CHAPTER 5

REGULATORY REQUIREMENTS OF LESS REGULATED MARKET

ASEAN REGION
Association of South Eastern Asian nations includes the following countries:

Brunei Darussalam

Cambodia
Indonesia
Laos y

Malaysia

Myanmar

Philippines

Singapore

Thailand

Vietnam

These countries have a common guideline applicable to all the 10 countries.

The registration checklist of ASEAN11 is as follows :

Part 1 : Table of Content Administrative Information and Prescribing

Information
SECTION A: INTRODUCTION
SECTION B: OVERALL ACTD TABLE OF CONTENTS
SECTION C: DOCUMENTS REQUIRED FOR REGISTRATION
1 Application Form
2 Letter of Authorization
3 Label
4 Package Insert
5 Summary of product Characteristics

90
6 Patient information leaflet
7 Manufacturing license
8 WHO-GMP certificate
9 Certification of Pharmaceutical product
10 Registration status in other countries
11 Sample of label
12 Sample of Finished product

Part 2 : Quality Document

SECTION A: TABLE OF CONTENTS

• Table of Contents of Part 2

SECTION B: QUALITY OVERALL SUMMARY

S DRUG SUBSTANCE
S 1 General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
S 2 Manufacture
2.1 Manufacturer
S 3 Characterization
3.1 Elucidation of Structure and other Characteristics
3.2 Impurities
S 4 Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedure ,
4.3 Validation of Analytical Procedure
4.4 Batch Analysis
S 5 Reference Standards or Material
S6 Container Closure System
S7 Stability
91
 P DRUG PRODUCT
P 1 Description and Composition
P 2 Pharmaceutical Development
2.1 Information on Development Studies
2.2 Components of Drug Product
2.3 Finished Product
2.4 Manufacturing Process Development
2.5 Container Closure System
2.6 Microbiological Attributes
2.7 Compatibility
P 3 Manufacture
3.1 Batch Formula
3.2 Manufacturing Process and Process Control
3.3 Control of Critical Steps and Intermediates
3.4 Process Validation and/or Evaluation
P 4 Control of Excipients
4.1 Specifications
4.2 Analytical Procedures
4.3 Excipients of Human or Animal Origin
4.4 Novel Excipients
P 5 Control of Finished Product
5.1 Specification
5.2 Analytical Procedures
5.3 Validation of Analytical Procedures
5.4 Batch Analysis
5.5 Characterization of Impurities
5.6 Justification of Specifications
P 6 Reference Standard or Material
P 7 Container Closure System
P 8 Stability
P 9 Product Interchangeability Equivalence Evidence

92
SECTION C: BODY OF DATA
S DRUG SUBSTANCE
S 1 General Information
1.1 Nomenclature
1.2 Structural Formula
1.3 General Properties
S 2 Manufacture
2.1 Manufacturer(s)
2.2 Description of manufacturing Process
2.3 Control of Material
2.4 Control of Critical Steps and Intermediates
2.5 Process Validation and/or Evaluation
2.6 Manufacturing Process Development
S 3 Characterization
3.1 Elucidation of structure and characterization
3.2 Impurities
S 4 Control of Drug Substance
4.1 Specifications
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analysis
4.5 Justification of Specifications
S 5 Reference Standard or Material
• Qualification Details of Reference Standard
• Certificate of Analysis
S 6 Container Closure System
• Specifications
• Certificate of Analysis
S 7 Stability
• Stability Summary and Conclusion
• Post Approval Stability Protocol and Stability Commitment

93
 Stability Data

P DRUG PRODUCT

P 1 Description and Composition

• Description of the dosage form

• Composition of the dosage form
- Qualitative composition
- Quantitative Composition
• Type of container and closure used for the dosage form

P 2 Pharmaceutical Development

2.1 Information on Development

2.2 Component of Drug Product
2.3 Finished Product
2.4 Manufacturing Process Development
2.5 Container Closure System
2.6 Microbiological Attributes
2.7 Compatibility

P 3 Manufacture
3.1 Batch Formula
3.2 Manufacturing Process and Process Controls
3.3 Controls of Critical Steps and Intermediates
3.4 Process Validation and/ or Evaluation

P 4 Control of Excipients
4.1 Specifications
4.2 Analytical Procedures
4.3 Excipients of Human or Animal Origin
4.4 Novel Excipients

94
P 5 Control of Finished Product
5.1 Specification (s)
5.2 Analytical Procedure
5.3 Validation of Analytical Procedures
5.4 Batch Analysis
5.5 Characterization of Impurities
5.6 Justification of Specification (s)

P 6 Reference Standard or Material

P 7 Container Closure System

• Summary of packaging system

• Components specification, standard testing procedure and analysis

report
- Specifications
- Standard test procedures
- Analytical Report
• Certification from supplier

P 8 Stability
• Stability Summary and Conclusion

• Post Approval Stability Protocol and Commitments

• Stability Data

P 9 Product Interchangeability
• Summary of Bioequivalence Study Report

Part 3 : Nonclinical Document

95
SECTION A: TABLE OF CONTENTS

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

SECTION E. LIST OF KEY LITERATURE REFERENCES

[

Part 4 : Clinical Document

SECTION A: TABLE OF CONTENTS

SECTION B: CLINICAL OVERVIEW

1 Product Development Rationale
2 Overview of Biopharmaceutics
3 Overview of Clinical Pharmacology
4 Overview of Efficacy
5 Overview of Safety
6 Benefits and Risks Conclusions

SECTION C: CLINICAL SUMMARIES

1 Summary of Biopharmaceutics and Associated Analytical Methods

96
 1.1 Background and Overview
1.2 Summary of Results of Individual Studies
1.3 Comparison and Analyses of Results Across Studies

Appendix 1
2 Summary of Clinical Pharmacology Studies
2.1 Background and Overview
2.2 Summary of Results of Individual Studies
2.3 Comparison and Analyses of Results Across Studies
2.4 Special Studies .
Example 1: Immunogenicity
Example 2: Clinical microbiology

Appendix 2
3 Summary of Clinical Efficacy
3.1 Background and Overview of Clinical Efficacy ,
3.2 Summary of Results of Individual Studies
3.3 Comparison and Analyses of Results Across Studies
3.4 Analysis of Clinical Information Relevant to Dosing
Recommendations
3.5 Persistence of Efficacy and/or Tolerance Effects

Appendix 3
4 Summary of Clinical Safety
4.1 Exposure to the Drug
4.2 Adverse Events
4.3 Clinical Laboratory Evaluations
4.4 Vital Signs, Physical Findings, and Other Observations
4.5 Safety in Special Groups and Situations
4.6 Post-marketing Data l
Appendix 4

97
 5 Synopses of Individual Studies

SECTION D: TABULAR LISTING OF ALL CLINICAL STUDIES

SECTION E: CLINICAL STUDY REPORTS

A TABLEOF CONTENTS OF CLINICALSTUDYREPORTS
B TABULAR LISTING OF ALL CLINICAL STUDIES
C CLINICAL STUDY REPORTS

1 Reports of Biopharmaceutic Studies

1.1 Bioavailability (BA) Study Reports
1.2 Comparative BA and Bioequivaience (BE) Study Reports
1.3 In vitro-ln vivo Correlation Study Reports
1.4 Reports of Bioanalytical and Analytical Methods for
Human Studies

2 Reports of Studies Pertinent to Pharmacokinetics using

Human Biomaterials
2.1 Plasma Protein Binding Study Reports
2.2 Reports of Hepatic Metabolism and Drug Interaction
Studies
2.3 Reports of Studies Using Other Human Biomaterials

3 Reports of Human Pharmacokinetic (PK) Studies

3.1 Healthy Subject PK and Initial Tolerability Study Reports
3.2 Patient PK and Initial Tolerability Study Reports
3.3 Population PK Study Reports

