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II. Related Laws and Regulations

1. Therapeutic Goods Act 1989

The objective of the Therapeutic Goods Act 19893 is to provide for the establishment and

maintenance of a national system of controls relating to the quality, safety, timely availability

and, where necessary, efficacy, of therapeutic goods that are :

- used in Australia, whether produced in Australia or elsewhere; exported from Australia;

and to provide a framework for the States and Territories to adopt a uniform approach

to control the availability and accessibility, and ensure the safe handling of poisons in

Australia.

The Therapeutic Goods Act 1989, and Regulations and Orders set out the requirements for

inclusion of therapeutic goods in the Australian Register of Therapeutic Goods, including

advertising, labelling and product appearance. The legislation also sets out the rights of

individuals to have a decision that affects them, reviewed.

The Therapeutic Goods Act 1989 consists of 8 chapters:

Chapter 1: Preliminary

Chapter 2: Australian Register of Therapeutic Goods

Chapter 3: Medicines and other therapeutic goods that are not medical devices

Chapter 4: Medical devices

Chapter 5: Advertising, counterfeit therapeutic goods and product tampering

Chapter 5A: Enforcement

Chapter 6: Administration

Chapter 7: Miscellaneous

Chapter 8: Repeal and transitional provisions

3 http://www.tga.gov.au/therapeutic-goods-act-1989-poisons-standard

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III. Classification of Pharmaceutical Products4

Australia has a two-tiered system for the regulation of medicines, including

complementary medicines:

- Higher risk medicines must be registered on the Australian Register of Therapeutic

Goods (ARTG), which involves individually evaluating the quality, safety and

effectiveness of the product.

- Lower risk medicines containing pre-approved, low-risk ingredients and that make

limited claims can be listed on the ARTG.

1. New drug

The TGA does not have a classification for the new drug but received applications and

fees as follow classified:

1) New chemical entity

2) New biological entity

3) New fixed combination

4) Extension of indications

2. Generic drug5

An 'originator' product (sometimes referred to as the 'innovator' product) is a medicine

that has been approved for marketing in Australia on the basis of a full dossier which

may include chemical, biological, pharmaceutical, pharmacological-toxicological and

clinical data.

The Therapeutic Goods Regulations 1990 (link is external), Regulation 2, defines a

generic medicine as a medicine that, in comparison with a registered medicine:

a) has the same quantitative composition of therapeutically active substances, being

substances of similar quality to those used in the registered medicine or previously

registered medicine

b) has the same pharmaceutical form

c) is bioequivalent

d) has the same safety and efficacy properties

Bioequivalence refers to whether the generic medicine releases the active ingredient

into the bloodstream at the same rate and to the same extent as the original medicine

Bioequivalence is demonstrated by conducting a bioavailability study in which

volunteers (usually healthy) are given the original Australian medicine and, on a

separate day, the generic medicine

Blood samples are taken at different times and the rate and extent of absorption of the

active ingredient into the blood is compared for the generic and original medicines

4 http://www.tga.gov.au/medicines-and-tga-classifications

5 http://www.tga.gov.au/book/6-generic-products

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3. Orphan drug6

An orphan drug is defined as a medicine, vaccine or in vivo diagnostic agent that is:

intended to treat, prevent or diagnose a rare disease; or not commercially viable to supply to

treat, prevent or diagnose another disease or condition.

The full definition of an orphan drug can be found in the Therapeutic Goods Regulations

1990 (link is external), section 16H.

3.1 Orphan drug designation7

A medicine, vaccine, or in vivo diagnostic agent is eligible to be designated as an

orphan drug if it:

- is intended to treat, prevent or diagnose a rare disease; or

- is not commercially viable to supply in Australia to treat, prevent or diagnose

another disease or condition.

Provided a medicine containing the same active ingredient was not registered for use

in the same disease or condition before 1 January 1998, orphan designation may be

granted for:

- a previously unregistered medicine

- an already registered medicine with a new 'orphan' indication

6 http://www.tga.gov.au/orphan-drugs

7 http://www.tga.gov.au/book/what-eligible-be-designated-orphan-drug

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IV. Drug Approval System

1. Investigational New Drug application8

1.1 Overview

Figure 1. Type of clinical trial in Australia

Under the Act, medical products for human use that are imported, manufactured in

Australia, supplied by a corporation, supplied interstate or to the Commonwealth, or exported

must be included in the Australian Register of Therapeutic Goods (ARTG) unless specifically

exempted from the operation of Part 3-3 of the Act. The CTN / CTX Schemes are required

for all clinical trials involving:

any product not entered on the Australian Register of Therapeutic Goods; or

use of a registered or listed product in a clinical trial beyond the conditions of its

marketing approval.

1.1.1 Clinical Trial Notification (CTN) Scheme

The CTN Scheme is a notification scheme only. It was intended to be a notification

scheme for those trials that did not require detailed scientific evaluation prior to

commencement. Specifically it was intended to be used for trials relating to new indications

or patient populations for products already approved for marketing, or for products which had

been evaluated and approved for clinical trials by either the US or UK regulatory authority.

Phase III trials are generally conducted under the Clinical Trial Notification (CTN) scheme.

1.1.2 Product required for clinical trial permission

The CTX Scheme is an approval process.

8 https://www.tga.gov.au/clinical-trials

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1.2 Procedure9

Clinical trials in which registered or listed medicines or medical devices are used within

the conditions of their marketing approval are not subject to CTN or CTX requirements. Such

Phase IV studies or trials, as long as they meet the definition of clinical research in the

NHMRC National Statement, still need to be approved by an HREC before the trial may

commence. Again, there is no legal requirement for this.

1.2.1 Clinical Trial Notification (CTN) Scheme

All material relating to the proposed trial, including the trial protocol is submitted

directly to the relevant HREC by the researcher at the request of the sponsor. The TGA

is not required to review any primary data relating to the clinical trial. The HREC is

responsible for ensuring the appropriate assessment of the scientific validity of the trial

design and the safety and efficacy of the medicine. It is also responsible, in the context

of the trial protocol, for assessing the ethical acceptability of the proposed trial. An

HREC may decide that it is not willing to review a trial under the CTN scheme and

may advise the investigator that it will review the trial only under the CTX scheme. The

institution or organisation at which the trial will be conducted, referred to as the

'Approving Authority', gives the final approval for the conduct of the trial at the site,

having given due regard to advice from the HREC.

CTN trials cannot commence until the trial has been notified to the TGA and the

appropriate notification fee paid. There is no legal requirement for sponsors to wait for

acknowledgment of the CTN notification but many do so to ensure that all procedures

have been followed correctly. The Therapeutic Goods Regulations require notification

to be in a 'form' approved by the Secretary of the Department of Health and Aging, i.e.

on the current CTN form.

The current fee for a CTN application is $240. There is some confusion over the fee

required for multicentre trials. The current guidelines clearly set out that there should

be a separate fee for each act of notification but that there is one fee for all sites notified

at the same time.

1.2.2 Clinical Trial Exemption (CTX) Scheme

A sponsor submits an application to conduct clinical trials to the TGA for evaluation

and comment. A TGA Delegate evaluates the information provided within 50 working

days and decides whether or not to object to the proposed Usage Guidelines for the

product. If an objection is raised, trials may not proceed until the objection has been

addressed to the Delegate’s satisfaction. Essentially if not addressed the CTX

application is rejected.

If no objection is raised, the sponsor may conduct any number of clinical trials under

the CTX application without further assessment by the TGA, provided use of the

product in the trials falls within the original approved Usage Guidelines. Each trial

conducted must be notified to the TGA.

9 http://www.tga.gov.au/clinical-trials-glance

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A sponsor cannot commence a CTX trial until written advice has been received from

the TGA regarding the application and approval for the conduct of the trial has been

obtained from an ethics committee and from the institution at which the trial will be

conducted.

The current fee for a CTX application is $15,300 (Phase II and III) and $1,240 (Phase I).

