international journal of innovative pharmaceutical sciences and … · 2019-07-17 · asean...

REVIEW ARTICLE Soniya Sandhal et.al / IJIPSR / 2 (11), 2014, 2898-2910

Department of Regulatory Affairs ISSN (online) 2347-2154

Available online: www.ijipsr.com November Issue 2898

REGULATORY PROCEDURE FOR PHARMACEUTICAL PRODUCTS

REGISTRATION FILING IN ASEAN AND EUROPEAN UNION

COUNTRIES & A COMPARATIVE STUDY OF REQUIREMENTS FOR

REGISTRATION OF GENERIC PRODUCTS IN ASEAN & EUROPEAN

UNION COUNTRIES

1Soniya Sandhal*,

2Dr. Manish Kumar Gupta,

3Anupam Patel

1,2Lloyd School of Pharmacy, LIMT, Greater Noida, Uttar Pradesh, INDIA

3Department of Drug Regulatory Affairs & Pharmaceutical Management, Jaipur National

University, Jaipur, Rajasthan, INDIA

Corresponding Author:

Soniya Sandhal

M.Pharm (Quality Assurance)

Lloyd School of Pharmacy, Greater Noida,

Uttar Pradesh, INDIA

Email: [email protected]

Mobile: +91 9501993659

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

The fundamental nature of national regulation on pharmaceutical products reflects the underlying national

attitudes towards the provision and financing of healthcare. The main approaches and specific measures are the

result of traditional attitudes of governments and their ad hoc responses to medical or financial crises. An

Association of South East Asian Nations (ASEAN) initiative to harmonize the requirements for drug

registration is in progress and there will be a single ASEAN market by 2015. ASEAN pharmaceutical market

mostly depends on imports to meet the demand of health facilities and through development of ACTD they

have provided a single window for drug approval in all 10 countries. Drug regulatory authorities and

international organizations such as the WHO are having to fill this drug development gap. There are two roles:

advocating or assisting in the development of needed products, and then once a dossier is prepared ensuring

that new products meet adequate quality standards and that there is sufficient clinical evidence to demonstrate

that the medicine is effective. One particular problem with this situation is that countries where the neglected

diseases are prevalent may not have the regulatory capacity to assess safety and efficacy of new medicines. In

this case, the new European Union pharmaceutical legislation may help, enabling the European Medicines

Evaluation Agency (EMEA) and Committee on Medicinal Products for Human Use (CHMP) to give scientific

opinion to the WHO about products not necessarily meant for EU markets. The primary aim to present this

paper is to describe current drug regulation and registration processes in ASEAN and European Union

Countries in order to understand how their different processes affect the quality and availability of medicines.

Key words: ASEAN, ACTD, CHMP, WHO, EMEA




INTRODUCTION


REGISTRATION IN ASEAN

Drug regulation is interplay between law and sciences, as well as between regulators and the

pharmaceutical manufacturers, with input and influences from patients and medical/health

professions. In addition, a drug regulatory authority (DRA) interrelates with many other

authorities active in the health sector, such as the Ministry of Health and other health protection

agencies. In certain cases effective cooperation with other law enforcement agencies, such as

customs and police, is necessary. Depending on the structure of the health sector, this may include

interaction and/or control over medical practitioners, pharmacists and drug sellers, as well as

interactions with agencies responsible for quarantine and control of imports and exports.

The ASEAN was established on 8 August 1967 in Bangkok by the five original member countries

(Indonesia, Malaysia, Philippines, Singapore and Thailand). Meanwhile five additional countries

(Brunei Darussalam, Vietnam, Laos, Myanmar and Cambodia) joined ASEAN [2]. The regulatory

agencies in the SE Asia countries, listed in Table 1, have been organized differently and some

changes have taken place in the recent years [2]

Regulatory Agencies in S.E. Asia

Indonesia : National Agency of Drug & Food Control

Malaysia: Drug Control Authority, NCE Unit

Philippines: BFAD, DoH

Thailand: Thai FDA Drug Control Div.

Singapore: Health Sciences Authority (HSA)

Brunei: Ministry of Health

Vietnam: Drug Administration of Vietnam

Myanmar: Food and Drug Administration

Laos: Ministry of Health, Food And Drug Department (FDD)

Cambodia: Department of Drug, Food and Cosmetics

FORMAT FOR DRUG REGISTRATION

ACTD - Common Technical Dossier

Common application format that will be submitted to ASEAN regulatory authorities for the

registration of pharmaceutical products for human use. Even though some of the Individual




ASEAN Countries have their own drug registration formats, all ASEAN countries accept the

ACTD Countries like Brunei Darussalam, Cambodia, Myanmar, Thailand, does not have any

separate drug registration format but follow ACTD [3].

