INTRODUCTION 1.

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THERAPEUTIC GOODS ADMINISTRATION

B.Sai Kumari^*, G.Sai Hanuja, M.V.Nagabhushanam, D.Nagarjuna Reddy, Brahmaiah Bonthagarala

Department of Pharmaceutical Management and Regulatory Affairs, Hindu College of Pharmacy, Amaravathi Road, Guntur, AndhraPradesh, India-522002.

ABSTRACT

The main objective of project is to make clear understanding of current Regulatory requirements for registration of medicines, compilation and submission of dossier in Australia.

Therapeutic Goods Administration (TGA) regulates all the medicines in Australia, which is a division or part of Australian Department of Health and Ageing administering. All the medicine should be registered in Australian Register of Therapeutic Goods (ARTG) in order to get marketed for sale or distribution. Medicines are classified into listed medicines (low risk medicines should be listed in ARTG) and registered medicines (high risk medicines which should be registered in ARTG). Based on risk factor, registered medicines are again classified into Non Prescription and Prescription medicines. Category 1, category 2 and category 3 are three types of application for registration of medicines. Category 1 applications (for new chemical entities, new drugs etc), Category 2 applications (for drugs to be registered in Australia which are accepted for marketing in other countries) and category 3 applications (for or if any post approval changes in medicine), this applications are to be submitted to agency which evaluates there quality, safety and efficacy. The processing time differs for each application.

Keywords: Regulatory requirements, Registration of medicines, Therapeutic Goods Administration (TGA), Australian Department of Health and Ageing administering, Australian Register of Therapeutic Goods (ARTG).

Corresponding Author: B.Sai Kumari, Department of Pharmaceutical Management and Regulatory Affairs, Hindu College of Pharmacy, Amaravathi Road, Guntur, AndhraPradesh,

India-522002.

1. INTRODUCTION

1.1.Overview of Pharmaceutical industries and their regulations:

The pharmaceutical sector is a high-technology and intensive industry. Medicines or chemicals with high therapeutic value are produced and distributed by pharmaceutical industries. The pharmaceutical industries are regulated heavily by regulatory authorities. Each and every aspect of new drug is regulated, starting from patent application, marketing approval, commercial exploitation, patent expiration and competition with generics. The industry deals with high costs of R&D. The estimated cost of bringing a new compound into market in 1970 was $318m, which was increased to $800m, in 1990s. This high cost of new drug approved reflects high failure rate, high costs of pre-clinical and human clinical trial. The requirement of regulatory authority also reflects on high cost of R&D in all industrialized

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Due to thalidomide tragedy in 1960, safety has become a critical issue. Most of the countries requires evidence of safety, efficacy of the drug and monitor manufacturing quality throughout the product life cycle, and regulate promotion to physicians and consumer¹.

The regulatory agency that has both medical and statistical experience can gather the information and can more accurately monitor and evaluate the evidence from clinical trials.

R&D cost in firms will be increased by the regulations which require long term pre- clinical trial on efficacy and safety which in turn increases delay in launch of new medicine reduces number of drugs developed and also extent of competition. Combination of R&D cost with new technologies for evaluating the information has given rise to new initiatives for accelerated approvals in pre-approval and post-approval clinical trials².

Any regulatory system for medicines should provide effective treatments for patients, safeguard patient safety, and should encourage research into new treatments. Government, regulatory agency, patients and the pharmaceutical industry share a common interest in ensuring that the system is transparent, efficient.

All regulatory agencies in the world have three main objectives:

a) Encouraging R&D, flow of new innovations and preserving the incentives;

b) assuring or ensuring public safety when drug is consumed; and c) Monitoring new drug quantity and quality.

Finally, the interesting question, what is the future structure of the industry, as it adapts to changing regulations and technology, with no correct answers. Biotechnology and genomics are new fields which are transforming nature of R&D and bringing new advantages in industries. Small firms play an increasingly important role in the development of new drugs and new R&D technologies. Biotechnology and gene therapy have raised important safety and ethical issues for regulation. The alliances that link biotech firms with large pharmaceutical companies raise interesting questions related to agency and the nature of the firm³.