There is no fee listed for the submission of additional data should TGA raise concerns

over an application. It has been reported that it is TGA practice to charge an additional

full fee for the submission of supplementary data. This is not the case; supplementary

data within the one application are free. If an application is rejected or withdrawn, and a

new application is made, then a new fee is payable. There is no fee for notification of

subsequent trials under the CTX scheme.

There are two forms, each reflecting these separate processes (Parts), which must be

submitted to TGA by the sponsor:

- Part 1 constitutes the formal CTX application. It must be completed by the sponsor

of the trial and submitted to TGA with data for evaluation.

- Part 2 is used to notify the commencement of each new trial conducted under the

CTX as well as new sites in ongoing CTX trials. The Part 2 form must be submitted

within 28 days of the commencement of supply of goods under the CTX.

1.3 Review period

The current fee for a CTX application is $15,300 (Phase II and III) and $1,240 (Phase I).

There is no fee listed for the submission of additional data should TGA raise concerns over

an application. It has been reported that it is TGA practice to charge an additional full fee for

the submission of supplementary data. This is not the case; supplementary data within the one

application are free. If an application is rejected or withdrawn, and a new application is made,

then a new fee is payable. There is no fee for notification of subsequent trials under the CTX

scheme.

Trial Fee

CTX 30 days AU$ 1,240

CTX 50 days AU$ 15,300

CTN AU$ 240

Table 1. Clinical trials and fee in Australia

1.4 Required dossiers10

1.4.1 CTN

The investigator is required to submit a research proposal to the HREC. The proposal

would normally include the protocol, the investigator's brochure, related patient

information, supporting data and the CTN form (Appendix 2).11

HRECs usually have

their own standard format for applications to conduct a clinical trial at their institution.

10

http://www.tga.gov.au/publication/access-unapproved-therapeutic-goods-clinical-trials-australia 11

http://www.tga.gov.au/form/ctn-scheme-forms

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A new online form is now available for the clinical trial notification (CTN) scheme,

which is the first in a series of developments to improve and streamline the

administrative processes of the clinical trial schemes.

1.4.2 CTX application & contents for medicine

Part 1: Contains administrative information and information complementary to the

summaries of scientific information.

Part 2: Contains a summary of chemical, pharmaceutical and biological documentation.

Part 3: Contains a summary of pharmaco-toxicological documentation.

Part 4: Contains a summary of clinical documentation.

Part 5: Contains the specified documentation on all fatal or life threatening adverse

events that have been associated with the use of the medicine prior to the date of the

application.

Part 6: Contains 'Information for Human Research Ethics Committees'.

2. New Drug Application approval

2.1 Procedure

2.1.1 Flowchart for NDA12

Figure 2. Workflow 1 non-generic application in Australia

12

http://www.tga.gov.au/fact-sheet-changes-prescription-medicines-registration-process-streamlined-

submission-process

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Figure 3. Workflow 2 generic application in Australia

2.1.2 Procedure

1) Pre-submission13

Pre-submission begins with the lodgement of the Pre-submission planning form

(PPF).14

A key element of the PPF is the provision of Module 2 (or equivalent) data

which contains information on the scope, scale, and the complexity of the proposed

dossier.

2) Submission15

a) Confirmation of dossier delivery by the expected lodgement date

b) Verification that any application fee has been paid

c) Workflow planning and it administration

d) Consideration of the application against the tga regulatory requirements

e) Issuance of a Notification letter, including notice of evaluation fee payable, if

applicable.

3) First round assessment16

All data provided in the dossier are considered by the evaluators during the first

round assessment phase.

Consolidated section 31 request from all evaluation areas within the TGA is

compiled and sent to the applicant by the date specified in the Planning letter.

4) Consolidated section 31 request response17

It allows applicants time to consider the TGA’s consolidated section 31 request for

information or documents, prepare a response and send the response to the TGA.

5) Second round assessment18

13

http://www.tga.gov.au/book/phase-1-pre-submission 14

http://www.tga.gov.au/form/pre-submission-planning-form-ppf 15

http://www.tga.gov.au/book/phase-2-submission 16

http://www.tga.gov.au/book/phase-3-first-round-assessment 17

http://www.tga.gov.au/book/phase-4-consolidated-section-31-request-response

- 14 -

Evaluators will consider the response provided by the applicant to the section 31

request (if applicable) and complete the evaluation of the data.

6) Expert advisory review19

The evaluation reports are considered by the delegate. The delegate may seek

independent advice on issues concerning the application. The main advisory group for

prescription medicines is the Advisory Committee on Prescription Medicines (ACPM),

Specific issues may also be referred to the Pharmaceutical Subcommittee (PSC) of the

ACPM, or to the Advisory Committee on the Safety of Medicines (ACSOM)

7) Decision20

The TGA delegate will determine whether the application is to be approved (possibly

modified or varied) or rejected.

8) Post-decision21

Administrative and regulatory activities are completed. Any outstanding payments are

finalised (if applicable) and the ARTG entry is finalised.

2.2 Pre-submission meetings22

What is beneficial?

Meetings can be beneficial for the sponsors and TGA to provide a consistent and

transparent approach to obtaining a common understanding of the therapeutic good,

what is required for evaluation and the evaluation process and any issues that may

need to be resolved prior to submitting applications. Meetings can enable the sponsor

and TGA to plan for the submission and to manage timeframes and resources required

for evaluation. Pre-submission meetings are most beneficial for complex therapeutic

goods, new or emerging technologies, combination of technologies and specific

regulatory issues for therapeutic goods that have multiple applications.

How to request a pre-submission meeting?

Complete the meeting request form and attach it to an email. Send the email at least

four weeks before the proposed meeting date to one of the following

- For prescription medicines:

the TGA case manager atstreamlinesubmission@tga.gov.au

- For other therapeutic goods, the relevant office in TGA for OTC medicines,

complementary medicines, medical devices, biologicals

How to prepare a pre-submission meeting?

- To ensure that both the sponsor and the TGA gain maximum benefit from the

meeting you should prepare a meeting dossier. Email the meeting dossier to the

TGA case manager. Organise the dossier content according to the proposed agenda,

number the pages sequentially, and include a table of contents, appendices, cross-

references and tab differentiating section.

- Content of a meeting dossier for pre-submission meetings

18

http://www.tga.gov.au/book/phase-5-second-round-assessment 19

http://www.tga.gov.au/book/phase-6-expert-advisory-review 20

http://www.tga.gov.au/book/phase-7-decision 21

http://www.tga.gov.au/book/phase-8-post-decision 22

http://www.tga.gov.au/guidance-5-pre-submission-meetings-tga

- 15 -

- Include a summary of the information relevant to the therapeutic good and any

supplementary information relevant to the objectives of the meeting.

- Any relevant summarised material that describes results of relevant studies; clinical

trials with a sufficient degree of quantification an explanation for any product

development plan that deviated from current guidelines or practices

- Any known issues with the design or evidence for the therapeutic good.

2.3 Review period23

The pre-submission phase commences with the lodgement of a PPF. PPFs are processed

on the first day of each month. The submission phase concludes when TGA sends the

applicant a Planning letter. This letter is sent to applicants before or on the fifteenth of the

month following the month in which the PPF was initially processed.

The TGA Planning letter outlines the key dates for each phase of the regulatory process,

including the expected date of dossier lodgment. The first round assessment phase

commences the day after Notification letter has been sent. First round assessment phase

concludes 4 (generic applications) or 5 (all other applications) months later when TGA sends

the applicant a Milestone 3 letter.

Following evaluation of the data, a consolidated section 31 request for information or

documents will be compiled, checked, and authorised within 1 month of the completion of

the first round assessment and sent to the applicant. This allows the TGA to ensure that issues

and concerns from all evaluation areas are clearly identified and consolidated into the request.

2.4 Required dossiers242526

The data submitted with an application is divided into three types: Quality data,

Nonclinical data and Clinical data.

1) Quality data

These data are evaluated by chemists, biochemists, microbiologists, toxicologists and

others working for the TGA.

e.g. the composition of the drug substance and the drug product; batch consistency;

stability data; sterility data (if applicable); and the impurity content.

2) Nonclinical data

These data are evaluated by toxicologists.

e.g. pharmacology data, toxicology data.