ACTD Format

Part I : Table of Content Administrative Information and Prescribing Information

Section A: Introduction

Section B: Overall ASEAN Common Technical Dossier Table of Contents

Section C: Documents required for registration (for example,application forms,labeling,

Product Data Sheet, prescribing information)

Part II : Quality Document

Section A: Table of Contents

Section B: Quality Overall Summary

Section C: Body of Data

Part III : Nonclinical Document


Section B: Nonclinical Overview

Section C: Nonclinical Written and Tabulated Summaries

1. Table of Contents

2. Pharmacology

3. Pharmacokinetics

4. Toxicology

Section D: Nonclinical Study Reports

1. Table of Contents

2. Pharmacology

3. Pharmacokinetics

4. Toxicology

Part IV : Clinical Document


Section B: Clinical Overview

Section C: Clinical Summary

1. Summary of Biopharmaceutics and Associated Analytical Methods




2. Summary of Clinical Pharmacology Studies

3. Summary of Clinical Efficacy

4. Summary of Clinical Safety

5. Synopsis of Individual Studies

Section D: Tabular Listing of All Clinical Studies

Section E: Clinical Study Reports

Section F: List of Key Literature References

PROCESS OF DRUG REGISTRATION: NEW CHEMICAL ENTITIES

In order to license/register a new chemical entity (NCE), a pharmaceutical company develops a

dossier that describes the pharmaceutical quality, safety (in animals and humans) and efficacy of

the product for a specified indication. An „ideal‟ registration process would include:

• Evaluation and assessment of the pharmaceutical quality data, including:

- assessing that the manufacturer(s) of all components, including that of the active pharmaceutical

ingredient and the finished product, are certified as meeting the international standards for GMP

that are appropriate for the component, with Mapping the registration process and describing a

normative framework, inspection of manufacturer(s).

- laboratory testing the product against the proposed specifications for content and impurities,

stability data, and packaging.

- evaluation of the labelling to ensure that it complies with specified standards

• Evaluation of animal (preclinical) toxicology studies in relation to acute and chronic toxicity,

genetic toxicity, teratogenicity, carcinogenicity and others, including whether the studies have

been carried out to international standards and whether the data and interpretation of the results

are valid.

• Evaluation of human clinical trials (either placebo or active comparator randomized controlled

clinical trials) that have been carried out to define the dose frequency and duration of treatment

that is effective and safe, including assessing that the design and conduct of the trials meets

international requirements, that the data are valid and have been interpreted correctly.

• Evaluation of the product information document (called the Summary of Product Characteristics

in the European Union), including the proposed indication and claims against the available data,

and based on this information, the patient information leaflet/package insert.4

The scientific skills that are required to carry out such a registration process are highly

specialized, and generally require experts in at least the following disciplines: pharmaceutical




chemistry, toxicology, statistics, and a clinical scientist in the relevant clinical field. Dossiers for

NCEs typically consist of hundreds of volumes of data. The time taken to review and evaluate

such dossiers is a common measure of the performance of a DRA, which unfortunately puts

pressure on small authorities to keep up with international standards set by agencies such as the

US Food and Drug Administration (FDA) and the EMEA [4].

PROCESS OF DRUG REGISTRATION: GENERIC PRODUCTS

The process of registration for generic products is similar to, but simpler than, the process of

registration of NCEs. For a new generic product, a company develops a dossier that contains data

primarily about the pharmaceutical chemistry of the product. The assumption is that an innovator

product exists (usually in the same market) and that the innovator has been shown to be clinically

effective and safe (although in poorly controlled markets this may not be the case). The data for

the generic product is therefore designed to establish that it is clinically interchangeable with the

innovator in terms of efficacy and safety. Such applications implicitly rely on the clinical data

provided in the dossier for the innovator, even though there is rarely a direct comparison of the

two dossiers during the evaluation. It is this implicit comparison of clinical information that may

be constrained under TRIPs because of the requirements for data exclusivity, which may be

interpreted as precluding reference to the clinical trials that originally established that a compound

was effective and safe [4]. In some instances, a product can be registered on the basis of chemical

and manufacturing data only (e.g. an injectable formulation for which there is a recognized

pharmacopoeial standard , such as the British Pharmacopoeia, or the United States

Pharmacopeia), describing the method of synthesis and quality control for the product. For

products that are for oral administration, the application will almost certainly need to include

dissolution testing and limited clinical data in the form of bioequivalence and/or bioavailability

studies which show that the generic product is bioequivalent to the innovator – i.e. that it is

clinically interchangeable. The most rigorous test of interchangeability is a clinical trial

comparing the proposed generic with the innovator and measuring the effects of both on clinical

outcomes; these trials are rarely carried out [4].