1.2.Therapeutic goods regulation in Australia^4,5: 1.2.1. Therapeutic Goods

Therapeutic Goods are defined as goods which can be represented in any form and which is for therapeutic use, as given in Therapeutic Goods Act 1989. It can be a medicine or a medical device. In general, a therapeutic good is used in or in connection with:

1. Preventing, diagnosing, curing or alleviating a disease, ailment, defect or injury; or 2. Influencing, inhibiting or modifying a physiological process; or

3. Testing the susceptibility of persons to a disease or ailment; or 4. Influencing, controlling or preventing conception; or

5. Testing for pregnancy; or

6. Replacement or modification of parts of the anatomy.

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©2016 RS Publication, [email protected] Page 146 Quality, safety and efficacy are three important aspects where regulatory authority aim to achieve in therapeutic goods which are available in Australia. In Australia medicinal drugs are controlled through three main processes:

• The pre-market evaluation and approval of products which are to be supplied in Australia

• The licensing of manufacturers; and

• Post market surveillance.

Table 1: No of clinical trials and CTNs conducted in Australia since 1998

Year Clinical trial notifications Trials

1998 1000 705

1999 800 539

2000 1102 740

2001 1109 559

2002 1247 601

2003 1597 603

2004 1908 685

2005 1710 679

2006 1989 941

2007 2235 865

2008 2374 748

2009 2378 673

2010 2776 574

1.3.Therapeutic good Administration (TGA):

The Therapeutic Goods Administration (TGA) is a division of the Australian Government Department of Health and Ageing, and is responsible for regulating therapeutic goods including medicines, medical devices, blood and blood products. Therapeutic goods are evaluated before they are marketed by TGA. Monitoring of the product once they are in market is also done by TGA. It also looks into suitability of medicines and medical devices for export from Australia. Therapeutic goods manufacturing unit is also regulated by TGA to ensure they meet acceptable standards of manufacturing quality. A team of manufacturing inspectors that audit manufacturing facilities around the world to ensure that products supplied in Australia are of high quality. TGA administers the Therapeutic Goods Act 1989. This legislation provides a framework for a risk management approach that allows the Australian

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Therapeutic goods are regulated by TGA through following steps:

• pre-market assessment;

• post-market monitoring and enforcement of standards; and

• Licensing of Australian manufacturers and verifying overseas manufacturers compliance with the same standards as their Australian counterparts.

1.4.Therapeutic goods classification^7,8:

Therapeutic Goods

Medical devices

Medicines

Registered Medicines

Listed Medicines

Prescription Medicines Non-Prescription Medicines

OTC Medicines

Complimentary Medicines

Listed Non-Prescription Fig 1: Classification of Therapeutic goods Medicines

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2. METHODS AND CATEGORIES

REGULATION OF PRESCRIPTION MEDICINES

A prescription medicine comes under registered medicines. Prescription (high risk) registered medicines are available on prescription only. These medicines are assessed by TGA for safety, quality and efficacy.

Types of applications submitted to the TGA for registration of medicines^9-11. Category 1 application:

These are applications submitted for new medicine, new dosage forms, new strengths, and new generics. Extensions to indications and changes to product information (PI) also constitute category 1 application.

Category 2 application:

Category 2 applications are an application to register a prescription medicine with the same formulation, dosage and indications as in two acceptable countries and for which two independent evaluation reports are available.

Category 3 application:

These are applications submitted when the change is made to quality information of registered medicines or medicines included in ARTG which may or may not render medicines separate and distinct (separate registration is needed). This application does not require the support of clinical, pre- clinical or bio-equivalence data.