3) Clinical data

Most results of clinical trials are usually evaluated by a medical doctor. Each data set

is evaluated separately, so three evaluators have the opportunity to ask the sponsor

questions about the data submitted. This ability to require the sponsor to provide

information is provided by section 31 of the Therapeutic Goods Act 1989. Once

completed, the evaluation reports are reviewed internally before they are authorised

and sent to the sponsor; the sponsor then has the opportunity to make comments.

23

http://www.tga.gov.au/prescription-medicines-registration-process 24

Appendix A - Specific mandatory requirements 25

http://www.tga.gov.au/publication/mandatory-requirements-effective-application 26

http://www.tga.gov.au/book/content-application-dossier#overview-ctd-docs

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Pre-submission planning form: Information for applicants completing a pre-submission

planning form

CTD Module 127

: Administrative information and prescribing information for Australia

CTD Module 2: being overviews, written summaries and tabulated summaries of the

data contained in the Modules 3, 4 and 5 as described below

- ICH M4Q Common technical document for the registration of pharmaceuticals for

human use - Quality (CPMP/ICH/2887/99 Rev 1 Quality)

- ICH M4S Common technical document for the registration of pharmaceuticals for

human use - Safety (CPMP/ICH/2997/99 Rev 1 Safety)

- ICH M4E Common technical document for the registration of pharmaceuticals for

human use - Efficacy (CPMP/ICH/2887/99 Rev 1 Efficacy)

- Use non-eCTD electronic submission (NeeS) format for the electronic copy of

dossier.

- Ensure Module 1 complies with the Australian CTD Module 1 requirements, and

that Modules 2, 3, 4, and 5 comply with the EU CTD documents adopted in

Australia.

Language

All information in the submission dossier is in English and legible any acronyms and

abbreviations are defined the first time they are used in each module. For information

that is not in English, include both: a copy of the information in the original language

and a full translation of the information into English.

File format for electronic copies of the submission dossier

Product information documents are in both MS Word and PDF format remaining

documents are PDF documents. PDF documents are text searchable (produced from an

electronic source document).

CTD Module 1:

section all : Administrative information and prescribing information Australia

1.0.1 : Cover letter

1.0.2 : Lifecycle management tacking table

1.0.3 : Response to request for information (if questions raised)

Module 1.0.1 Cover letter

Module 1.0.2 Lifecycle management tracking table

Module 1.0.3 Response to request for information

Module 1.1 Comprehensive table of contents

Module 1.2 Administrative information

Module 1.2.1 Application form

Module 1.2.2 Pre-submission details

Module 1.2.3 Patent certification

Module 1.2.4 Change in sponsor

Module 1.3 Medicine information and labelling

27

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1.3.1 Product information and package insert

1.3.2 Consumer medicines information

1.3.3 Label mock-ups and specimens

Module 1.4 Information about the experts

1.4.1 Quality

1.4.2 Nonclinical

1.4.3 Clinical

Module 1.5 Specific requirements for different types of applications

1.5.1 Literature-based submission documents

1.5.2 Orphan drug designation

1.5.3 Genetically modified organisms consents

1.5.5 Co-marketed medicines declarations

1.5.6 Combination medicines consent

1.5.7 OTC New product assurances

1.5.8 Umbrella brand assessment

Module 1.6 Master files and Certificates of suitability

1.6.1 Relevant external sources

1.6.2 Applicant’s declaration

1.6.3 Letters of access

Module 1.7 Compliance with meetings and presubmission process

1.7.1 Details of compliance with pre-submission meeting outcomes

1.7.2 Details of any additional data to be submitted

1.7.3 Declaration of compliance with Pre-submission planning form and

Planning letter

Module 1.8 Information relating to pharmacovigilance

1.8.1 Pharmacovigilance systems

1.8.2 Risk management plan for Australia

Module 1.9 Biopharmaceutic studies

1.9.1 Summary of bioavailiability or bioequivalence study

1.9.2 Justification for not providing biopharmaceutic studies

Module 1.10 Information relating to pediatrics

Module 1.11 Foreign regulatory information

1.11.1 Foreign regulatory status

1.11.2 Foreign product information

1.11.3 Data similarities and differences

1.11.4 Foreign evaluation reports

Module 1.12 Antibiotic resistance data

Module 2 Common technical document summaries

2.1 Common technical document table of contents (Module 2-5)

2.2 CTD introduction

2.3 Quality overall summary

2.4 Nonclinical overview

2.5 Clinical overview

2.6 Nonclinical written and tabulated summaries

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(pharmacology, pharmacokinetics, toxicology)

2.7 Clinical summary (Clinical pharmacology studies, Clinical efficacy,

Clinical safety), Literature references, Synopses of individual studies

Module 3 : Quality

3.1 : Module 3 table of contents

3.2 : Body of data

3.3 : Literature references

Module 4 : Safety (nonclinical study reports)

4.1 : Module 4 table of contents

4.2 : Study reports

4.3 : Literature references

Module 5 : Efficacy (clinical study reports)

5.1 : Module 5 table of contents

5.2 : Tabular listing of all clinical studies

5.3 : Clinical study reports

5.4 : Literature references

Section 31 of the Therapeutic Goods Act 1989.

The Secretary may, by notice in writing given to a person :

(aa) who is an applicant for the registration of therapeutic goods; or

(ab) in relation to whom therapeutic goods are registered; or

(ac) in relation to whom therapeutic goods were, at any time during the previous 5

years, registered;

require the person to give to the Secretary, within such reasonable time as is specified

in the notice and in such form as is specified in the notice, information or documents

relating to one or more of the following:

(a) the formulation of the goods;

(b) the composition of the goods;

(c) the design specifications of the goods;

(d) the quality of the goods;

(e) the method and place of manufacture or preparation of the goods and the procedures

employed to ensure that proper standards are maintained in the manufacture and

handling of the goods;

(f) the presentation of the goods;

(g) the safety and efficacy of the goods for the purposes for which they are to be used;

(ga) whether the goods comply with conditions (if any) on the registration of the goods;

(gb) the conformity of the goods to a standard applicable to the goods;

(h) whether either of the following has not been complied with in relation to the goods:

(i) an applicable provision of the Therapeutic Goods Advertising Code;

(ii) any other requirement relating to advertising applicable under Part 5-1 or the

regulations;

(ha) if the goods are registered in relation to the person—whether the goods are being:

(i) supplied in Australia; or

(ii) imported into Australia; or

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(iii) exported from Australia;

(j) the regulatory history of the goods in another country.

(k) any other matter prescribed by the regulations for the purposes of this paragraph in

relation to goods of that kind.

The application dossier must provide appropriate documentation (in the correct format and

locations, as determined by the CTD modules), including outcomes of trials and studies, to

allow the Delegate of the Secretary to assess quality, safety, and efficacy claims. The

technical data requirements that establish the documentation to be provided in the dossier are:

Australia-specific requirements are identified in CTD Module 1: Administrative

information and prescribing information for Australia and TGA guidelines.

EU guidelines adopted in Australia - guidelines prepared by the European Committee

for Medicinal Products for Human Use (CHMP) and/or those prepared within the ICH

process that have been adopted by the TGA.

3. Generic drug approval application

3.1 Procedure28

Table 2. Generic drug approval procedure in Australia

Expert advisory review is optional for generic application.

28

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3.2 Review period29

Figure 4. Generic Drugs Work Flow Chart and Review Period in Australia

Expert advisory review (Phase 6) is not required for generic application. For all generic

applications, the Round 1 and Round 2 Assessment phases will be 4 months and 2 months,

respectively. The second round assessment reports will be issued at Milestone 5. For

submissions with no outstanding issues and where no expert committee advice is required,

the decision date will be 6 weeks after the completion of the Round 2 Assessment phase.

3.3 Required dossiers

As new drugs and generic drugs are classified in category 1, the procedures undergone and

all requirements must basically meet criteria mentioned in NDA documents. Moreover, no

more documents are required, when the indication, the shape and the dosage information are

similar with the original drug, and when the safety and effectiveness supporting documents

have been submitted.