4 Reports of Human Pharmacodynamic (PD) Studies

4.1 Healthy Subject PD and PK/PD Study Reports
4.2 Patient PD and PK/PD Study Reports

98
 5 Reports of Efficacy and Safety Studies
5.1 Study Reports of Controlled Clinical Studies Pertinent
to the Claimed Indication
5.2. Study Reports of Uncontrolled Clinical Studies
5.3 Reports of Analyses of Data from More Than One Study,
Including any Formal Integrated Analyses, Meta­
analyses, and Bridging
Analyses
5.4 Other Clinical Study Reports

6 Reports of Post-Marketing Experience

7 Case Report Forms and Individual Patient Listings

SECTION F: LIST OF KEY LITERATURE REFERENCES

99
AFRICAN REGION

This region includes many counties like

Algeria

Angola

Botswana

Cameroon

Chad

Congo
C0M60

Ethiopia

Ghana

Ivory Coast

Kenya

Liberia

Madagascar

Malawi

Mali

Mauritius
25SS2C
Morocco

Namibia

Nigeria

100
 Senegal

Somalia

Tanzania

Uganda

Zambia

Zimbabwe

However for our analysis purpose, we have considered only five countries and
looked into their regulatory requirements. These countries are -

• Ethiopia
• Kenya
• Senegal
• Tanzania
• Uganda

101
ETHIOPIA

Ethiopia is one of the very less regulated country located in African continent. They
have a guideline, which is very lenient in term of its requirements. The regulatory
body of Ethiopia is called Drug Administration and Control Authority of Ethiopia
(DACA).

The registration checklist of Ethiopia12 is as follows :

1.0 APPLICATION FORM

/

2.0 AGENCY AGREEMENT

3.0 COPP

4.0 CHEMICAL AND PHARMACEUTICAL DOCUMENTATION

4.1 Quality of Raw Material
4.1.1 API
4.1.1.1 Name, chemical structure, solubility & other physic-chemical characteristics
4.1.1.2 Name and Address of API facility
4.1.1.3 Synthetic route of API
4.1.1.4 API specification
4.1.1.5 API stability Data
4.1.2 Excipient Specification

4.2 Finished Product

4.2.1 Formulation Development
4.2.2 Data on composition (Qualitative and Quantitative composition with function
of excipients and quantity required per batch)

4.3 Data on Packaging Material

4.3.1 Specification
4.3.2 Test Method
4.3.3 Safety Certificate
102
 4.3.4 COA (Vendor and Applicant)
4.3.5 Manufacturer information

4.4 Data on manufacturing and packaging procedure

4.4.1 Brief description on manufacturing and packaging procedure
4.4.2 Description of in process controls
4.4.3 Process validation report from 3 batches
4.4.4 Batch Manufacturing Report of 1 batch

4.5 Analytical Report

4.5.1 Finished product Specification (release and shelf life)
4.5.2 Method of analysis
4.5.3 Certificate of Analysis
4.5.4 Method validation report of assay

4.6 Stability Data

(2 batches for fairly stable active ingredient and 3 batches for degaradable
API. Zone II and Zone IV data acceptable. Labeling to be made accordingly.
24 M can be requested with 6M. data)

5.0 BE REPORT
(Should be against innovator or market leading product registered with
authority. Minimum 12 subjects, representative chromatograms also required.

6.0 LABELING
6.1 Package Leaflet
6.2 Container label
6.3 Carton label
6.4 Finished product, API and WS samples

103
KENYA

Kenya is one of the very less regulated country located in African continent.
They have a guideline, which is very lenient in term of its requirements. In
this dossier most of the documents are required in CTD format. The
regulatory body of Kenya is called Kenya Medical Supplies Agency (KMSA).

The registration checklist of Kenya13 is as follows :

MODULE 1 : ADMINISTRATIVE INFORMATION

1.0 Application Form

1.1 Details of Applicant
1.2 Trade Name
1.3 Generic Name
1.4 Strength of the product
1.5 Dosage Form
1.6 Proposed Pack Size
1.7 Physical Description of the product
1.8 Proposed Shelf Life
1.9 Therapeutic category/ ATC Code
1.10 Legal category
1.11 Country of Origin
1.12 Marketing status in country of origin/other countries
1.13 Certificate of Analysis of pre registration analysis of product from
National Quality Control Laboratory - Kenya
1.14 Name and Address of manufacturer
1.15 GMP status of Manufacturer and GLP/GCP status of CRO
1.16 Details of Local Technical Representative
1.17 Summary of Product Characteristics
1.18 Product Information for Health Professional
1.19 Patient Information Leaflet

104
MODULE 2 : CHEMICAL, PHARMACEUTICAL, NON CLINICAL AND
CLINICAL OVERVIEWS AND SUMMARIES
2.2 Introduction
2.3 QOS
2.3.1 Overview of Active Pharmaceutical Ingredients
2.3.1.1 General Information
2.3.1.2 Manufacture
2.3.1.3 Characterization
2.3.1.4 Control of Drug Substance
2.3.1.5 Reference standard or material
2.3.1.6 Container closure system
2.3.1.7 Stability

2.3.2 Overview of Drug Product

2.3.2.1 Description and Composition of Drug Product
2.3.2.2 Pharmaceutical development
2.3.2.3 , Manufacture
2.3.2.4 Control of Excipients
2.3.2.5 Control of Drug Product
2.3,2.6 Reference Standards or Materials
2.3.2.7 Container Closure System
2.3.2.8 Stability

2.4 Overview and Summary of Non Clinical and Clinical

Documentation
2.4.2.1 Clinical Overview and Summary

MODULE 3 : CHEMICAL, PHARMACEUTICAL DOCUMENTATION

3.1 Table of Content
3.2 Body of Data

105
 Particulars of Active Pharmaceutical Ingredients
(Requires CEP or DMF. If open Part of DMF is shared, a signed
declaration by API holder on the authenticity of data incorporated is
required
3.2.1.1 Nomenclature
3.2.1.2 Structure
3.2.1.3 General Properties
3.2.1.4 Name and address of manufacturer
3.2.1.5 Manufacturing process and process controls
3.2.1.6 Specification and control of Raw materials and intermediates
3.2.1.7 Control of Critical Steps and Intermediates
3.2.1.8 Process validation/Evaluation
3.2.1.9 Manufacturing process Development
3.2.1.10 Characterization of API/Impurities
3.2.1.11 Control of Active Pharmaceutical Ingredients
3.2.1.12 Reference standards
3.2.1.13 Container closure system
3.2.1.14 Stability

3.2.2 Particulars of Drug Product

3.2.2.1 Description and Composition Including packing system
3.2.2.2 Pharmaceutical development Report
3.2.2.3 Manufacture of the FPP
3.2.2.3.1 Site address with GMP certificate
3.2.2.3.2 Batch Formula
3.2.2.3.3 Manufacturing process and Process controls (executed BMR of one
batch)
3.2.2.3.4 Control of Critical steps and Intermediates
3.2.2.3.5 Process Validation and Evaluation (3 batches)
3.2.2.4 Control of Excipients
3.2.2.4.1 Specification
3.2.2.4.2 Analytical Procedure

106
 3.2.2.4.3 Validation of Analytical Procedure
3.2.2.4.4 Justification of Specification
3.2.2.4.5 Excipients of Human or Animal Origin
3.2.2.5 Control of Drug Product
3.2.2.5.1 Specification
(Both release and shelf life specification. Assay limit should be 95-
105%. Identification of colorant to be done)
3.2.2.5.2 Analytical Procedure
3.2.2.5.3 Validation of Analytical Procedure
3.2.2.5.4 Batch Analyses (3 batches)
3.2.2.5.5 Characterization of Impurity
3.2.2.5.6 Justification of Specification
3.2.2.6 Reference standards or Materials
3.2.2.7 Container closure system
3.2.2.7.1 Specifications
3.2.2.7.2 Standard Test Procedure
3.2.2.7.3 Certificate of Analysis
3.2.2.7.4 Drawing
3.2.2.7.5 Safety Certificates
3.2.2.7.6 Container Labeling
3.2.2.8 Stability data (3 batches Zone IV, Minimum 12 Months data at the time
of filing)

MODULE 5 CLINICAL STUDY REPORTS

5.1 Bio Equalance Report
(Waiver request to be supported by 3 media dissolution profiling. Study
to be done against EU innovator)

107
SENEGAL

Senegal is one of the very less regulated country located in African continent. They
have a guideline, which is very lenient in term of its requirements. The regulatory body
of Senegal is called Ministry of Health and Medical Prevention.