The quality changes subject to category 3 application may include:

a) The specifications for the active ingredient, finished products b) The method of manufacture of active ingredient

c) The manufacturing procedure for finished product

d) The site of manufacture of active ingredient or finished product e) Shelf life

f) Storage g) Labeling

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Table 2: Timeframes for Processing Applications for the Entry of Prescription Medicines onto the Australian Register of Therapeutic Goods

Category Statutory time limit (working day)

1 255

2 175

3 45

Table 3: Registration fee for application for Prescription Medicines onto the Australian Register of Therapeutic Goods

Application Evaluation

Registration fee fee $ Fee $

New chemical entity 39,800 159,200

Extension of indication 23,700 94,600

Major variations 15,400 61,600

New generic product 15,200 60,700

Additional trade name 2,500 10,000

Minor variations (Change in

formulation, 910 3,630

composition, design specifications,

type of

container or change of trade name)

Minor variations (Change in Not

formulation, 1,300 applicable

composition, design specifications

or type

of container) submitted as a

notification of

a ―Self Assessable Change‖

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Regulatory phase Milestone

Pre-submission Outcome of pre-submission planning sent Submission Outcome of submission consideration sent 1st round assessment Outcome of 1st round assessment sent Consolidated s. 31 response End of s. 31 response period

2nd round assessment Outcome of assessments sent

Expert advisory review Outcome of advisory committee sent

Decision Decision made by delegate

Post-decision Administrative and regulatory activities Complete

Table 5: Different submissions and their phase

Pre

1

^st

2^nd Post

round round

Decision

Decision

submission Submission Consolidated Expert

assessment s.31 request aseesment review

New Chemical A A A A A A

A entities,

Extensions of Indications

Generic A A A A A Optional

A

medicines, Product Information changes,

Variations To Existing

Products

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Additional N/A A A Optional Optional N/A

A

trade names

A: Applicable N/A: Not Applicable

Common Technical Document (CTD):

Dossier was compiled according to the European CTD (Common Technical Document) format.

Data is compiled into Five modules

Module 1: Australian Specific Administrative & Prescribing information.

Module 2: Quality overall summary.

Non –clinical Overview and Summary Clinical Overview and Summary Module 3: Quality data

Module 4: Non-clinical Data Module 5 Clinical data

MODULE 1

Australian Specific Administrative & Prescribing information

MODULE 2

Quality overall summary

Module 2 is divided into sections:

Module 2.1 Table of Contents Module 2.2 CTD Introduction Module 2.3 Quality Overall Summary

Module 2.4 Non Clinical Overview Module 2.5 Clinical Overview Module 2.6 Non clinical Summary Module 2.7 Clinical Summary MODULE 3: QUALITY DATA

Quality Module is divided into two parts:

3.2.S Drug Substance, 3.2.P Drug Product

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3.1 Table of Contents:

MODULE 3 QUALITY Volume Tab Identifier

3.1 TABLE OF CONTENTS OF 3.1 TABLE OF CONTENTS OF

MODULE 3 MODULE 3

3.2 BODY OF DATA 3.2 BODY OF DATA

3.2 S DRUG SUBSTANCE 3.2 S DRUG SUBSTANCE

3.2.S.1 General Information 3.2.S.1 General Information 3.2.S.1.1 Nomenclature

3.2.S.1.2 Structure

3.2.S.1.3 General Properties

3.2.S.2 Manufacture 3.2.S.2 Manufacture

3.2.S.2.1 Manufacture(s)

3.2.S.2.2 Description Of Manufacturing process and Process controls 3.2.S.2.3 Control of materials

3.2.S.2.4 Control of critical steps and Intermediates

3.2.S.2.5 Process Validation and/or Evaluation

3.2.S.2.6 Manufacturing Process Development

3.2.S.3 Characterization 3.2.S.3 Characterization 3.2.S.3.1 Elucidation Of structure and

other characteristics 3.2.S.3.2 Impurities

1

3.2.S.4 Control of Drug substance 3.2.S.4 Control of Drug substance 3.2.S.4.1 Specification

3.2.S.4.2 Analytical Procedures

3.2.S.4.3 Validation Of analytical procedures

3.2.S.4.4 Batch analysis

3.2.S.4.5 Justification of specification

3.2.S.5 Reference standards or 3.2.S.5 Reference standards or

materials materials

3.2.S.6 Container closure system 3.2.S.6 Container closure system

3.2.S.7 Stability 3.2.S.7 Stability

3.2.S.7.1 Stability Summary and conclusions

3.2.S.7.2 Post-approval Stability protocol and stability commitment 3.2.S.7.3 Stability Data