3.3.1 Bioequivalence30

Use the Australian reference product wherever possible as the comparator in a

bioequivalence study for a generic medicine. However, in certain circumstances, we

may accept bioequivalence studies using an overseas reference product, provided the

conditions below are met. Also use this approach for a locally acting medicine where

clinical equivalence has been demonstrated against the overseas reference product.31

Where the efficacy of the product is likely to be formulation dependent (see below for

examples), the efficacy of the particular formulation proposed for registration will

need to be established.

29

http://www.tga.gov.au/fact-sheet-changes-prescription-medicines-registration-process-streamlined-

submission-process 30

http://www.tga.gov.au/book/6-generic-products

31 http://www.tga.gov.au/book/156-choice-reference-product-bioequivalence-generic-medicines

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Head lice preparations, Aciclovir for treatment of cold sores, Minoxidil, NSAIDs,

Antiseptics/skin disinfectants [See ARGOM Appendix 6 Antiseptics/skin

disinfectants (still to be finalised)], Antidandruff shampoos containing imidazole

antifungals as active ingredients, Dithranol preparations, Corticosteroids (except

hydrocortisone) (see 'Section 7.1 Nasal corticosteroid sprays'), Products containing

glyceryl trinitrate (see 'Section 7.5 Oral nitrate products')

For OTC oral immediate release tablets, capsules and suspensions containing active

substances with high solubility and high permeability and where the medicinal

product has a high dissolution rate, bioequivalence data will not be required if an

acceptable justification for not providing such data can be provided (see also 'Section

8 Products with a new dosage form').

For multiple strengths of generic transdermal and modified release oral dosage forms,

bioequivalence studies should be performed at least on the lowest and highest

strengths versus the corresponding reference products.32

3.3.2 CTD module33

Module Requirement

2.4

A Module 2.4 must be supplied for all new generic applications where the

active ingredient is a different salt/ester from the Australian reference

product's active ingredient.

A Module 2.4 must also be supplied where the levels of impurities and

degradants lie outside the levels permitted in ICH guidelines. Except for

biotechnology-derived products, ans assessment of the impurities and

degradants present in the drug substance and product should be included

along with what is known of their potential pharmacologic and

toxicologic effects. This assessment should form part of the justification

for proposed impurity limits in the drug substance and product, and be

appropriately cross- referneced to the quality documentation.

2.5 Module 2.5 must be supplied for all new generic applications.

2.7 Module 2.7 must be supplied for new generic applications where

biopharmeceutic studies have been provided in support of the application.

3 limits above the ICH threshold may also be qualified by comparison with

the Australian reference product near or just past expiry date.

5.3.1

For all new generic applications, applicants must provide appropriate

information to demonstrate clinical equivalence of the proposed product

with the corresponding Australian reference product, unless specifically

precluded by listed in "Biopharmaceutic studies-Medicines which do not

require biopharmaceutic data.

Immediate release oral dosage forms : Comparative bioavailability data

32 http://www.tga.gov.au/book/content-application-dossier 33

http://www.tga.gov.au/publication/common-technical-document-ctd#eumod5

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must be provided to establish the bioequivalence of the generic medicine

and the corresponding reference product in Australia

Modified release oral dosage forms: The following studies are required:

fed and fasted / steady state study versus the reference modified release

reference product or an appropriate scientific justification must be

included in the application.

Clinical usability and safety: Generic medicines should have comparable

dose forms and identical (or a subset of) indications, directions for use

and strengths in comparison with the Australian reference product's

presentations.

Table 3. CTD Module for generics in Australia

3.4 Patent-approval linkage system

3.4.1 Background34

Australia has restricted patent linkage provisions for minimising the adverse effect of

patent linkage over generics in contrast to US, China and Singapore due to the

experiences in these countries. There are provisions against ever-greening and drug

patents are to be based strictly on proved therapeutic importance of the drug. There is

also a patent linkage provision under Section 26(b) of Therapeutic Goods Administration

Act, 1989. The most striking feature of the Australian patent linkage provision is that,

heavy penalty is imposed for false and misleading information.

3.4.2 Patent-approval linkage system in Australia

Therapeutic Goods Administration is not in charge of the information management and

enforcement of the original drug patent. However, it is taking submission of the patent

justification or explanatory materials from applicants who are applying for the generic

drug patent.35

26B (1) The certificate required under this subsection is either:

(a) a certificate to the effect that the applicant, acting in good faith, believes on

reasonable grounds that it is not marketing, and does not propose to market, the

therapeutic goods in a manner, or in circumstances, that would infringe a valid

claim of a patent that has been granted in relation to the therapeutic goods; or

(b) a certificate to the effect that:

(i) a patent has been granted in relation to the therapeutic goods; and

(ii) the applicant proposes to market the therapeutic good before the end of the

term of the patent; and

(iii) the applicant has given the patentee notice of the application for registration

or listing of the therapeutic goods under section23.36

34

Ravikanr Bhardwaj,KD Raju and M Padmavai,“The Impactof Patent Linkage on Marketing of Generic

Drus”,Journalof IntellectualPropertu Rights, 2013, p.319.

35 Silvia Park, Eun-Jung Kang, Eun-Ja Park, Korea-US FTA and Future Directions of Pharmaceutical Policy in

Korea, 2007, p.233. 36

Therapeutic Goods Act, 1989 26B (1)

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26D (1) This section applies where:

(a) an applicant gives notice to a patentee in accordance with subparagraph

26B(1)(b)(iii); and

(b) the patentee and/or its exclusive licensee (in this section the party or parties is or

are referred to as the patentee) applies to a prescribed court for an interlocutory

injunction to restrain the applicant from marketing the therapeutic goods the

subject of the application on the ground that such conduct will constitute an

infringement of its patent.37

Patentee who receives the above mentioned notification can file a patent infringement

lawsuit. However, there is no regulation on the suspension system of the licensing

procedures on the market approval of the third party's generic drug, there is no

regulation about the autostay caused by the patent-Drug approval linkage system, even

its equivalent of 180 days of monopoly market(right to expel) does not exist.38

A person is guilty of an offence if :

(a) the person gives a certificate required under subsection (1); and

(b) the certificate is false or misleading in a material particular.

Penalty: 1,000 penalty units.39

4. Orphan drugs

4.1 Designator

Prescription Medicines Authorisation Branch.

4.2 Orphan drug designation procedure40

TGA recommends that applicants commence the orphan drug designation process at

least 2-3 months prior to the intended start of the pre-submission planning process.

The Sponsor of an orphan drug may apply to the Secretary for the medicine to be

designated as an orphan drug.

The application must be made using an application form approved by the Secretary

The application must show why the medicine is an orphan drug.

For a vaccine or in vivo diagnostic agent, the application must also state that the

vaccine or agent will be administered in Australia to not more than 2000 people in each

year after it is registered for use for the disease or condition.

If the Secretary designated the medicine, the Secretary must publish a notice in the

Gazette, as soon as practicable after making the decision, giving the following

information: the sponsor’s name, the medicine’s dose form and indication, and a

statement that the medicine is a designated orphan drug.

Locate the TGA letter granting orphan drug designation and check the designation

letter and the application to ensure:

37

Therapeutic Goods Act, 1989 26D (1) 38

Oh, Seung-Han, Comparative study on the Patent Linkage System of Major Countries, Journal of Legislation

Research 43, 2012, p.344 39 Therapeutic Goods Act, 1989 26B (2) 40

https://www.comlaw.gov.au/Details/F2013C00670/Html/Text#_Toc364778160

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- the applicant identified on the designation letter is identical to the applicant for the

submission

- the active ingredient(s) specified on the designation letter is/are identical to those in

the application

- the indications proposed in the application are identical to, or narrower than, those

stated on the designation letter

- the dose form stated on the designation letter is identical to the dose form in the

application

- Include a copy of the TGA letter granting orphan drug designation in Module 1.5.2.

Fees for variations to the registration of a medicine, that is, regulatory activities under

section 9D of the Act, cannot be waived for an orphan drug.