The registration checklist of Senegal14 is as follows :

ADMINISTRATIVE FILE
1 Name and Address of Applicant
2 Name and Address of manufacturer
3 Mfg. License
4 Certificate ff Pharmaceutical Product
5 GMP certificate
6 List of countries where the product is registered,
7 Name and Address of Active Pharmaceutical Ingredients manufacturer
8 Certificate of Analysis of Active Pharmaceutical Ingredients and Finished
Product
9 API Sample
10 Finished Product Samples
11 Receipt of Payment
12 Certificate of responsible Pharmacist
13 Certificate of Price

PRODUCT CHARACTERISTICS
1 Name of the product, dosage form and strength
2 Qualitative and Quantitative composition
3 Pharmacological Class
4 Proposed Pack Size
5 Therapeutic Indication
6 Dosage and Route of Administration

108
7 Limitations for use and side effects, warning statement and special
precaution of use, interactions , usage in case of pregnancy, instructions in
case of over dosage, medication incompatibilities

8 Pharmacological Properties
9 Shelf Life
10 Storage Condition
11 Proposed Dispensing Category

PHARMACEUTICAL AND CLINICAL SECTION

Pharmaceutical Section
1 Qualitative and Quantitative composition with function of excipients
2 Chemical Name, Structure, Molecular weight of API
3 Batch manufacturing Formula with list of excipients
4 Brief Description of Manufacturing process with flow chart.
5 Active Pharmaceutical Ingredients specification and Certificate of Analysis
6 Raw Material specification and Certificate of Analysis
7 . In process Specs and Certificate of Analysis

8 Finished Product specs with Certificate of Analysis

9 Stability Data (3 batches under 25±2°C/60±5% RH)
10 Expert Report for chemical section
11 Bio Equivalence Report

Clinical Section

1 Studies on toxicity, pharmaco kinetic, pharmacodynamics and clinical trials

2 Expert Report for Clinical section

109
TANZANIA

Tanzania is one of the very less regulated country located in African continent. They
have a guideline, which is very lenient in term of its requirements. The regulatory body of
Tanzania is called Tanzania Food and Drug Authority (TFDA).

The registration checklist of Tanzania15 is as follows :

SECTION I: GENERAL INFORMATION

1 Application Form

SECTION II: SUMMARY OF PRODUCT CHARACTERISTICS

2.1 Generic Name
2.2 ATC Classification
2.3 Qualitative and Quantitative Composition
2.4 Pharmaceutical Form
2.5 Clinical Particulars
2.5.1 Therapeutic Indication
2.5.2 Posology and method of Administration
2.5.3 Contra indication
2.5.4 Special warnings and Precautions for use
2.5.5 Interaction with other medicinal products and other form of interaction
2.5.6 Pregnancy and Lactation
2.5.7 Effects on ability to drive and use machine
2.5.8 Undesirable Effects
2.5.9 Overdose
. 2.6 Pharmacological Properties
2.6.1 Pharmacodynamic Properties
2.6.2 Pharmacokinetic Properties
i 2.6.3 Preclinical safety Data
2.7 Pharmaceutical Particulars
2.7.1 Incompatibilities
110
 2.7.2 Shelf Life
2.7.3 Special Precautions for Storage
2.7.4 Nature and Contents of Container
2.7.5 Special Precautions for Disposal
2.8 Registrant
2.9 Registration Number
2.10 Date of first Registration/ renewal of registration
2.11 Date of Revision of Text

SECTION III: ACTIVE PHARMACEUTICAL INGREDIENTS

3.1 Nomenclature Require CEP or DMF. If open Part of DMF is shared, a
signed declaration by API holder on the authenticity of data incorporated
required
3.2 Properties
3.3 Manufacturing Site
3.4 Route of Synthesis
3.5 Specifications
3.6 Container Closure System
3.7 Stability Testing

SECTION IV: FINISHED PHARMACEUTICAL PRODUCTS

4.1 Manufacturing and Marketing Authorization in the country of origin
4.2 Pharmaceutical Development
4.3 Formulation Unit and Batch formula to be provided
4.4 Sites of Manufacture
4.5 Manufacturing process
4.5.1 Brief Description
4.52, Flow Chart
4.5.3 Intended Batch Record
4.5.4 Executed BMR one batch
4.6 Manufacturing process controls of critical steps and intermediates
4.7 Process Validation and Evaluation 3 batches
111
4.8 Specification of Excipient
4.9 Control of FPP Requires both release and shelf life specifications. Assay
limit should be 95-105%. Identification of colorant to be done
4.9.1 Analytical Procedure
4.9.2 Validation of Analytical Procedure
4.9.3 Batch Analysis 3 batches data
4.10 Container closure system
4.10.1 Specification
4.10.2 Standard Testing Procedure
4.10.3 Certificate of Analysis
4.11 Stability Testing 3 batches Zone IV Data. Minimum 12M at the time of
submission
4.12 Container Labeling
4.13 Pack insert leaflet

112
UGANDA

Uganda is one of the less regulated country located in African continent. They
have a guideline, which is very lenient in term of its requirements. The regulatory
body of Uganda is called National Drug Authority (NDA)
The registration checklist of Uganda16 is as follows : 1
1. Application form
2. Appendix I of Application Form
2.1 Specification of the Packaging Material
) 2.2 Composition of the Product
3. Appendix 2 of Application Form
3.1 Raw Material Specification
3.2 Brief Manufacturing Summary ,
3.3 Details of in process controls
3.4 Specification of Finished Product
3.5 Stability (3 batches Zone IV Data./ Method validation data for
Assay to be provided if the method is non pharmacopoeial)
3.6 Executed Batch Manufacturing Record (1 batch)
4. Appendix 3 of Application Form
• Certificate of Pharmaceutical Product
5. Appendix 4 of Application Form
5.1 Particulars of Toxicological Trials
5.2 Indication
5.3 Pharmacological and clinical trials on laboratory animals
5.4 Side effects, contra indication
5.5 Bio Equivalence Data (Waiver request to be supported by
dissolution profiling pH 1.2,4.5 and 6.8)
6. Appendix 5 of Application Form
• Literature reference
• Specimen Packing Material
• Finished Product Samples

113
LATAM REGION

This region includes many counties like

Argentina

Bahamas

II Barbados

Bolivia

Chile

Colombia

Costa Rica

Cuba

Dominican Republic

Ecuador

El Salvador

£3 Haiti

Honduras

mi Jamaica

114
 Mexico

Panama

© Paraguay

Peru

Trinidad & Tobago

Uruguay

Venezuela

However for our analysis purpose, we have considered only five countries and
looked into their regulatory requirements. These countries are;
• Costa Rica
• Peru
• Venezuela
• Colombia
• Dominican Republic

115
COSTA RICA

Costa Rica is one of the less regulated country located in Latam region. They have
a guideline, which is very lenient in term of its requirements. The regulatory body of
Costa Rica is called Ministerio de Saluda Costa Rica.