3.2.P DRUG PRODUCT 3.2.P DRUG PRODUCT

3.2.P.1 Description and composition of 3.2.P.1 Description and composition of

the Drug Product the Drug Product

3.2.P.2 Pharmaceutical development 3.2.P.2 Pharmaceutical development 3.2.P.2.1 Components of the Drug product 3.2.P.2.1 Components of the Drug product

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3.2.P.2.2 Drug Product

1

3.2.P.2.2 Drug Product

3.2.P.2.3 Manufacturing Process 3.2.P.2.3 Manufacturing Process

Development Development

3.2.P.2.4 Container Closure System 3.2.P.2.4 Container Closure System 3.2.P.2.5 Microbiological Attributes 3.2.P.2.5 Microbiological Attributes 3.2.P.2.6 Compatibility 3.2.P.2.6 Compatibility

3.2.P.3 Manufacture 3.2.P.3 Manufacture

3.2.P.3.1 Manufacturer(s) 3.2.P.3.1 Manufacturer(s)

3.2.P.3.2 Batch Formula 3.2.P.3.2 Batch Formula

3.2.P.3.3 Description of Manufacturing 3.2.P.3.3 Description of Manufacturing Process and Process Controls Process and Process Controls 3.2.P.3.4 Controls of Critical Steps and 3.2.P.3.4 Controls of Critical Steps and

Intermediates Intermediates

3.2.P.3.5 Process Validation and/or 3.2.P.3.5 Process Validation and/or Evaluation

2

^Evaluation

3.2.P.4 Control of Excipients 3.2.P.4 Control of Excipients

3.2.P.4.1 Specifications 3.2.P.4.1 Specifications

3.2.P.4.2 Analytical Procedures 3.2.P.4.2 Analytical Procedures

3.2.P.4.3 Validation Of Analytical 3.2.P.4.3 Validation of Analytical

Procedures Procedures

3.2.P.4.4 Justification of Specifications 3.2.P.4.4 Justification of Specifications 3.2.P.4.5 Excipients of Human or Animal 3.2.P.4.5 Excipients of Human or Animal

Origin Origin

3.2.P.4.6 Novel Excipients 3.2.P.4.6 Novel Excipients

3.2.P.5 Control of Drug Product 3.2.P.5 Control of Drug Product 3.2.P.5.1 Specification(s) 3.2.P.5.1 Specification(s)

3.2.P.5.2 Analytical Procedures 3.2.P.5.2 Analytical Procedures

3.2.P.5.3 Validation Of Analytical 3.2.P.5.3 Validation of Analytical

Procedures Procedures

3.2.P.5.4 Batch Analyses 3.2.P.5.4 Batch Analyses

3.2.P.5.5 Characterisation of Impurities 3.2.P.5.5 Characterization of Impurities 3.2.P.5.6 Justification of Specification(s) 3.2.P.5.6 Justification of Specification(s) 3.2.P.6 Reference Standards or 3.2.P.6 Reference Standards or

Materials

3

Materials

3.2.P.7 Container Closure System 3.2.P.7 Container Closure System 3.2.P.8 Stability 3.2.P.8 Stability

3.2.P.8.1 Stability Summary and 3.2.P.8.1 Stability Summary and

Conclusion Conclusion

3.2.P.8.2 Post-approval Stability Protocol 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment and Stability Commitment 3.2.P.8.3 Stability Data 3.2.P.8.3 Stability Data

3.2.A APPENDICES 3.2.A APPENDICES

3.2.R REGIONAL INFORMATION 3.2.R REGIONAL INFORMATION

3.3 LITERATURE 3.3 LITERATURE

REFERENCES REFERENCES

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MODULE 4

Non-clinical Data

MODULE 5

Clinical data

4. SUMMARY AND CONCLUSION

For registration of prescription medicines three types of applications have to be submitted to TGA.

Category 1 applications:

These are applications submitted to register a new medicine, new dosage form, new strengths and new generic drug products. After submission of Application, it will take 40 working day period for TGA to take decision whether to accept or reject the application. After the acceptance of application, 255 working days is required by TGA to completely evaluate the application.

These are Applications which are submitted to register generic drug products which are already accepted in other regulated countries such as U.S.A, Canada, Europe..etc.