Examples of the use of each type of data are:

Registering a new version of a generic product, where the major change is in the excipients – e.g.

a folic acid supplement – dissolution testing would be required, but not other forms of data.

Registering a new generic for a brand product where there is an established relationship between

the plasma concentration of the drug in a patient and the clinical effect – e.g. fluoxetine tablets – a




bioequivalence study in healthy subjects would be necessary. Registering a new generic version

of a product where there is no established relationship between the plasma concentration and

clinical effect – e.g. warfarin – a clinical trial comparing the available product with the new

version would be required [4]. One of the current issues in relation to ARVs is what type of data

would be required for a fixed-dose combination (FDC) of currently available innovator products.

The EU has guidelines for the registration of FDCs in general, and these indicate that usually

limited clinical data (i.e. clinical trials) are required to establish that there is at least therapeutic

equivalence of the FDC compared to the individual components. In the case where a combination

is well established from clinical practice (e.g. use of a thiazide diuretic plus an angiotensin

converting enzyme inhibitor for the treatment of hypertension, or some of the triple therapies for

HIV), it might be possible to make an argument for registration on the basis of bioequivalence

data alone, as was the case for Trizivir®, an FDC containing lamivudine, stavudine and

nevirapine. Where the combinations are not clinically established, it is highly unlikely that

bioequivalence data without some clinical trial data would be accepted [4]. For biological

products, requirements are different. Biological products - for example, insulin - are not usually

regarded as having „generic‟ versions. It is generally accepted that bioequivalence data alone is

insufficient for registration and that clinical trial data must be provided. It is often the evaluation

of bioequivalence data that presents the major challenge for small DRAs in a developing country.

Firstly, not all local manufacturers in these settings are capable of carrying out bioequivalence

studies. These studies require (1) access to the innovator product (note, not necessarily the

innovators‟ dossier - a purchased batch of marketed product is adequate) (2) the capacity to carry

out high standard controlled trials in humans that compare the proposed generic product with the

innovator, including (3) measurement of plasma concentrations of substances using a reliable,

sensitive and specific assay. For new innovator products, even if the generic company is able to

„reverse engineer‟ the product, there may not be a readily available standard assay method [4].

Secondly, if bioequivalence data is available, the comparator may not be a product available in

the local market. If it is not a local product, there are two problems: lack of access to original data

about the product, and difficulties arising if the proposed product turns out not to be clinically

interchangeable with what is available. This is less of an issue with new products where there is

only the innovator, but in the case of old medicines (e.g. diuretics) where there may be multiple

small manufacturers even in a single country, clinicians need to know that different brands of the

same drug have the same effect. If clinicians do not have this confidence, it undermines their




acceptance of cost-control measures such as generic prescribing [4]. Thirdly, again assuming data

is available, the evaluation of bioequivalence data requires statistical and pharmacokinetic skills

that may not be readily available. For example, in Sri Lanka, product registration for generic

products is carried out by five pharmacists, none of whom have had training in assessing

bioequivalence studies (personal communication, Fernandopulle). However, with the increasing

availability of user friendly software and training, it should be possible for small countries to

acquire the necessary skills [4]. Given the sensitivity of the manufacturing data in a dossier for an

innovator product, if a multinational company believes that there is a risk of such information

„leaking‟ to generic companies, including government-owned manufacturers in some countries, it

may be an incentive for them not to submit the application for the originator product. In such

circumstances, a regulatory authority would have to make a judgement about whether it would be

prepared to evaluate a generic copy of the innovator on its merits using a limited dossier that

provided bioequivalence data, for example, plus published clinical trials. Otherwise the access of

generic medicines to the market would clearly be delayed or obstructed completely [4].