The registration checklist of Costa Rica17 is as follows :

1 Certificate of Pharmaceutical Product
2 Composition of the Product
3 Finished Product
4 Specification
5 Standard Test Procedure
6 Certificate of Analysis
7 Analytical Method Validation
8 Stability Studies (zone IV with 3 batches stability data)
9 Product Monograph
10 Pack Insert
11 Art work of Packing materials

116
PERU

Peru is one of the less regulated country located in Latam region. They have a
guideline, which is very lenient in term of its requirements. The regulatory body of
Peru is called Ministerio de Salud del Peru Instituto Nacional de Salud del Peru
(INS).

The registration checklist of Peru18 is as follows :

1 Certificate of Analysis of Active Pharmaceutical Ingredients
2 Certificate of Analysis of Excipients
3 Method of Analysis of Active Pharmaceutical Ingredients
4 Method of Analysis of Excipients
5 Packaging Material Specification
6 Certificate of Analysis of Finished Product
7 Analytical Method of Finished Product
8 Method Validation Report
9 Stability Data (zone IV with 3 batches)
10 Pack Insert
11 Art work of Packing materials
12 Certificate of Pharmaceutical Product
13 GMP Certificate
14 Information on Efficacy and Safety of Drug

117
VENEZUELA

Venezuela is one of the very less regulated country located in Latam region. They
have a guideline, which is very lenient in term of its requirements. The regulatory
body of Venezuela is called Drug Administration of Vietnam
Ministry of Health.

The registration checklist of Venezuela19 is as follows :

1 Certificate of Pharmaceutical Products
2 Good Manufacturing Practice certificate
3 Manufacturing process
4 Batch Formula
5 List of equipment with capacity
6 In process specification
7 In process Standard Test Procedure
8 Flow Chart of Manufacturing Process
9 All Standard Operating Procedure used in manufacturing
10 Standard operating Procedure on Batch Numbering System
11 Specification and analytical procedure for primary packing material
12 Route of Synthesis of Active Pharmaceutical Ingredients
13 Unit Composition
14 Active Pharmaceutical Ingredients
15 Physico chemical properties
16 Specification
17 Analytical Procedure
18 Active Pharmaceutical Ingredients, Certificate of Analysis
19 Excipients
20 Specification
21 Standard Test Procedure
22 Stability Data (Zone IV 3 batches. Minimum data requirement is 12 M at the
time of submission)
23 Finished Product Specification and STP
118
24 Finished product Certificate of Analysis
25 Working standard Certificate of Analysis
26 Dissolution Profiling
27 Bioequivalence Study
28 Documentation- Pre clinical and Clinical

119
 COLUMBIA

Columbia is one of the less regulated country located in Latam region. They have a
guideline, which is very lenient in term of its requirements. The regulatory body of
Columbia is called Instituto Nacional de Salud.
The registration checklist of Columbia20 is as follows :

LEGAL DOCUMENTS
1 Authorization Document
2 COPP
3 Applicant Declaration
4 Registration Authorization

TECHNICAL DOCUMENTS
1 Pharmaceutical Dosage Form Description
2 Quantitative Formula
3 IUPAC, INN name and structural Formula of API
4 Batch Formula
5 Brief Description of Manufacturing Process
6 Finished Product Specification
. 7 Finished Product Analytical Method
8 Finished Product COA
9 Pharmacological Information
10 Stability Data (3 batches/zone IV)
11 BE Study Report
12 Raw Material Specs
13 Packing Material Specs
14 In Process Specs
15 Finished Product analytical Method Validation Report
16 Artwork
17 GMP certificate of MHRA

120
DOMINICAN REPUBLIC

Dominican Republic is one of the less regulated country located in Latam region.
They have a guideline, which is very lenient in term of its requirements. The
regulatory body of Dominican Republic is called Ministry of Health Dominican
Republic.
The check list of Dominican Republic21 is as follows : -
1. Free Sale Certificate attested by Chamber of Commerce and duly legalized
in Dominican Embassy.
2. GMP Certificate attested by Chamber of Commerce duly legalized in
Dominican Embassy
3. Manufacturing License duly legalized in Dominican Embassy
4. Introduction - Company Profile.
5. Manufacturer Information.
6. Product Information.
7. Container Information.
8. Composition (Qualitative & Quantitative Formula).
9. Manufacturing Flowchart.
10. Identification of Batch Number.
11. Certificate of Analysis (in original).
12. Raw material data sheet.
13. Raw material specification (for Active material).
14. Raw material Analytical Method (for Active material).
15 Finished product specification.
16. Finished product Analytical Method.
17. Stability Data (Accelerated and Long term study data).
18. Specification of packing material.
19. Draft of product Label and Carton.
20 Package insert.
21. Bioequivalence study report and/or clinical trial studies.

121
 MIDDLE EAST REGION
This region includes many counties like :
□HIIUH llllll HU 1H

Egypt

Turkey

Iran

Sudan

Algeria

Iraq

Yemen

Syria

Israel

Jordan

Libya

Lebanon

However for our analysis purpose, we have considered only four countries and
looked into their regulatory requirements. These countries are -
• Iraq
• Iran
• Jordan
• Tunisia

122
IRAQ

Iraq is one of the less regulated countries located in Middle East continent. They
have a guideline, which is very lenient in term of its requirements. The regulatory
body of Iraq is called Ministry of Health and Medical Education
According to the pharmaceutical regulations in Iraq, a pharmaceutical product
cannot be marketed unless it is registered. Registration is the filing of certain
information about the safety efficacy, quality and origin of products to be marketed
in Iraq. Registration should be done by manufacturers, marketing authorization
holder, contract manufacturers.
The registration checklist of Iraq22 is as follows :
1.0 Companies required to be registered are:
• Pharmaceutical companies that have one or more of a pharmaceutical
factory
• Companies producing General products (Appendix 1)
• Medical appliances and disposables producing companies.
• Laboratory diagnostic kit manufacturers
2.0 Products that are required to be registered are any pharmaceutical
products, vaccines and sera with a therapeutic effect.
a - prescription only drugs (full documentation is required)
b- OTC drugs (Appendix 2) (reduced documentation is required)
• reduced documentation no bioavailability or bioequivalence study is
required, however dissolution profile to be submitted.
• Registration of a pharmaceutical product is valid for 5 years but for national
pharmaceutical products is valid for 10 years, re-registration will be
required thereafter.
• A new registration file for registered Product should be submitted prior to
major modifications to the formulation, manufacturing process or method of
preparation while upon minor modifications only notification with samples is
required.

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 • Requirements for resubmission of a product for registration after it’s refusal
depends on the reason of that refusal.
, • Registration of a pharmaceutical product will be revoked whenever new
scientific evidence proves facts contrary to the information supplied with the
original registration documents.
• Hospital packs of the registered product could be marketed though not
registered, provided that specifications of packaging materials are
consistent with the specifications used in the stability data, submit samples
of outer packaging with application.
• The Registrant is responsible for the product quality and the recalling
process of the product.
• The product label can carry the name of its owner/applicant regardless of
country and has the right to mention the name of collaborators/ contract
manufacturer in that product.
• Names and copy rights of a product registered by a research company need
to be respected and no violation of such copy right that resemble the
original product directly or in directly will be allowed.
• All documents submitted by a pharmaceutical company concerning
registration of a product shall treated as confidential and should not be
passed to any other party.
• In the registration of a drug the following priorities shall be followed L
first priority new chemical entry
second priority : national drugs.
third priority : other drugs.

