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Modern Medicine: Biomedical Devices, Medical Gases, Radiopharmaceuticals, New Drug Discovery,
Volume 2 is a companion volume to Life Sciences Research to Product Development: Regulatory
Requirement Transforming, Volume 1 (2024), by the same authors.
 Modern Medicine

Biomedical Devices, Medical Gases,

Radiopharmaceuticals,
New Drug Discovery, Volume 2

Pronobesh Chattopadhyay and

Danswrang Goyary
First edition published 2024
by CRC Press
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Contents

Acknowledgement................................................................................................. xxiii
Preface...................................................................................................................xxiv
Author Biographies................................................................................................xxvi
Disclaimer........................................................................................................... xxviii

Chapter 17 New Drug or Investigational New Drug Applications’ (INDA)

Approval Process with the Drugs and Cosmetics Act..........................1
17.1 Introduction................................................................................ 1
17.2 Different Types of Investigation New Drug Approval...............1
17.3 Rule of the Drug Approval Process in India..............................3
17.4 Some Important Application Forms for Registration.................5
17.5 Approval Process and Required Data of New Drug..................8
17.6 Permission to Import a New Drug According to
Provision 122A......................................................................... 10
17.7 Authorisation to Carry Out Clinical Trials for a Newly
Developed Medicine (Section 122D)........................................ 11
17.8 Permission to Produce a New Drug in Schedules Other
Than C or C (1) (122B)............................................................. 12
17.9 Application for Permission to Import a New Drug.................. 13
17.10 Documents for Requirement for the Approval of
Importing Drugs....................................................................... 13
17.11 Plant Master File....................................................................... 18
17.12 Personnel.................................................................................. 18
17.13 Premises................................................................................... 18
17.14 Equipment................................................................................. 19
17.15 Sanitation.................................................................................. 19
17.16 Documentation......................................................................... 19
17.17 Production and Inventory......................................................... 19
17.18 Quality Control......................................................................... 19
17.19 Loan Licences for Manufacturing............................................20
17.20 Distribution Method, Customer Complaints, and Product
Withdrawal...............................................................................20
17.21 Self-inspection..........................................................................20
17.22 Export of Drugs........................................................................20
17.23 Rules for Importing..................................................................20
17.24 Drug Approval in USA............................................................. 21
17.25 FDA Clearance Needs to be Based on a Study........................ 21
17.26 Common Technical Document (CTD) for Approval of
New Drugs................................................................................ 22
17.26.1 Module I: Administrative/Legal Information............. 22

 v
vi Contents

17.26.2 Module II: Summaries................................................24

17.26.3 Module III: Quality Information Including the
Chemical, Pharmaceutical, and Biological.................25
17.26.4 Module IV: Non-clinical information......................... 27
17.26.5 Module V: Clinical information..................................28
17.27 Raw Material or Bulk Drug Substances Already
Approved in the Country.......................................................... 29
17.28 Fixed-dose Combination (Section 122-D) of a New Drug
(Formulation) Already Approved in the Country.................... 30
17.29 Already-Approved Drug (Rule 21) to be Used
and Proposed to be Marketed as a “New Route of
Administration”........................................................................ 32
17.30 Approval Process as a Definition of “New Medication”
for Use in New Indication and the Individual Component
Previously Approved under Rule 21 of Drugs and
Cosmetics Rules, also Known as Repurposing Drugs.............34
17.31 Approval Process as a New Drug Use in New Dosage
Forms (Without Fixed Dosage) and the Individual
Component Already Approved under the Rule 21 of the
Drug and Cosmetics Rules....................................................... 36
17.32 Approval Process as a New Drug Use in Additional
Strength and the Individual Component Already
Approved Under the Rule 21 of the Drug and Cosmetics
Rules......................................................................................... 38
Bibliography........................................................................................40

Chapter 18 Medical Device Rules and Enforcement............................................. 41

18.1 Introduction.............................................................................. 41
18.2 Regulation Enforcement........................................................... 41
18.3 The Central Licensing Approval Authority (CLA).................. 41
18.4 Chapter I: Titles, Applications, and Definitions....................... 42
18.5 Chapter II: Regulation of Medical Devices.............................. 42
18.6 Chapter III: Authorities, Officers, and Bodies......................... 43
18.7 Chapter IV: Manufacture of Medical Devices for Sale or
Distribution...............................................................................44
18.7.1 Application for Manufacture for Sale and
Distribution of Medical Devices.................................44
18.7.2 Loan Licence to Manufacture for Sale and
Distribution..................................................................44
18.8 Chapter V: Import of Medical Devices....................................46
18.9 Chapter VI: Labelling of Medical Devices.............................. 48
18.10 Chapter VII: Clinical Investigation of Medical Devices
and Clinical Trial Evaluation of New In-vitro Diagnostic
Medical Devices....................................................................... 49
Contents vii

18.11 Chapter VIII: Permission to Import or Manufacture of

a Medical Device Which Does Not Have a Predicate
Medical Device......................................................................... 52
18.12 Chapter IX: Duties and Power of the Medical Device
Officer, Medical Device Testing, and the Notified Body......... 53
18.13 Chapter X of the Medical Device Rule, 2017, Which is
Titled “Registration Of Laboratory For Carrying Out
Test Or Evaluation”.................................................................. 54
18.13.1 Responsibilities of the Medical Device Officer.......... 54
18.13.2 The Confiscation of Medical Equipment,
Machinery, and Other Types of Property.................... 55
18.13.3 Delegated Responsibilities to the Medical Device
Testing Officer and Notified the Appropriate
Agencies...................................................................... 56
18.14 Chapter XI: Sale of Medical Devices....................................... 56
18.15 Chapter XII: Miscellaneous..................................................... 56
Bibliography........................................................................................ 57