Registration of generic products, as for innovator products, also requires inspection and quality

control of manufacturing plants. This is particularly where manufacturing standards are critical

and internationally, the benchmark for manufacturing standards is defined in the International

Standards for Good Manufacturing Practice (GMP). There have been anecdotal reports from

many developing countries that when GMP standards were introduced, many local manufacturers

could not meet the standards required under GMP for documentation, process and management

controls over the production of a product. This situation has led to debate about what are the

appropriate standards for good manufacturing in resource-poor settings. In addition, local capacity

to carry out GMP-standard inspections of facilities and processes is often limited, as the training

and skills required to become a certified GMP inspector are significant. Training programmes

have been developed, however, but need further support [4]. The time required to register a

generic product varies. If it is a straightforward application with high quality data from a licensed

and qualified manufacturer, then a dossier can be reviewed in 2-4 weeks. If, on the other hand, the

substance is relatively poorly defined, the chemistry is complex and bioequivalence studies are

needed as well as inspections of manufacturers, the process of evaluation and registration can and

should take much longer. If a small DRA is registering large numbers of generic products rapidly,

the quality of the evaluation and assessment of the products may well be compromised [4].




PROCESS OF REGISTRATION: OTHER ASPECTS

A DRA may undertake a large number of other types of regulatory reviews. These include, but are

not limited to, evaluating:

#changes in formulation of registered products (e.g. tablets to capsules)

#changes in excipients

# changes in dose sizes (e.g. 2mg to 4mg tablets)

# changes in labelling

# changes in product information documents

# changes in clinical aspects such as modifications to indications, safety information, interactions

etc.

# licensing of manufacturers, distributors, wholesale premises, pharmacies etc.

# controlling imports and exports of products

# controlling clinical trials.4

Thus, the workload for a DRA will depend on the scope and nature of the activities it undertakes.

In the developing country context, it is probably most critical that a DRA spends adequate time

and resources on controlling the products on the local market for pharmaceutical quality as well

as controlling importation of products [4].


REGISTRATION IN EUROPEAN UNION

EUROPEAN UNION

The European Union (EU) is an economic and political union of 28 member states which are

located primarily in Europe. The European Union is composed of 28 sovereign member states:

Austria, Belgium, Bulgaria, Cyprus, the Czech Republic, Denmark, Estonia, Finland, France,

Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the

Netherlands, Poland, Portugal Romania, Slovakia, Slovenia, Spain, Sweden, and the United

Kingdom [4].

THE NEW PROCEDURES FOR EVALUATING MEDICINAL PRODUCTS AND

GRANTING MARKETING AUTHORISATIONS

A new European system for authorising medicinal products since January 1995. The new

European system offers two routes for authorising medicinal products:

-a "centralised" procedure, with applications made directly to the European Agency for the

Evaluation of Medicinal Products (commonly known as the European Medicines Evaluation

http://en.wikipedia.org/wiki/Economic_and_Monetary_Union_of_the_European_Union

http://en.wikipedia.org/wiki/Member_state_of_the_European_Union

http://en.wikipedia.org/wiki/Special_member_state_territories_and_the_European_Union#Outermost_regions

http://en.wikipedia.org/wiki/Europe

http://en.wikipedia.org/wiki/Sovereign_state

http://en.wikipedia.org/wiki/Austria

http://en.wikipedia.org/wiki/Belgium

http://en.wikipedia.org/wiki/Bulgaria

http://en.wikipedia.org/wiki/Cyprus

http://en.wikipedia.org/wiki/Czech_Republic

http://en.wikipedia.org/wiki/Denmark

http://en.wikipedia.org/wiki/Estonia

http://en.wikipedia.org/wiki/Finland

http://en.wikipedia.org/wiki/France

http://en.wikipedia.org/wiki/Germany

http://en.wikipedia.org/wiki/Greece

http://en.wikipedia.org/wiki/Hungary

http://en.wikipedia.org/wiki/Republic_of_Ireland

http://en.wikipedia.org/wiki/Italy

http://en.wikipedia.org/wiki/Latvia

http://en.wikipedia.org/wiki/Lithuania

http://en.wikipedia.org/wiki/Luxembourg

http://en.wikipedia.org/wiki/Malta

http://en.wikipedia.org/wiki/Netherlands

http://en.wikipedia.org/wiki/Poland

http://en.wikipedia.org/wiki/Portugal

http://en.wikipedia.org/wiki/Romania

http://en.wikipedia.org/wiki/Slovakia

http://en.wikipedia.org/wiki/Slovenia

http://en.wikipedia.org/wiki/Spain

http://en.wikipedia.org/wiki/Sweden

http://en.wikipedia.org/wiki/United_Kingdom






Agency - EMEA) leading to the grant of a European marketing authorisation by the Commission.