Inspection of pharmaceutical manufacturing establishments :

Legal basis : drug registration system
Authority : Ministry of Health (MOH) / registration department
, registration department have the right to inspect any
pharmaceutical establishment for compliance with GMP
regulations. If an inspection is deemed necessary by

124
 the Registration Department, then it will be at the
\

Registrant expense.
Procedure:
1 The responsible authority for registration is MOH/ technical affairs
directorate/ registration department.
2 Registration documents should be submitted to the receiving unit/
communications section of the Registration Department. Documents shall
be checked by the pharmacists in that unit and if they meet all of the
requirements , then the applicant shall be informed to pay the registration
fee, the communication section shall accomplish documents checking within
21 days from submission of pharmaceutical product and 14 days for
companies in order to assure that all necessary information is included in
the submission.
3 Registrant shall pay the applicable fee within 2 weeks of notification from
the communication section. Once the fee has been received, documents
shall be transferred to the responsible section to be evaluated by the
registration committees, if the applicant failed to pay the fee, the registration
process shall be delayed pending payment .If the payment is not received
within two (2) months, the Registrant will be required to reapply.
4. Time required for evaluation from the date of full data submission is not
more than one year for pharmaceutical products and not more than 90 days
for companies.
5 Arabic and English are the accepted languages for the application forms.
6 Scientific data should be in English.
7 During the course of registration and whenever the committee required
additional information from the Registrant, such a request will be made in
writing. The Registrant will have up to one year to provide the requested
information otherwise the Registrant will be required to reapply.
8 Files to be submitted should be numerated and have a table of contents.

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Requirements for the registration of pharmaceutical Product
1 Registration form to be filled in one copy.fappendix 5) Should be stamped and
signed by company.
2 CPP issued by the health authority of the country of origin, of the
manufacturer legalized officially from Ministry of Health, Ministry of Foreign
affairs and Iraqi Embassy in the country of origin of the manufacturer
(including the number and date of registration and that the product is freely
sold in the country of origin), e.g.: according to WHO form.
3 Product(s) of significant therapeutic and pharmaceutical value that are not
marketed in the country of origin but available in other countries can be
exempted from the country of origin stipulation through the submission of an
approval certificate from one of the following authorities (FDA, HPFB,
EMEA,EU or any of its countries, MHLW or GCC.)
4 If the product is marketed in the country of origin in a trade name differ from
/

that submitted for registration in Iraq, the company should mention that and
explain the reasons for such change with conformation of similarity in
composition and other specifications.
5 Method of manufacturing in detail for the drug product.
6 Specifications of the finished products certified by the Q.A./ Q.C. legalized
from the health authority or other authorized firm responsible for this
subject.
7 Certificate of analysis for the finished products.
8 Quantities and specifications of both active and non-active ingredients
which should be according to the latest edition of BP, EP, USP, or
Japanese. If the product is non- pharmacopoeial submit in-house
specification.
9 Specifications of the packaging materials.
10 List including countries where the item had been registered including
number and date of registration.
11 In process and finished product Q.C. test methods along with the validation
of that method unless the product is a pharmacopeial one.

126
12 Bioavailability or bioequivalence study (with a number of volunteers 18-24)
for the following items: (see appendix 6)
13 A certificate stating that the gelatin and other components of animal source
are not of pork origin, and these components are free from contamination
with BSE (issued by the health authority of country of origin of raw material).
14 A certificate stating the safety of blood products from HIV.,HAV ,HDV , HCV,
HBS, test control methods used to assure that individual blood and pooled
samples are tested for the mentioned viruses .should be submitted.
15 In addition to the above-mentioned requirements, firms producing oral liquid
containing propylene glycol must submit a certificate that there is no
contamination with diethylene glycol in the raw materials used in the
production of these products.
16 If alcohol is used in the formula, specify its percentage and state the
reasons for such percentage.
17 Any scientific studies (pharmacological, clinical, toxicological and antidotes
studies) must be submitted for new chemical entity drugs .
18 Stability studies derived from tests on the final dosage form in its final and
marketed container and packaging. Data submitted are obtained from
accelerated study at least according to WHO requirements (3 different temp,
for 3 batches including real time study whenever its available). Additionally ,
published and/ or recently obtained experimental supporting stability data
may also be submitted.(e.g.: On the stability of the active ingredients and
related formulations).
* once the product has been registered, additional stability studies are
required whenever modifications are made to the formulations
manufacturing process, packaging or method of preparation.
* Firms must to submit the validated test method for stability studies ( i.e.
stability- indicating method)
19 In case of manufacturing by contract whether importing the finished and
packed, bulk products to be packed or semi finished to be processed and
packed, the GMP certificate of the contract manufacturer of the relevant
product is required.

127
20 In case of under license arrangement the applicant should submit an official
letter from the mother company conforming its approval to export this item
to Iraq.
21 For herbal products and food supplements (any product of plant or animal
origin that may improve the welfare of health in human being without known
toxic or adverse effects) all the mentioned above requirements are required
except what is mentioned at number 12. and in addition to: A / A certificate
confirm that there are no dangerous side effects for the herbal products
legalized by authorized firm responsible for this subject. B Study including
the chronic and acute toxicity of herbal products. C / A certificate confirm
that the herbs used in the formula of herbal product are free from
contamination, of radiation, and pesticides legalized officially.
22 Registration and analysis samples required are as stated in (appendix 7)
23 Companies who wish to register their products should submit all the
requirements for analysis (International reference standards for the active
components and the related substances). For non pharmacopoeia products
submit enough active constituent(s) of'working standard quality to conduct
all required tests a minimum of three times. Detailed method of analysis for
this (these) component(s) should also be submitted In addition to the
required chemicals and equipments.
24 If there is more than one pack (individual pack, hospital pack) submit
sample for one and mentioned it in the registration form. Samples of the
primary label and outer carton must be in Arabic and English (if space is
available) otherwise in English as follows:
Primary Label:
- Trade name and generic name
- Strength
- Quantity of Active Ingredient
- Route of Administration
- Storage Conditions
- Dosage form (tablet, suppository etc.)
- Manufacturers name and address

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 - Expiration Date
- Date of Manufacture
- Batch Number

Outer Carton: /
All above listed requirements plus special instructions for use. For non-prescription
drugs mention the normal adult dose and pediatric dose (if applicable ) and the
main indication .
Inner Leaflets :
Samples of inner leaflets (should be same as approved one in country of origin)
including : (to be written in English and Arabic)

• Trade Name and generic name

• Strength
• Name and Quantity of active Ingredient
• Name and Quantity of Inactive Ingredient
• Dosage form
• Rout of Administration
• Dosing Information
• Manufacturers Name and Address
• Cautions
• Precautions
• Drug Interaction
• Indication
• Side Effects.
• Storage conditions.
25 For national pharmaceutical products all the mentioned above requirements
to be submitted except what is mentioned at no. 2,3 ,12.
26 Registration fee $ 165 for each product.
* Registration fee for the national products is 2500 ID.

129
IRAN

Iran is one of the less regulated country located in Middle East continent. They
have a guideline, which is very lenient in term of its requirements. The regulatory
body of Iran is called Food and Drug Department.
The registration checklist of Iran23 is as follows :
The procedures of drug registration and reducing its long stages, registration would
take place through two stages after requisition of the Local agent.
1} A justification letter should be emitted citing to the minimum essential
documents for drug importing.
II) Drug registration and Iran Registration Code emission, citing to
supplementary documents.
Stage I:
In this stage exposing minimum of following documents is essential in order to
inspect and emit
Import Justification letter by legal association:
1) Original Certificate of Pharmaceutical product (CPP) issued by Drug
Regulatory Authority
2) Original checklist of buyer companies which mentions the information about
drugs generic name, form, dosage, name of buyer countries, brand name in
those countries, registration No. and date, production date, expiry date. This
checklist should be confirmed by Regulatory Authority of the Origin country
or buyer country and also Iranian Embassy in that country.
3) Original checklist of the countries within which the branches of a
manufacturer factory are located with name and exact address of the
branch, which should have been verified by Authority of the Origin country
or Authority of the company within which the branch is situated and plus
Iranian Embassy in that country.
4) Enough samples for QC lab accompanied with analysis certificate, essential
folders, and related standards (According to attached guide).
5) Filled in Drug Application form (Appendix 2)
6) Submitting of DMF which will be inspected in stage II.