At the time of submission two independent evaluation reports where the drug product is accepted for marketing has to be submitted. TGA will take 20 working day period to take decision whether to accept or reject the application. After the acceptance of application, 175 working days is required by TGA to completely evaluate the application.

These are applications submitted to bring a post approval change to quality data of registered medicine. These applications has single processing period. TGA will take 40 working day period to accept or reject the change. After the decision extra 30 working day is given to sponsor for consideration of decision i.e. accept or rejection of change.

Streamline Submission process:

TGA has introduced new submission process “Streamline Submission process” to register the prescription medicines that require evaluation of quality, clinical and non- clinical data (category 1 and 2 applications).This new submission process was brought into force in order to improve significantly efficacy and timelines of registration of prescription medicines without compromising the scientific data of evaluation process and maintaining the appropriate standards of quality, safety and efficacy.

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Phases and milestones

The streamline submission process consists of eight phases and eight milestones,

allowing effective planning and tackling by

TGA and sponsor.

During pre submission phase, sponsor

completes and lodges a Pre-submission

Pre-submission Planning Form (PPF). The PPF provides

information of quality, non-clinical and

clinical evidences. The PPF should be

provided at least two and half months prior to

actual submission dossier. The information

provided in PPF allows TGA to effectively

assign resources for evaluation process.

Sponsor must lodge well planned, high

quality complete submission dossier. Sponsor

Submission

must ensure submission meet the TGA requirements for format and content. When

sponsor submit in complete, delayed and

poor quality submission, the submission will

be considered not effective and will not be

considered for evaluation.

In this phase submissions are screened and

decisions are taken to accept for evaluation or

not. The previous 40 working days period for

screening of submission on receipt has been

replaced by shorter period for ascertaining

Submission consideration whether the submission will be considered effective and will be accepted for evaluation

or not effective and will not be considered for evaluation in streamline submission process and thus it will be completed in 15 days.

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Consolidated s.31 request for In streamline submission process, this multiple information request for information is replaced by single

consolidation s.31 request for information.

This request will be send through pre determined data specified in planning letter so sponsor can conduct necessary planning activities.

The dada submitted during submission phase No addition or supplementary data after will be considered as final and complete

submission Lodgment submission. No supplementary or additional is required to submit.

Submission of Dossier:

Dossier was submitted in Common Technical Document (CTD) Format. European CTD and guidelines followed in Australia for submitting dossier.

This CTD contains five modules:

Module 1: Australian specific Administrative and Prescribing Information.

Module 2: Quality overall summary.

Non clinical summary Clinical summary Module 3: Quality Data.

Module 4: Non clinical Data.

Module 5: Clinical Data.

As dossier was compiled for Generic drug (Parental preparation), submission of Module 4& 5 data is not required.

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5. REFERENCES

1) The Pharmaceutical Industry in Australia. Pharmaceutical Industry Project Working Paper Series. Kim Sweeny.

2) Competition and Regulation Issues in the Pharmaceutical Industry 2000. Mr. Darryl Biggar.

3) Text book on Regulation of the Pharmaceutical-Biotechnology Industry. Patricia M.

Danzon, Eric L. Keuffel.

4) The Pharmaceutical Industry. Patricia M. Danzon.

5) Medicines regulation and the pharmaceutical industry. Alasdair Breckenridge, Kent Woods.

6) History of Therapeutic goods in Australia. Available at, http://www.tga.gov.au/pdf/history-tg-regulation.pdf . 7) Basic Regulation of Therapeutic goods,

Available at http://www.tga.gov.au/industry/basics.htm.

8) Regulatory guidelines for Prescription medicines in Australia, Available at http://www.tga.gov.au/pdf/pm-argpm.pdf.

9) Streamline Submission process for Prescription medicines Available, http://www.tga.gov.au/industry/pm-ssp-transition.html.

10) Australian Newzeland Regulatory Agency,

Available at http://www.tga.gov.au/about/international-anztpa-factsheet.html.

11) Common Technical Document ,Module 1,

Available at http://www.tga.gov.au/industry/pm-ctd.htm#aumod1.