Use of this procedure is compulsory for products derived from biotechnology, and optional for

other innovative medicinal products; -a "mutual recognition" procedure, which is applicable to the

majority of conventional medicinal products. Applications are made to the Member States

selected by the applicant and the procedure operates by mutual recognition of national marketing

authorisations. Where this is not possible, the EMEA is called upon to prepare a binding

arbitration. Purely national authorisations are still available for medicinal products to be marketed

in one Member State [6].

EUROPEAN MEDICINES EVALUATION AGENCY - EMEA

The EMEA was established in 1995, partly in response to demands from consumers'

organisations, particularly the BEUC (Bureau Européen des Consommateurs) and the European

Parliament [6].

EMEA aims

The EMEA's key aims are to:

- protect and promote public health by providing safe and effective medicines for human and

veterinary use;

- give patients quick assess to innovative new therapy;

- facilitate the free movement of pharmaceutical products throughout the EU;

- improve information for patients and professionals on the correct use of medicinal products, to

improve animal health;

- protect consumers of animal products and harmonise scientific requirements in order to optimise

pharmaceutical research worldwide [6].

1. The centralised procedure

The centralised procedure for authorising biotechnology-derived and high-technology medicines

is laid down in Council Regulation (EEC) N° 2309/936 and Directive 93/41/EEC7 [6]. The

centralised procedure, which came into operation in 1995, allows applicants to obtain a marketing

authorisation that is valid throughout the EU. It is compulsory for medicinal products

manufactured using biotechnological processes, but may also be used for other innovative

products, on a voluntary basis [6]. When a company wishes to place a medicinal product that is

eligible for the centralised procedure on the market, it sends an application directly to the

Agency, to be assessed by the Committee for Proprietary Medicinal Products (CPMP) or

Committee for Veterinary Medicinal Products (CVMP). Both the CPMP and the CVMP meet




every month [6]. The procedure results in a Commission decision, which is binding on all EU

Member States, to authorise the product. Centrally-authorised products may be marketed in all

Member States [6]

2. The mutual recognition procedure

The mutual recognition procedure works on the principle of the mutual recognition by EU

Member States of their respective national marketing authorisations. An application for

recognition may be addressed to one or more Member States. The applications submitted must be

identical and all Member States must be notified of them. As soon as one Member State decides

to evaluate the medicinal product (at which point it becomes the "Reference Member State"), it

notifies this decision to other Member States ("Concerned Member States"), to whom applications

have also been submitted. Concerned Member States may then suspend their own evaluations,

and await the Reference Member State's detailed assessment report on the product. As soon as the

assessment is completed, copies of this report are sent to all Member States and they then have 90

days to recognise the decision of the Reference Member State and the SPC as approved by it (by

granting a marketing authorisation with an identical SPC). Should any Member State refuse to

recognise the original national authorisation, e.g. on public health grounds, are submitted to the

appropriate EMEA scientific committee (CPMP or CVMP, as appropriate), for arbitration [6].

The EMEA committee opinion is then forwarded to the Commission, for the start of the decision

making process. As in the centralised procedure, this process entails consulting various

Commission directorates-general and the regulatory standing committees on human or veterinary

medicinal products, as appropriate. Once the Commission decision is taken, it is binding on all the

Member States concerned, which must withdraw, grant, or vary the marketing authorisations as

necessary to comply with the decision. Other Member States not directly concerned at the time of

the decision are also bound as soon as they receive a marketing authorisation application for the

same product [6]. In the event of a serious disagreement among Member States, which makes it

impossible for the Commission to decide, a decision may be taken by the Council of the European

Union [6].

3. Decentralized procedure

For products that fall outside the scope of the European Medicines Agency (EMA) with regard to

centralized procedures, a sponsor can submit under the decentralized procedure. Using this

process, a sponsor can apply for simultaneous authorization in more than one EU country for

products that have not yet been authorized in any EU country.6




ICH-CTD FORMAT

Module 1 : Administrative Information and Prescribing Information

1.1 Comprehensive Table of Content

1.2 Introduction

1.3 Application Form

Module 2 : Quality overall summaries

2.1 Overall CTD Table of Contents of Modules 2,3,4 &5.

2.2 Introduction

2.3 Quality Overall Summary

2.4 Non- Clinical Overview*

2.5 Clinical overview

2.6 Non-clinical Summary* (Not Applicable)

2.7 Clinical Summary* (Not Applicable)

Module 3: QUALITY

3.1 Table of Content

3.2 S Drug Substance (Active Substance)

3.2.P Drug Product

3.2 A Appendices

Module 4 : Non clinical Study Reports (Not Applicable For Generic Drugs)