130
7) Drug Pricelist form, filled in by drug Importer Company (Appendix 3). After
sending and investigating on the above documents and receiving
acceptance letter from drug QC lab, it will be forwarded to legal association
in order to issuing the justification letter:
a) The drug Brand name in buyer country should be the same as origin
country with the same manufacturer name.
b) The drug Brand name in other countries should be the same as origin
country with the same manufacturer name.
c) Private Companies are only authorized to import generic products
from prominent producers.
d) Drug should be produced in the manufacturer company and
“Contract Manufacturing” is not accepted.
e) Purchasing from reliable resources and Western European countries,
North America and Japan is preferred.
NB: In case purchasing is taking place from other resources mentioned in (e) the
following conditions should be taken into account:
I. GMP Certificate from Drug Regulatory Authority.
II. Any available international approvals.
III. Export to Euro countries, North America, Switzerland and Japan.
IV. Iran Drug and Medications Administration may ask for visiting the
GMP condition of the manufacturer after the emission of Import
Justification letter, stages and number of the importing justification
letter to Iran should be submitted to the Importer Company, in order
to print this number on the importing drug packages in Persian.
Stage II:
The subject drug will be registered for the importer company, and “IRC” will be
issued in case of confirming the DMF.

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JORDAN

Jordan is one of the less regulated country located in Middle East continent. They
have a guideline, which is very lenient in term of its requirements. The regulatory
body of Jordan is called Jordan Food and Drug Administration (JFDA).

The registration checklist of Jordan24 is as follows :

Part 1
1 Check List (Signed & Stamped) (
2 Technical Committee Form "A" (10 copies)
3 Drug Leaflet (10 copies)
4 Similar Product Available in Local Market
5 Computer application Form "B"
6 JFDA approval of the Manufacturing site /s or request of approval (date
and number)
7 Drug Registration form (LF4)
8 List from manufacturer declare the worldwide registration status
(registered .under registration, rejected)
9 Declaration from the manufacturer about the ingredient from human or
animal origin entering in the composition of the product and their source
and the related certificates.
Part 2
10 Certificates
10-1 Certificate of Pharmaceutical product (CPP) according to WHO format
Certified and Legalized :
Product description.
Active ingredient/s & Cone.
Inactive ingredient/s & Cone.
Freely Sold Statement.
Registration Number.
Registration Date.
GMP statement

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 10-2 MAH & Manufacturer/s Name & Address.
10-2-1 Prices: (Exported products)
10-2-1 -1 Public Price Certificate showing Ex.f, WSP, PP,
( Certified and Legalized):if vat included specify
10-2-1-2 Price Structure.
10-2-1-3 Prices including price structure from median countries (UK, Spain,
France, Greece, Italy, Belgium, and Holland).
10-2-2 Prices (local products)
10-2-2-1 Suggested pharmacist price or hospital price
10-2-2-2 Suggested Public price .
10-3 Export price from Saudi Arabia (if marketed
10-3-1 Export Price Certificate
11 Inner leaflet Certified and Legalized from country of origin :
11 -1 Leaflet Comparison between Generic & Originator

Part 3
12 1 Technical file

12-1 Drug formula

12-2 Manufacturing Procedure
12-3 Stability protocol
12-4 Specifications of Raw Material & tests (active & inactive)
12-5 Finished Product Specifications & Tests Stamped & Signed
12-6 Specifications of packaging material (primary & secondary).
12-7 Methods of Analysis
12-8 Analytical Validation method with raw data and chromatograms
12-9 Certificate of Analysis of Active ingredient
Stamped & Signed (from manufacturer & applicant company)
12-10 Certificate of Analysis of Finished Product
Stamped & Signed.
12-11 Stability Data Stamped& signed .
A. Full Composition

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 B .Batch Analysis
C. Real Stability Data with raw data and chromatograms
D. Accelerated Stability with raw data and chromatograms
E. Photo stability
F. special stability due to dosage form
(reconstitution , inverted position , etc)
G. Discussion of results
H. Conclusion (Shelf life & Storage condition)
13 Stability Commitments
13-1 Real data as annual report
13-2 Ongoing stability
14 Registration samples & copy of the outer & inner pack & leaflet for the
file
Part 4
15 Other requirements
15-1 Recent Published literatures (5 copies)
15-2 Bioavailability studies
15-3 Bioequivalence studies ,and copy of committee approval
15-4 Comparative Dissolution Profile.
15-5 Clinical assessment report (ND)(5 COPIES)
15- 6 Periodic Safety Update Report(PSUR))
16 For Sera & Vaccine
16- 1 fulfilled special registration form
16-2 Batch record for three consecutive production batches
16-3 Suitability certificate (for products containing bovine origin materials)
EDQM
16-4 Certificate to prove freedom of BSE
16 -5 Plasma master file(for products containing plasma)

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TUNISIA

Tunisia is one of the less regulated country located in Middle east continent. They
have a guideline, which is very lenient in term of its requirements. The regulatory
body of Tunisia is called Direction de la Pharmacie et du Medicament (Pharmacy
and Medicines Directorate (DPM).

The registration checklist of Tunisia25 is as follows :

ADMINISTRATIVE FILE
1 Manufacturing License of facility
2 Certificate of Pharmaceutical product
3 List of countries, where the product is registered
4 Statement of whole sale price excluding tax in country of origin
5 Cost price and shipping proposal
6 Proof of payment of registration fee .
7 Specimen Label
8 Specimen Pack Insert
9 Information sheet

PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL FILE

1 Unit Composition
2 Pharmaceutical development Report
3 Brief Manufacturing Summary with flow chart
4 Active Pharmaceutical Ingredients /Excipients Specification
5 Active Pharmaceutical Ingredients /Excipients Standard Test
Procedure
6 Active Pharmaceutical Ingredients /Excipients Certificate of Analysis
7 In process specification
8 In Process Standard Test Procedure
9 In process Certificate of Analysis
10 Finished Product Specification

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11 Finished Product standard test procedure
12 Finished Product Certificate of analysis
13 Analytical Method validation Report
14 Stability Data (zone II with 2 batches)
15 Clinical, Toxicology and Pharmacology Details
16 Active Pharmaceutical Ingredients sample with Certificate of analysis
17 Finished Product Samples with COA

136
INDIAN SUBCONTINENTS

Indian Subcontinents includes following countries: -

Sri Lanka

Pakistan

Bhutan

Nepal

Bangladesh

Maldives

China

Afghanistan

However, we have considered only five countries for the analysis purpose and
looked into their regulatory requirements. These countries are : -
• Sri Lanka
• Pakistan
• Bhutan
• Nepal
• Bangladesh

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SRI LANKA

Sri Lanka is one of the less regulated country located in Indian subcontinents.
They have a guideline, which is very lenient in term of its requirements. The
regulatory body of Sri Lanka is called Drug Regulatory Authority,
Ministry of Health.