Broader indications than those designated for the orphan drug

If the indications proposed in the application are wider than those stated in the orphan

drug designation letter, then either:

- the full evaluation fee will be payable, or

- a new orphan drug designation request must be lodged with the TGA and if

designation is received, a new PPF lodged.

4.3 Required dossiers for designation

1) A medicine, vaccine or in vivo diagnostic agent is an orphan drug if it complies with

this regulation;

must be intended to treat, prevent or diagnose a rare disease

must not be commercially viable to supply to treat, prevent or diagnose another

disease or condition.

2) It is not an orphan drug if any of the following persons or bodies has refused to approve

it for use for the disease for a reason related to the medicine's safety:

the Secretary; the Food and Drug Administration of the United States of America; the

Medicines Control Agency of the United Kingdom; the Bureau of Pharmaceutical

Assessment of Canada; the Medical Products Agency of Sweden; the Medicines

Evaluation Board of the Netherlands; the European Agency for the Evaluation of

Medicinal Products.

3) It is not an orphan drug if it has been registered for use for the disease or condition

before 1 January 1998. However, it may be registered before 1 January 1998 for another

use or indication.

Regulation 2

A rare disease is defined in Regulation 2 as a disease, or condition, likely to affect not more

than 2,000 individuals in Australia at any time.

Regulation 16 I(4)

concerning applications for designation as an orphan drug, requires: "for a vaccine or in vivo

diagnostic agent, the application must also state that the vaccine or agent will be administered

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in Australia to not more than 2,000 people in each year after it is registered for use for the

disease or condition."

4.4 Review process and period41

Target timeframe for orphan drug designation is 20 working days from receipt of an

application to decision being made.

4.5 Required dossiers42

Any application for orphan drug designation must demonstrate why the product should be

considered to be an orphan drug product. (subregulation 16I (3) of the Regulations) For a

vaccine, or in vivo diagnostic agent, the application must also state that, in each year after

registration, the vaccine or agent will not be administered to more than 2000 people in

Australia after it is registered for use for the disease or condition. (subregulation 16I (4) of

the Regulations)

1) Name of the active ingredients

Check each active ingredient has one of the following approved terms:

- Australian Approved Name (AAN)

- Australian Approved Biological Name (ABN)

- Australian Approved Herbal Name (AHN)

Use the approved terms in the application for orphan drug designation.

If the active ingredients have not yet been allocated an approved name, ensure you

make an application for this before, or in parallel to, your application for orphan

designation

Make an application for an approved name using the relevant form; AAN, ABN,

AHN and

Use the proposed name (AAN/ABN/AHN) in the application form for orphan

designation, including the word ‘proposed’ in brackets after the name.

2) Proposed orphan indication

Include the proposed orphan indication. Ensure you include (ass attachments)

A discussion of the rationale for the use of this medicine for the rare disease or

condition in question

If the product is being specifically developed for a distinct subset of persons with

that rare disease or condition ; demonstrate the medical plausibility as to why any

remaining persons with the same rare disease or condition are not appropriate

candidates for use of the medicine

3) Summary of development status and regulatory history

Include a summary of the world-wide regulatory status and marketing history (including

dates) for the medicine, which details (where applicable):

current investigational uses

previous marketing approvals

orphan status

41

http://www.tga.gov.au/book/what-will-happen-application-designation 42

http://www.tga.gov.au/book/how-apply-orphan-drug-designation

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adverse regulatory actions (if any) in any country

Ensure the summary also outlines whether any of the regulatory agencies listed above

has refused to approve the medicine (for the same disease as that proposed in Australia)

for reasons related to the medicine’s safety

4) If the product is proposed to treat, prevent, or diagnose a rare disease

Attach documentation (with authoritative references) to demonstrate that the number of

people affected by the disease in Australia is below the statutory prevalence threshold

for a rare disease. Include the following:

a description of the methodology used for gathering the data

the data sources (including dates of information provided and literature sources)

all calculations and their results

5) IF the product is not commercially viable to supply for treatment, prevention, or

diagnosis of another disease or condition. Provide documentation (with authoritative

references) demonstrating that the marketing of the medicine in Australia is unlikely to

be commercially viable for the treatment, prevention, or diagnosis of another disease or

condition. Include, as attachments:

A description of the disease or conditions for which the medicine, vaccine or in vivo

diagnostic agent is being or will be investigated.

A discussion of the actual (and potential) development of the medicine to treat,

prevent or diagnose another disease or condition.

6) For literature based submissions involving a systematic literature search, three items

need to be prepared:

Module 1.5.1.1 - methodology of literature search, including complete details of

database search strategies

Module 1.5.1.2 - a copy of the letter from the TGA in which approval for the search

strategy is given

Module 1.5.1.3 - complete search output

4.6 Incentives4344

section 23 of the Act

An application fee is not payable for applications made under section 23 of the Act and

involving a medicine which has been designated an orphan drug.

When the Orphan drugs program45

was established it was generally recognised that

support was required to bring these products to market due to low demand and the lack

of financial incentive to develop or market a medicine for such a small patient

population. At the time, this support was in the form of waiving fees for evaluation and

registration, this was the minimum support given by other regulators with orphan drugs

programs. Some jurisdictions have extended this support, providing tax benefits,

increased periods of market exclusivity and grant programs for the development of

drugs for rare diseases in Australia,

43

http://www.tga.gov.au/consultation/consultation-orphan-drugs-program 44

Consultation: Orphan drug programs discussion paper 45

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Regulation 45 (12) provides a waiver of fees associated with an application for

designation, for fees considering the application and for fees as part of the registration

of a designated orphan drug.

Regulation 45 (12) The Secretary must waive the following fees:

- a fee that would have been payable, but for this subregulation, for applying to the

Secretary under subregulation 16I(1) to have a medicine designated as an orphan

drug;

- a fee that would have been payable, but for this subregulation, for the Secretary

considering the application under regulation 16J;

- a fee that would have been payable, but for this subregulation, as part of the

registration of a designated orphan drug.

5. Priority review46

There is no formal priority evaluation system and an applicant should not request

priority status for an application. The registration process relies on the advance

allocation of resources to evaluate applications, thus limiting opportunities for

conducting evaluations any faster than the standard registration process.

If an application is considered by the TGA to be a significant therapeutic advance or of

critical importance, the TGA will, wherever possible, work with the relevant applicant

with a view to facilitate early access to the new product, provided the product meets the

TGA's quality, safety, and efficacy requirements.

46

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V. Others

1. Good Manufacturing Practice

1.1 GMP conformity assessment of oversea manufacturing product (including

drug substance)47

All Australian sites participating in the manufacture of the medicine must have a

Licence to Manufacture Therapeutic Goods issued by the TGA that permits the

manufacturing steps and dosage forms relevant to the goods being supplied. For sites

located overseas, the sponsor must obtain a GMP clearance for the site that permits the

manufacturing steps for the required dosage forms to be undertaken.

Steps of manufacture for which a licence/clearance is required include that of the

dosage form (e.g. tablet, ointment), packaging and labelling, all quality control testing,

sterilisation (if relevant) and release for supply. For all biological and non-biological

prescription medicines, the manufacturer of the active pharmaceutical ingredient (API)

must also be licensed, or a clearance obtained. For overseas manufacturers of APIs for

over-the-counter and complementary medicines, no GMP clearance is required,

although the sponsor is expected to hold evidence of the site's compliance to GMP.

Through the Therapeutic Goods (Manufacturing Principles) Determination No. 1 of

2009 (link is external), the TGA has adopted the PIC/S Guide to Good Manufacturing

Practice for Medicinal Products, PE 009-8 - 15 January 2009 as the Manufacturing

Principles. Through the operation of section 36 and other provisions within the Act, the

Guide has legal force in Australia.48

PIC/S membership also provides for the confidential exchange of regulatory

information including the planning of inspections, compliance status of a manufacturer

and the results of inspections.

The TGA does not automatically accept GMP Certification from PIC/S member

countries unless also covered by an MRA with Australia. Certificates and inspection

reports from an overseas regulator for inspections that predate its official membership

to PIC/S will not be accepted.49

1.2 Overview of the GMP clearance process for overseas manufacturer

1.2.1 Requirement for GMP Clearance application

A separate application is required for each sponsor and for each overseas

manufacturing site. Applications are required for renewals, changes to scope,

changes to steps of manufacture and major facility changes.