Module 5 : Clincal Study reports

5.1 Table of Content

5.2 Tabular Listing

5.3 Clinical Study Reports

5.3.1 Comparison BA-BE Study Report

5.3.2 Bio Analytical Method for Human

5.3.3 Case Reports7

COMPARATIVE STUDIES OF PHARMACEUTICAL PRODUCT REGISTRATION

FILING IN EUROPEAN COUNTRIES & ASEAN

Table1: DOCUMENTS LOCATION IN FORMAT OF ICH -CTD (EU) & ASEAN CTD8

DOCUMENTS LOCATION

ICH- CTD (EU) ASEAN CTD

Administrative Documents &

Product Information Module 1 Part 1




Common Technical

Documents

Overview and

Summaries

Module 2 Incorporated in

Part II, III and IV

Quality Documents Module 3 Part II

Non-Clinical Documents Module 4 Part III

Clinical Documents Module 5 Part IV

Table 2: COMPARISON OF REGULATORY REQUIREMENTS BETWEEN

EUROPEAN UNION & ASEAN

ADMINISTRATIVE

REQUIREMENTS EU ASEAN

Filling Procedure ICH- CTD format ACTD format

Approval time line 12 months 110 working days

Copies 1 1

Letter of Authorization Not Required Requried

Presentation eCTD Paper

MANUFACTURING & CONTROL


No. of Batches 3 3

Packaging Not Required Not Required

Process Validation Required if it is MR formulation

or asceptic Product Required

FINISHED PRODUCT CONTROL


Assay 95-105% As based on Reference

Pharmacopoeia

Identification Test Test Required Required /As based on Reference

Pharmacopoeia

Colour Identification Required May or May Not Required

Water Content Not Required Not Required

Disintegration Test Required As based on Reference

Pharmacopoeia/ Required

LABELLING


Country Registration No. Required Required

Name & strength of API Required Required

Labelling & Product

Information Vials/Carton & PIL/SPC

Carton/Inner label or Blister pack &

PI/PIL/SPC

Readability Test Required Not Required

STABILITY


No. of Batches 2

2 batches for

conventional dosage

form & stable drug substances &

3 batches for critical dosage form &

unstable drug substance.

Date & Time of Submission 6 months accelerated & 6 months

long term

Min. 6 months accelerated & Min.

12 months long term




CONCLUSION

There are clear indications that the availability of good quality drugs is directly linked to a well-

functioning drug regulatory control system through production, importation and distribution. In

order to have such a system, the functions and powers of regulatory authorities have to be clearly

stated from the beginning. Regulatory standards in ICH countries (EU, USA and Japan) have

been progressively tightened. They have developed a common for submission for MAA. All drug

application submissions must be made in the CTD format. Non – ICH countries include all the

countries outside the ICH. Non – ICH countries represent countries with low income and less

developed regulations. They do not have sufficient technical and regulatory resources to comply

with the ICH guidelines.

REFERENCES

1. AESAN/About asean/History. Available from website : {http://www.asean.org.}

2. Wong Ellick et al (2003) “Regulatory Environment and Clinical Trials in South East Asia”

Drug Information Journal, 2003.

3. http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/wester

n_m edicines/files_guidelines.Par.22449.File.dat/ACTD_Organization of Dossier.pdf.}

4. Hill S. Johnson K. et al (2004) “Emerging Challenges and Opportunities in Drug

Registration and Regulation in Developing Countries” / Mapping the registration process

and describing a normative framework/ General description of registration

processes/London DFID Issues paper-Access to medicines 2004.

5. European Union. Available from website: {www.wikipedia.org/wiki/European_Union}.

6. {http://ec.europa.eu/enterprise/newsroom/cf/_getdocument.cfm?doc_id=1684}.

7. {http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R3_Organisatio

n/M4_R3__organisation.pdf}.

8. Sharma Priyank et al (2012)“Procedure for Pharmaceutical Generic Dossier Filling of

Solid Oral Dosage Forms for “ASEAN Countries” & A Comparative Study of ASEAN

CTD & ICH – CTD” Asian Journal of Pharmaceutical Sciences and Research Volume

2.issue no. 5, ISSN 2249-4898, May 2012.

http://www.asean.org/

http://www.hsa.gov.sg/

http://www.wikipedia.org/wiki/European_Union