The registration checklist of Sri Lanka26 is as follows:

1 Name of the Applicant

2 Address
3 Status of Applicant
4 Name of the Drug .
5 Dosage Form
6 Unit Composition
7 Main Pharmacological Group
8 Certificate of Pharmaceutical Product
9 Published Report on Controlled Clinical Trials
10 Summary of Toxicity tests including test for teratogenicity
11 Data sheet
12 Pharmacology
13 Clinical Information
14 Pharmaceuticallnformation
15 Dosage Form and Strength
16 Description of Product
17 Packing and Package Sizes
18 Manufacturing Formula
19 Brief Manufacturing Process
20 Process Validation Report
21 Quality Control
22 Raw Material Specification
23 Method of Analysis

138
24 General Test Procedure
25 In Process Controls
26 Finished Product Specification
27 FP Analytical Procedure
28 Analytical Method Validation Report
29 Stability Study Report (3 batches with zone IV)
30 Packaging Material
31 Specification
32 Method of Analysis
33 List of countries where the product is registered
34 Active Pharmaceutical Ingredients sample
35 Finished Product sample
36 Certificate of Analysis of Active Pharmaceutical Ingredients , Excipients,
Finished Product

139
PAKISTAN

Pakistan is one of the less regulated country located in Indian subcontinents. They
have a guideline, which is very lenient in term of its requirements. The regulatory
body of Pakistan is called Drugs Controller, Ministry of Health.

The registration checklist of Pakistan27 is as follows :

1 Application Form

2 Name and complete address of the applicant

3 Name and complete address of manufacturer
4 Name of drug
5 Strength of active ingredient(s) per unit
6 Country of Exporting
7 Registration status in other countries
8 Pharmacological group
9 Proposed route of administration
10 Composition (Qualitative and Quantitative)
11 Recommended clinical use
12 Manufacturing operations

a. Master formula
b. Manufacturing procedure

c. Flow chart
d. Equipment used

e. Critical steps
f. In process quality control
g. Process Validation protocol
h. Process Validation report
13 Active raw material

140
 a. Specification

b. Analytical procedure
( c. Certificate of analysis
14 In-Active raw material
a. Specification

b. Analytical procedure
c. Certificate of analysis
15 Finished product
a. Specification

b.. Analytical procedure

c. Certificate of analysis
d. Method validation protocol (for non-pharmacopoeial test)
e. Method validation report (for non-pharmacopoeial test)
16 Labeling and prescribing information
a. Leaflet information
b. Specimen label and carton
c. Finished product samples
17 Proposed dosage of the drug
18 Proposed shelf life of the drug

a. Stability studies
b. Shelf life and Expiry date
c. Storage conditions
19 Unit price of the drug
20 Technical persons involved in Manufacturing & Control of product

a. Total no. of technical persons

b. Details of technical persons
21 Production capacity per shift
22 Equipment list for the quality control
23 Facility of the water processing

141
24 Environment control processing
a. cleaning validation

b. HVAC system
c. Maintenance of clean area
25 Inspection report by Regulatory Authority

26 Clinical data
27 Free Sale Certificate & GMP certificate
28 Copy of agreement between manufacturer and agent
29 Certificate of company registration

30 Treasury Challan of fee

142
BHUTAN

Bhutan is one of the less regulated country located in Indian subcontinents. They
have a guideline, which is very lenient in term of its requirements. The regulatory
body of Bhutan is called Ministry of Health, Royal Government of Bhutan

The registration checklist of Bhutan28 is as follows :

Application Form

General Documents
i Company profile
ii cGMP certificate
iii Manufacturing licence

iv WHO Model Certificate of Pharmaceutical Product

v Free Sale Certificate
vi Summary of product information sheet
vii Letter of authorization
viii Dealership certificate (of Dealer)
ix Credentials of the dealer

x Product sample
xi Price structure

Pharmaceutical Documents
i Physico-chemical properties of active and inactive ingredients
ii Analytical method for identification of active substance and excipients
iii Manufacturing process for the product
iv List of raw material and specifications
v QC procedure and report on raw materials
vi Finished product specifications
vii Disintegration and dissolution profile
143
viii Analytical method for the finished product

ix Certificate of analysis
x Stability test report for Zone IV
xi Packaging specifications
xii Specimen of package, label and package insert
xiii QC procedure and report on label and package

Pharmacological Documents

i Data on basic pharmacological and microbiological studies

ii Pharmaco-kinetics data
iii Bio-availability and bio-equivalence data (for generic drugs)
iv Data on clinical studies and Clinical pharmacokinetics (for new drug)
v Toxicity data (for new drug)
vi Teratogenicity data (for new drug)
vii Mutagenicity data (for new drug)

144
NEPAL

Nepal is one of the less regulated country located in Indian subcontinents. They
have a guideline, which is very lenient in term of its requirements. The regulatory
body of Nepal is called Ministry of Health and Population Department of Drug
Administration.

The registration checklist of Nepal29 is as follows :

Registration of New Company:
1 Application
2 Letter of Authority
3 Copy of Wholesale registration of the importer
4 Site Master File
5 Manufacturing License
6 List of Products intended to be registered.
7 Letter of Warranty
8 Latest GMP Self Audit Report

Registration of the Drug Product:

1 Application form
2 Manufacturing License
3 Certificate of Pharmaceutical Products (CPP)
4 Detail formulation including excipients
5 . Product Specification
6 Methods of Analysis
7 Samples of Labels and cartoon
8 Samples of the Product (2-unit pack).
9 Analytical report from government laboratories or approved
Nepalese Laboratories
10 Analytical reports from Manufacturer of the same batch
11 Real time stability testing reports

145
BANGLADESH

Bangladesh is one of the less regulated country located in Indian subcontinents.

They have a guideline, which is very lenient in term of its requirements. The
regulatory body of Bangladesh is called Directorate General of Drug
Administration.

The registration checklist of Bangladesh30 is as follows:

Application Form of the Registration of Drugs (which are not included as

monographs in BP/BPC/USP-NF/Int. Ph. or are not introduced in Bangladesh)
1. Name and address of the Manufacturer of the Drug:
2. Manufacturing Licence Number (for locally manufactured drugs):
(a) Biological:
(b) Non-Biological:
3. Name of the Drug:
(a) Generic name (use INN name if included in INN List)
(b) Name under which the Drug is proposed to be sold.
4. Product Data Sheet
(Including Presentation, Uses, Dosage & Administration, Contra-indication,
Use in pregnancy and lactation, Side-effects,
Precautions, Warning, Drug Interaction, Absorption, Fate, Distribution,
Exrertion, Elimination, Package Quantities, etc.)
5. Technical Data:
(a) Composition/Formula;
(b) Manufacturing Instruction;
(c) Control Data for the Active Constituents;
(d) Pharmacopoeial References or Control Data for other constituents;
(e) Control data for Finished Product;
(f) Stability data (if not done, then to be submitted at the time of inclusion);
(g) Proposed shelf life (must be expressed on Finished Product in the form
of manufacturing Data and Expiry Date).

146
Note:
1. Excipients should always be mentioned in generic/chemical name; but may
be followed by brand name, if desired.
2. Overage to be shown separately in Composition/Formula, eg., 2.5% for
antibiotics Capsule/Tablet, 5% for antibiotics Dry syrup/lnjectiop, 10% for
Vitamins, etc.
3. Capsule size to be mentioned by number; name/Monogram should be
printed on capsule or engraved in tablet.
4. Coating material should be shown separately.
5. Pharmacological data:
(a) Human Pharmacokinetics and metabolism;
(b) Studies related to intended therapeutic activity;
(c) Studies related to secondary pharmacological activity;
(d) Drug interaction studies.
6. Toxicological Data: !
(a) Acute, sub-acute and chromic toxicity studies in animals;
(b) Mutagenicity studies;
(c) Studies on reproduction and teratogenicity;
(d) Other studies.
7. Clinical Data:
(a) Design and result of phase I and phase II clinical trials (mention
name and address of investigators);
(b) Studies on side-effects/adverse reactions in human subjects;
(c) Reprints of publications on clinical and pharmacological studies.
8. (a) Number of manufacturer/importer already manufacturing/importing the
product in Bangladesh; and
8 (b) Estimated market of this product/product group in Bangladesh.
9. (a) Proposed Maximum Retail Price (MRP); and
(b) Estimated Price-per dose; per day treatment; cost for the recommended
course of treatment.
10. For locally manufactured drugs :
Particulars of quality Control manager and Factory/Production manager.