1.2.2 Pathways for obtaining GMP Clearance

Assessment of an application is based on the following evidence:

◦ Mutual Recognition Agreements (MRA)

◦ Compliance Verification (CV)

◦ a TGA on-site audit (Applications for a TGA audit will not be accepted while an

MRA or CV assessment is in progress.)

1.2.3 Identify and obtain required documentation

47

https://www.tga.gov.au/overview-supplying-therapeutic-goods-australia 48

https://www.tga.gov.au/publication/manufacturing-principles-medicinal-products 49

https://www.tga.gov.au/book/appendix-b-international-agreements

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The extent of the review process increases with product risk and the complexity of

manufacture.

Refer to Tables 1(a) and 1(b).

1.2.4 Submit electronic Clearance application and pay application fees

Refer to Appendix E and the current 'schedule of fees' at Schedule of fees and

charges. Additional fees may be payable if the TGA is requested to obtain evidence

from an overseas regulator or if the application is subject to a CV.

1.2.5 and 2.6 TGA assessment

If requested submit additional information (Go to Step 5)

TGA may request additional information. Application may be rejected if

information is not supplied within due dates. Assessment timeframes can be

found in appendix I

Ineffective application (Go to Step 5)

If the application is ineffective and requested information cannot be presented,

the TGA will notify the sponsor of a proposal not to issue a clearance and

provide the sponsor the opportunity to respond.

1.2.6 Clearance Letter or GMP Certificate

Sponsor is issued a GMP Clearance letter following a successful MRA or CV

assessment or a TGA on-site audit. A Certificate of GMP Compliance may be

issued to the manufacturer on request following a successful TGA on-site audit.

1.2.1 GMP Clearance application requirements

1) GMP Clearance

GMP Clearances are required for all the steps of manufacture of registered and

listed medicinal products (including APIs used for the manufacture of registered

products) before the products can be supplied in Australia.

Although the TGA does not currently require sponsors to submit Clearance

applications for APIs used in listed medicines or registered over-the-counter

(OTC) and complementary medicines, sponsors must ensure that any step of

manufacture undertaken outside of Australia is undertaken in GMP compliant

facilities. Evidence of licensing or approval of the manufacturer of the API(s)

does not need to be submitted to the TGA unless it is an intermediate product (e.g.

premixes).

2) Renewing a GMP Clearance

GMP Clearances relating to overseas manufacturers are provided for a specified

period and have an expiry date. Sponsors must therefore apply periodically to renew

their clearances for overseas manufacturing sites for as long as they continue to use

that manufacturer. This permits the TGA to review the manufacturing and quality

controls and provide continuous confidence to the public of the manufacturer's

compliance with relevant international GMP standards.

3) Changes to a GMP Clearance

When a sponsor becomes aware of a need to change or renew a GMP Clearance, a

new application with all required documentation must be submitted, and applicable

fees paid.

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1.2.2 Pathways for obtaining GMP Clearance

There are three procedures used to grant a GMP Clearance:

Mutual Recognition Agreements (MRA)

Compliance Verification (CV)

after a TGA on-site audit.

The available procedure for assessment will depend on:

whether the TGA has agreements with the regulatory agency that has inspected a

manufacturing site;

where the site is located;

the TGA's level of confidence of compliance with an equivalent Code of GMP

demonstrated by the evidence submitted by the sponsor;

the type of product(s) or manufacturing steps undertaken at the site;

the timing of the inspection.

Mutual Recognition Agreements (MRA): In accordance with international agreements with

certain countries, the TGA accepts compliance of an overseas site with the local GMP

requirements based on a current GMP Certificate issued by the regulatory agency of the

other party to the MRA. A list of countries with which Australia has an MRA or

equivalent is contained in Appendix B

Compliance Verification (CV): The assessment will include a review of recent inspection

reports of the relevant manufacturing site undertaken by a competent overseas regulatory

agency together with other available regulatory information. Compliance verifications are

permitted wherever the TGA has an international cooperation arrangement, such as a

memorandum of understanding or PIC/S membership.

TGA on-site audit: If a sponsor is unable to provide current documentary evidence of

acceptable GMP compliance for an overseas manufacturer, or if the TGA's assessment of

evidence does not support a GMP Clearance, the TGA will advise the sponsor of the need

to conduct an on-site audit. Clearance will be granted by the TGA if the audit concludes

that the facility operates at an acceptable level of GMP compliance.

1.2.3 Identify and obtain the required documentation

Table 4 identifies the method of assessment and applicable list of evidence required

(Evidence List) where a Compliance Verification is required. Note that GMP Clearances are

required where contracted laboratory and sterilisation services are engaged to support the

release of a product or API.

- 31 -

Table 4. Required assessment type

Table 5 lists the specific documents required for the Compliance Verification assessment.

Explanatory notes for some of these documents are set out in Appendix C.

Table 5. Documentary evidence requirements

Required Evidence Comments/Exclusions

Evidence List A

Current GMP Certificate

(GLP for testing laboratory, ISO

Standards for sterilisation facility)

Certificates must be sufficient to

cover the scope of the Clearance

application.

Evidence List B

Compliance

Verification for:

APIs(other than

sterile and

biotech)

Current GMP Certificate

GMP agreements may be

requested if the overseas

manufacturer performs the

release for supply function.

A list of all regulatory inspections

conducted within the past 3 years

and a copy of the most recent

inspection report. (Processing can

be expedited if reports for two or

more of the above inspections are

provided).

Inspection reports must be

applicable to the scope of the

application. These may be sent

to the TGA directly from the

manufacturer.

Details of any regulatory actions in

past 3 years.

For example, product alerts,

warning letters, import alerts,

recalls due to defects.

- 32 -

Site Master File, Quality Manual or

equivalent.

Not required if the scope of the

application is only for the step of

release for supply.

GMP agreement between the

sponsor and the manufacturer.

Only applicable to products and

related steps of manufacture in

the Clearance application.

Not required for APIs unless

requested.

List of products intended for supply

in Australia.

Copy of the procedures for release

for supply of products included in

the Clearance application).

Not required for APIs unless

requested.

An applicant may also be

requested to provide a

Validation Master Plan or

Product Quality Review

(applicable to Finished Product

medicines included in the

Clearance application).

Evidence List C

Compliance

Verification for:

Finished sterile

medicines

Sterile and

biotech APIs

Validation Master Plan.

Not required if the scope of the

application is only for the step of

release for supply.

Latest Product Quality Review. Applicable to APIs listed in the

Clearance application only.

Evidence List D

Contract testing

laboratories

Contract

sterilisers

Current GMP Certificate.

For contract sterilisation

facilities certification to

applicable ISO sterilisation

standards (e.g. ISO 11137, ISO

11135) may be used in lieu of a

GMP Certificate.

A list of all regulatory inspections

conducted within the past 3 years,

and a copy of the most recent

inspection report.

(Processing can be expedited if

Inspection reports must be

applicable to the scope of the

application. These may be sent

to the TGA directly from the

manufacturer.

- 33 -

reports for two or more of the

above inspections are provided.)

Details of any regulatory actions in

past 3 years.

For example, product alerts,

warning letters, import alerts,

recalls due to defects.

Quality Manual/Laboratory Manual

or equivalent.

GMP agreement between the

sponsor and the contract test

laboratory or steriliser.

For contract test laboratories and

3rd party sterilisation companies

sub-contracted by an overseas

manufacturer, a contract/

agreement may not exist with the

Australian sponsor. A copy of

the agreement between the

manufacturer and contract test

laboratory should be submitted

in such a case.

A list of tests a laboratory is

authorised to perform.

For botanical ingredients, evidence

that authenticated standard

reference materials are used.

For contract testing laboratories

only.