147
 Full name, Qualifications, Date of Joining in the applicant's company, Total
experience in the pharmaceutical industries, Registration Number and
Signature.
11. In case of imported drugs, the following additional information are to be
provided
(a) Name and address of the Indenter/or Manufacturer's authorized
agent.
(b) Registration status in the country of origin (including Free Sale
Certificate)
(c) Registration status in other countries (include Sale Certificates from
at least 2 other development countries)
(d) Signature of the Indenter/or Manufacturer's authorized agent.
12 Date of submission: -
13. Additional information (if any):

Note; information supplied if found wrong will lead to immediate cancellation of

registration of the product.

Application Form for the Registration of Drugs (which are included as

Monographs in BP/BPC/USP-NF/Int. Ph. or are already introduced in
Bangladesh)
1. Name and address of the Manufacturer of the Drug :
2. Manufacturing Licence Number (for locally manufactured drugs):
(a) Biological:
(b) Non-Biological:
3. Name of the Drug:
(a) Generic name (use INN name if included in INN List):
(b) Name under which the Drug is proposed to be sold :
4. Product Data Sheet
(Including Presentations, Uses, Dosage & Administration, Contra-indication,
Use in pregnancy and lactation, Side-effects, Precaution, Warning, Drug

148
 Interaction, Absorption, Fate, Distribution, Excretion, Elimination, Package
Quantities, etc.)
5. Technical Data:
(a) Composition/Formula
(b) Manufacturing Instruction
(c) Control Data for the Active Constituents
(d) Pharmacopoeial References or Control Data for other constituents
(e) Control data for Finished Product
(f) Stability data (if not done, then to be submitted at the time of
inclusion)
(g) Proposed shelf life (must be expressed on Finished Product in the
form of Manufacturing Date and. Expiry Date).
Note :
1. Excipients should always be mentioned in generic/chemical names; but
may be followed by brand names, if desired.
2. Overage to be shown separately in Composition/Formula, eg., 2.5% for
antibiotics Capsule/Tablet, 5% for antibiotics Dry syrup/lnjection, 10% for
Vitamins, etc.
3. Capsule size to be mentioned by number; name/Monogram should be
printed on capsule or engraved in tablet.
4. Coating material should be shown separately.
5 (a) Number of manufacturer/importeralready manufacturing/importing the
product in Bangladesh;
5(b) Estimated market of this product/product group in Bangladesh.
6(a) Proposed Maximum Retail Price (MRP);
6(b) Estimated Price-per dose; per day treatment; cost for the recommended
course of treatment.
7. For locally manufactured drugs:
Particulars of quality Control manager and Factory/Production manager.
Full name, Qualifications, Date of Joining in the applicant's company; Total
experience in the pharmaceutical Industries, Registration Number and
Signatures.
149
8. In case of imported drugs, the following additional information are to be
provided :
(a) Name and address of the Indenter/or Manufacturer's authorized
agent.
(b) Registration status in the country of origin (including Free Sale
Certificate)
(c) Registration status in other countries (include Sale Certificates from
at least 2 other development countries)
(d) Signature of the Indenter/or Manufacturer's authorized agent:
9. Date of submission:
10. Additional information (if any):

Summaries of LRM

1. Administrative Requirements
The application forms of the respective countries are required to be filled.
This application may vary from Asian region to African region and Latam
region. In Asian region they follow the limited requirements as per the Asian
regulations. The Asian dossiers are called ACTD. These countries do not
have the stringent regulation in line with highly regulated market. In rest of
the LRMs, company registration is a prerequisite for the registration of the
drugs. Almost all the countries in these regions require valid legal
documents like COPP, FSC & WHO GMP certificates. These documents
are also required to be notarized and legalized from the Embassy of the
respective countries.

2. Raw Material Controls

In this region the raw materials are required to comply with USP or EP
requirements. There are no specific requirements of having DMF procedure
in this region. However if the DMFs are filed then this can be refereed to.
They also accept the USDMFs/ EDMFs/ CEPs. Alternately these countries
ask for the DMF kind of dossiers called technical package of the API. These
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countries are not much concerned about other stricter requirement like TSE/
BSE certificate, non GMO certificate, Residual solvents certificate etc.

3. Packaging Material Controls

The requirements of packaging materials are very simple. There is no
requirement of DMF for the primary packaging material like highly regulated
market. This means the primary packaging which comes in contact with the
product can be sourced from any manufacturer. These all can be used
without looking in to the quality of the product.

4. Finished Product Controls

There is no concept of having a release or shelf life specification for these
countries like Highly Regulated Market. The finished products are supposed
to be controlled as per the ICH Q6 in case of highly regulated market. These
countries have only concern about the testing of the final product as per
Pharmacopeia. In case of less regulated market, we do not need two test of
identification such as HPLC & UV, test for breakability, test for content
uniformity, test for dissolution profiling, and residual solvents analysis in line
with highly regulated market. These LRMs also do not require the method
validation data like HRM. They also do not require test for identification of
color in the finished product in line with HRM. Analytical method validation
data is also required.

5. Manufacturing Controls
Manufacturing Controls are divided into three types
(a) Manufacturing formula
There is a requirement of providing the details of ingredients used in the
formula with there quantity. The ingredients should comply with the current
edition of USP / EP. There is no reaction like IIG limit and GRAS listing in
line with HRM.

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 (b) Manufacturing procedure
A brief write up of the manufacturing procedure is given in the dossier. The
justification in the section of the manufacturing procedure is usually not
required in case of LRM. They also do not require exhibit BMR as well as
intended BMR in the dossier.

(c) Batch Size

There is no restriction on the. batch size of Finished Product like HRM. As
we know the HRM requires at least 100,000 units. In case of LRM the
minimum requirement is to provide data from three exhibit batches.

6. Microbiological controls
Microbiological controls do not play a very important role. There is no
concept of having a hold time study in this region. Other microbial tests like
MLT, BET & stability are required for parenterals and ophthalmic
preparations.

7. GMP Requirements.
These countries do not have any specific GMP guidelines. They also do not
carry out any GMP inspection. LRM countries accept the GMP certificate of
any leading agency like USFDA, MHRA, and TGA & HPFB. They only look
for WHO GMP certificate. It means GMP does not play a very important role
for these countries.

8. Bioequivalence requirements
In the LRM there is no specific guideline for BE studies. The BE studies are
carried out with any of the international innovator like US or EU. In certain
countries even if they go with comparative profiling data. There is no
concept of F1 or F2 factor in this region. There is no requirement of
proportionality similarity in this region.

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9. Stability Requirements
In case of LRM the stability is required to be carried out at different storage
conditions. These are :
• Long term stability study (25°C±2/60±5% RH)/(30°C±2/75±5% RH)
• Intermediate stability study (30 °C ±2/65±5% RH)
• Accelerated stability study (40 °C ±2/75±5% RH)

Most of the countries in LRM require stability from Zone IV condition

(30°C±2/75±5% RH), since the climate condition of these are hot and
humid. These countries mostly require to stability data up to 12 months
duration and from 3 batches. There are no requirements of photo-stability in
these countries. There is no requirement to provide a stability commitment
in line with HRM. They are also not much concerned about critical stability
test parameters like related substances, water content & dissolution testing
during studies.

10. Post-approval requirements

There is no concept of having post-approval changes in this region. There is
also no requirement to submit supplement and post approval changes. As
we know the post approval changes play an important role in keeping the
dossier updated in line with changes those take place to time to time.

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