1) General documentary requirements

Documentary evidence must adhere to the following requirements:

all certificates and other supporting documents must be in English or supplied with

a certified translation into English;

translated documents must be accompanied by a signed and dated statement, by the

certified translator, stating that it is a true and accurate translation of the original

document;

documents must be the most recent and reflect current manufacturing conditions

and practices and dated (expired/superseded documentation cannot be used);

documents must provide sufficient information to cover the scope of dosages for

which clearance is sought; and

documented evidence must be unambiguous, clearly demonstrating that the

overseas manufacturer operates with an adequate level of GMP Compliance

(ambiguous material will be disregarded).

2) Certified copies of original documents

All documents are to be submitted electronically and are not required to be certified as

original copies unless requested by the TGA. Certification of a document may be

requested if for example, there was concern over the validity of the supplied

documents.

The TGA can request certified copies of original documents at any time. Certified

copies must be legible and authenticated as true copies by any one of the following:

- 34 -

an official of the regulatory agency of a country that is a party to an MRA or is a

Memorandum of Understanding (MOU) partner;

an Australian embassy or consulate office; or

a Justice of the Peace, Public Notary or a lawyer, solicitor or accountant (include

details of the relevant practice certificate or licence number).

The following is an example of a declaration that should appear on the front page of

the document being certified:

Declaration of Authenticity

As a ………. for the state of (xxxxx), (country xxxxx), I declare that the attached

copy of the document issued by (xxxxx) (certificate) is a true and accurate copy of an

original certificate presented to me for review.

Signed (xxxxx) Date (xxxxx)

3) Documents for a TGA on-site audit

After receiving an application, but prior to confirming an audit, the TGA will require

the Site Master File (SMF). The sponsor should ensure the manufacturer supplies a

current, up-to-date SMF. The SMF provides an overview of the manufacturer, its

manufacturing activities and its quality system. The SMF is necessary to allow

effective planning of the audit.

Guidance for preparing a SMF can be found in :

http://www.tga.gov.au/publication/site-master-file-preparation-pics-explanatory-

notes-pharmaceutical-manufacturers

Sponsors may submit other documents from the manufacturer, such as a

Plant/Equipment File or a Quality Manual, which individually or collectively

provides the same details.

Where the TGA will be undertaking an initial audit in a non-English speaking country,

English translations/versions of the following will be required:

Site Master File

Validation Master Plan

Deviation/Out of Specification Procedures

Release for Supply Procedures

Product Quality Reviews (as requested)

1.2.4 Submit application and pay fees

1) Lodging an application for clearance by MRA and Compliance Verification

Sponsors applying for a GMP Clearance must complete the Overseas Manufacturer

Clearance application found on the TGA online business system - eBusiness (eBS).

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

New users will need to establish an eBS account - refer to Appendix E.

The online system allows the progress of an application to be tracked by the

Sponsor and the TGA. For assistance contact the TGA - GMP Clearance Unit by

email at gmpclearance@tga.gov.au.

- 35 -

To complete a GMP Clearance application the following requirements are essential:

Dosage Form selected in the drop down menus within eBS.

Copies of GMP Certificates and any other documents required to support the

application are to be submitted electronically. A file size of 100MB is available

and files may be zipped. Paper copies may be accepted if they cannot be submitted

electronically.

An electronic application checklist is provided in Appendix F50

which is to be

attached to the application.

2) GMP Clearance fees and charges

Refer to the Section 6. Fees in this text.

Original text link: http://www.tga.gov.au/schedule-fees-and-charges

Application fees will be forfeited where an application is rejected.

1.2.5 TGA assessment

1) Target timeframes

A schedule of the target timeframes for the different types of assessments and tasks is

available in Appendix I

Table 6. TGA's target timeframes for GMP Clearance applications

Any application for a GMP Clearance that is not accompanied by correctly completed

documentation will be considered ineffective and the sponsor will be notified within 20

working days (with forfeiture of the fees paid).

1.2.6 Outcomes of TGA assessment

Clearance approval: Once a GMP Clearance application has been assessed and

considered to be acceptable, the TGA will update the status of the application to

'Approved'. Sponsors are able to view this status through eBS. A notification letter of

the clearance approval will be mailed to the applicant.

GMP Certification: Where a TGA on-site audit has found acceptable compliance, a

50

http://www.tga.gov.au/book/appendix-f-electronic-application-checklist

- 36 -

GMP Certificate will be issued and mailed to the manufacturer.

Conditional Clearance: Where marginal compliance has been demonstrated through the

Compliance Verification process or other issues have been identified, the TGA may

grant a conditional GMP Clearance. The conditions may relate to the scope of the

GMP Clearance or the expiry date, and/or may stipulate that the next GMP Clearance

will only be granted following a successful outcome of an on-site TGA audit.

Rejection of an application: If the TGA determines that the evidence available does not

demonstrate that the manufacturer complies with relevant GMP standards the sponsor

will be notified of the deficiencies and provide the sponsor with the opportunity to

respond. If the GMP Clearance application was assessed through a Compliance

Verification, an on-site TGA audit may be required. If so, the sponsor will have to

lodge an application on eBS. Where a TGA on-site audit has taken place and the TGA

has not found acceptable compliance, the GMP Clearance application will be rejected

and any current GMP Clearances will be revoked.

1.3 Maintenance of a Clearance

The expiry of GMP Clearances will depend on the type of product(s) and/or APIs

manufactured and the outcome of the assessment (MRA or Compliance Verification).

The period of GMP Clearance given to a manufacturing site is normally a maximum

of the certification expiry plus 6 months; or three years plus 6 months from the date of

inspection. (The additional 6 month period facilitates the completion and assessment

of re-inspections/audits.) The expiry period may be reduced based on a risk

assessment or other justification.

Where a GMP Clearance has expired, or is about to expire, a new GMP Clearance

application must be submitted for assessment.

The TGA may also require information from a sponsor under Section 31 of the Act to

obtain evidence of GMP compliance for a manufacturing site outside of Australia.

1.4 Flowchart for GMP clearance

1. Who is the certifying authority?

MRA Country? (Go to Step 2)

PIC/S regulators outside own country

US FDA, Medsafe complementary medicines

Non-PIC/S regulators

No Certification? (Go to Step 3)

US FDA all locations, not complementary medicines

Medsafe in NZ only, not complementary medicines

PIC/S Regulators in own country only? (Go to Step 4)

2. For a site in their own country?

Yes? (Go to Step 4)

No? (Go to Step 5)

3. TGA On-site audit - End flow chart

4. MRA Clearance Evidence list A: Current GMP Certificate - End flow chart

5. Compliance verification

- 37 -

What step(s) is the facility performing for the product?

Evidence List B

Current GMP Certificate

List of all regulatory inspection conducted in last three years and copy of most

recent inspection/audit report

Site Master File

GMP Agreement between sponsor and manufacturer

Details of any regulatory actions in last three years

List of products intended for supply in Australia

Copy of Release for Supply procedures for products in application - End flow

chart

Evidence List C

Validation Master Plan

Latest Product Quality Review - End flow chart

Evidence List D

Current GMP Certificate

List of all regulatory inspection conducted in last three years and copy of most

recent inspection/audit report

Quality or Laboratory Manual

GMP Agreement between contract site and manufacturer

A list of tests the laboratory is authorised to perform

Details of any regulatory actions in the past three years - End flow chart

Figure 5. Flow chart for GMP clearance

- 38 -

2. Drug Master File51

2.1 Overview

2.1.1 What substances require a DMF

A DMF is required for all drug substances that are sourced from a third-party

manufacturer.

For ingredients of animal or human origin, a CEP does not contain sufficient

information and will not alone be accepted.

Except for the following substances:

- common inorganic salts that are used and regarded as drug substances in products

such as: injections, dialysis solutions (e.g. sodium chloride and other common

electrolytes)

- simple organic compounds that are commercially available in high purity e.g.

naturally occurring organic acids and their salts, including: ascorbic acid, sodium

citrate, simple monosaccharides, disaccharides, such as glucose and sucrose

- when a CEP(Certificates of Suitability of a Monograph of the European

Pharmacopoeia) has been provided in lieu of a DMF.

However, sponsors should include information (e.g. a certificate of analysis) to

demonstrate that any common inorganic salts or simple organic compounds used as

drug substances:

- are obtained from a reliable source

- consistently comply with applicable pharmacopoeial or nonpharmacopoeial

specifications.

2.1.2 Format for DMF

The preferred format for DMF is the European Common Technical Document (CTD)

format or the European format. However if the manufacturer has not used either of these

formats, the TGA will accept a drug master file in the United States format.

2.1.3 Letters of access to DMF

A Proforma Letter of Access to DMF is available in Module 1.6.3 of the CTD.

Request the manufacturer to

- use the proforma in Module 1.6.3 of the CTD

- prepare the Letter of Access to DMF

- clearly identify the sponsor the letter relates to

- provide information and assurances required by the TGA in Module 1.6 of the CTD

- send the letter directly to the TGA, either with the DMF or separately.

51

http://www.tga.gov.au/guidance-11-drug-master-files-and-certificates-suitability-monograph-european-

pharmacopoeia-drug-substances

- 39 -

3. Labeling and package inserts

3.1 Overview

3.1.1 TGA regulation of product labelling and packaging52

Language: the information is the English language and durable, eligible lettering that

is not less than 1.5 millimetres in height (except for the ARTG number which must be

no less than 1 millimetre in height).

General Labelling requirements

- the product name

- names of all active ingredients and their quantity

- In some cases, excipient information

- batch number

- expiry date

- relevant warning/ advisory statements

- storage conditions

- directions for use

- in most cases the indications for which the product is used

Attachment53

: diagram of the TGA labelling and packaging framework

3.1.2 Package Insert54

A package insert is a document that provides consumers with more detailed

information about the medicine, such as more detailed directions for use than those

provided on the medicine container or primary packaging. Not all medicines have a

pack insert. Where a pack insert is included with the medicine, the medicine container

or primary packaging notifies consumers of this.

Advertising material will not be permitted to be included as a separate pack insert or

incorporated into an approved pack insert

A pack insert must be in a form separate to the packaging; i.e. it cannot be printed on

the inside of a carton

General labelling requirements linked to :

https://www.comlaw.gov.au/Details/F2009C00264

4. Certificate of a Pharmaceutical Product5556

Not included in the documentation for new drug approval application

52

http://www.tga.gov.au/tga-labelling-and-packaging-regulatory-framework 53

http://www.tga.gov.au/tga-labelling-and-packaging-regulatory-framework#attach1 54

http://www.tga.gov.au/book/pack-inserts 55

http://www.tga.gov.au/publication/exporting-medicines-australia-operational-guidelines

56

- 40 -

5. Manufacturing Licenses

5.1 Confirm manufacturer requirements57

All Australian sites participating in the manufacture of the medicine must have a

Licence to Manufacture Therapeutic Goods issued by the TGA that permits the

manufacturing steps and dosage forms relevant to the goods being supplied. For sites

located overseas, the sponsor must obtain a GMP clearance for the site that permits

the manufacturing steps for the required dosage forms to be undertaken.

Steps of manufacture for which a licence/clearance is required include that of the

dosage form (e.g. tablet, ointment), packaging and labelling, all quality control testing,

sterilisation (if relevant) and release for supply.

For all biological and non-biological prescription medicines, the manufacturer of the

active pharmaceutical ingredient (API) must also be licensed, or a clearance obtained.

For overseas manufacturers of APIs for over-the-counter and complementary

medicines, no GMP clearance is required, although the sponsor is expected to hold

evidence of the site's compliance to GMP.

The manufacturing steps shown on a manufacturing licence or GMP clearance issued

by the TGA are not necessarily identical to the manufacturing steps that need to be

entered on the prescription medicine application form.58

new/renewed/updated TGA manufacturing licences (for Australian manufacturing

sites) and good manufacturing practice (GMP) clearances (for overseas sites) issued

for those sites identified in the application.59

6. Fees60

6.1 Prescription medicines (V1.1, 14 July 2015)

1) Registration fees for prescription medicines

Registration fees Application Fee Evaluation Fee

$ $

New chemical entity 45,100 181,000

Extension of indications 26,900 107,500

Extension of indicators of a generic medicine

to maintain currency with indications already

registered to the corresponding innovator

product and where clinical and/or

bioequivalence data are not required

1,035 4,120

Major variations 17,600 70,000

New generic product 17,400 69,000

Additional trade name 2,845 11,400

57

https://www.tga.gov.au/overview-supplying-therapeutic-goods-australia 58

http://www.tga.gov.au/ctd-module-1 59

http://www.tga.gov.au/prescription-medicines-registration-process 60

https://www.tga.gov.au/summary-fees-and-charges-1-july-2015

- 41 -

Minor variations (Change in formulation,

composition, design specifications, type of

container or change of trade name)

1,035 4,120

Table 7. Registration fees for prescription medicines in Australia

2) Administrative charges for prescription medicines

Administrative charges Fee $

Correction of a register entry 1,590

Table 8. Administrative charge for prescription medicines in Australia

3) Annual charges for prescription medicines

Annual charges Charge $

Biological medicines 6,725

Non-biological medicines (higher amount)1 3,835

Non-biological medicines (lower amount) 3,110

Table 9. Annual charges for prescription medicines in Australia

Two levels of charges for non-biological medicines will be introduced on 1 July 2015.

The changes are included in the Therapeutic Goods (Charges) Amendment (2015

Measures No. 1) Regulation 2015

The higher amount ($3,835) will apply to relevant goods until the eight years have

passed since registration. The lower amount ($3,110) will apply to most generic

medicines, and relevant goods past eighth anniversary. Relevant goods are defined to

include new chemical entity, extension of indications, or change to intended patient

group. Other major variations such as new formulation, change of strength, dosage

forms will incur higher or lower amount depending on parent goods.

Goods containing certain active ingredients will always attract the higher amount.

These ingredients are thalidomide, leflunomide, lenalidomide, mifepristone, clozapine

and isotretinoin.

Orphan drug: An application fee is not payable for applications made under section 23

of the Act and involving a medicine which has been designated an orphan drug.

6.2 Non-prescription medicines (V1.1, July 2015)

1) Registration of non-prescription medicines including complementary medicines

Application fee 1,475 $

Additional/concurrent application fee 650 $

Processing fee (variation to an existing registration) 1,475 $

Annual charge 1,380 $

Table 10. Registration of non-prescription medicines including complementary

medicines in Australia

- 42 -

6.3 Non-prescription medicines (V1.1, July 2015)

1) Overseas manufacturers - GMP inspection fee

All types of therapeutic goods: 1,275 Hourly rate per inspector $

2) Overseas manufacturers - GMP clearance fees

Assessment of GMP evidence

(per manufacturer, per site and per sponsor) 370 $

Obtaining evidence from overseas regulatory agency

(per manufacturer, per site and per sponsor) 650 $

Reinstatement of expired GMP clearance approval

(per manufacturer, per site and per sponsor) 1,100 $

Compliance verification

(in-lieu of an overseas GMP inspection) 1,955 $

Table 11. Overseas manufacturers GMP clearance fees in Australia

- 43 -

VII. References

Website

1. Therapeutic Goods Administration (TGA): http://www.tga.gov.au

2. Ministry of Health (MoH): www.moh.gov.my/english.php

Laws and Regulations

1. Therapeutic Goods Act, 1989 26B (1)

2. Therapeutic Goods Act, 1989 26B (2)

3. Therapeutic Goods Act, 1989 26D (1)

4. Therapeutic Goods Regulations, 1990:

https://www.comlaw.gov.au/Details/F2013C00670/Html/Text#_Toc364778160

Publications

1. Oh, Seung-Han, Comparative study on the Patent Linkage System of Major Countries,

Journal of Legislation Research 43, 2012, p.344.

2. Ravikanr Bhardwaj,KD Raju and M Padmavai,“The Impactof Patent Linkage on

Marketing of Generic Drus”,Journalof IntellectualPropertu Rights, 2013, p.319.

3. Silvia Park, Eun-Jung Kang, Eun-Ja Park, Korea-US FTA and Future Directions of

Pharmaceutical Policy in Korea, 2007, p.233.