Chapter 19 Schedule of Medical Device and Minimum Requirement of

Approval.............................................................................................. 58
19.1 Introduction.............................................................................. 58
19.2 Legitimate Medical Device as Drug Categorisation and
Enforced Drugs Controller General of India............................ 59
19.3 Schedule of Medical Device..................................................... 59
19.4 First Schedule of Medical Device (Classification of
Medical Devices and In Vitro Diagnostic Medical Devices)... 59
19.4.1 Part I of First Schedule............................................... 59
19.4.2 Part II (In Vitro Diagnostic Medical Devices)............ 63
19.4.3 The Fundamental Principles behind the
Categorization of In Vitro Diagnostic Medical
Devices........................................................................ 63
19.4.4 The Utilization of a Medical Device for
the Diagnosis of Several Life-Threatening
Conditions That Have a High Risk............................. 63
19.5 Second Schedule of Medical Device (Fees Payable for
License).....................................................................................64
19.6 Third Schedule of Medical Device (Registration
Procedure and the Minimum Documents Required)...............64
19.6.1 Part I............................................................................ 65
19.6.2 Part II........................................................................... 65
19.7 Fourth Schedule of Medical Devices (Documentation
Requirements for the Granting of Permission, Licence,
and Import of Medical Devices)...............................................66
19.7.1 Power of Attorney.......................................................66
viii Contents

19.8 Guidelines for the Issuance of Regulatory Licences

Regarding the Importation of Medical Devices in India......... 67
19.9 Appendix I: Site or Plant Master File....................................... 69
19.10 Appendices II and III: Device Master File for In Vitro
Medical Devices Other Than In Vitro Diagnostic
Medical Devices....................................................................... 70
19.11 Fifth Schedule of Medical Device (Quality Control of the
Medical Device)....................................................................... 71
19.11.1 Medical Device Validation, Verification, and
Documentation............................................................ 71
19.12 Compatibility of Medical Devices........................................... 71
19.13 Studies of a Medical Device in Pre-clinical Settings............... 71
19.14 Sterilization of Medical Equipment and Supplies.................... 71
19.15 Biological Safety of Medical Devices...................................... 72
19.16 Information Regarding the Shelf Life or Stability................... 72
19.17 Post-marketing Surveillance or Vigilance Reporting.............. 72
19.18 Sixth Schedule (Labelling of Medical Devices)....................... 73
19.19 Seventh Schedule of Medical Devices (Clinical
Investigation)............................................................................ 73
19.19.1 Required Application for Participation in a
Clinical Trial of a Medical Device.............................. 74
19.19.2 Clinical Trial of Medical Devices............................... 74
19.20 Clinical Investigation: Pivotal Scale........................................ 76
19.21 Clinical Research on Certain Populations................................ 76
19.22 Surveillance after Product Release and Distribution............... 77
19.23 Authorisation of the Import or Production of Newly
Developed In Vitro Diagnostic Medical Devices..................... 77
19.24 Authorisation for the Import or Manufacture of a New
In Vitro Diagnostic Medical Device as well as a Medical
Device that has not yet been Predicated................................... 78
Bibliography........................................................................................ 79

Chapter 20 Approval and Registration Process of a Medical Device.................... 81

20.1 Introduction.............................................................................. 81
20.2 Indigenous Manufacturing of a Medical Device...................... 82
20.3 Medical Device and the Requisite Forms................................ 82
20.4 Clinical Investigation in Order to Obtain Clearance to
Use an Investigative Medical Device....................................... 88
20.5 Clinical Investigation Prior to the Importation or
Production of Medical Devices................................................ 88
20.6 Permission for Manufacturing on Loan Licence to
Manufacture Medical Devices in Classes A and B in India..........91
20.7 Certifications for Quality and Compliance with Regulations........91
Contents ix

20.8 Establish a Master Plant File for All Medical Devices in

India.......................................................................................... 91
20.9 Medical Devices in India That Have a Device Master
File (DMF)...............................................................................92
20.10 Concerning the Labelling of Medical Devices (Rule 109A)....92
20.11 Permission for Manufacture on Loan Licence to
Manufacture Class A and B Medical Devices in India............ 93
20.12 Authorisation to Apply for a Testing Licence in Order to
Produce a Medical Device........................................................ 93
20.13 Authorisation to Sell and Distribute (Forms MD-14 and
MD-15); Required for Import Licence.....................................94
20.14 Documents Necessary for the Manufacturing and
Importation of Medical Devices............................................... 95
Bibliography........................................................................................ 98

Chapter 21 Quality Assurance of Medical Devices Central Drugs Standard

Control Organization (CDSCO), the United States Food and
Drug Administration (US FDA), and European Union (EU)
Regulations..........................................................................................99
21.1 Introduction..............................................................................99
21.2 Comparison of the Standards for Medical Devices
Established by the FDA and the CDSCO............................... 100
21.3 Regulation and Quality Control of Medical Devices in
the US..................................................................................... 100
21.3.1 Changing the Medical Devices and Updating the
Laws.......................................................................... 100
21.3.2 The FDA Modernization Act of 1997....................... 101
21.3.3 The Medical Device User Fee and
Modernization
Act (MDUFMA)....................................................... 101
21.3.4 Food and Drug Administration Safety and
Innovation Act (FDASIA)......................................... 102
21.3.5 The Cures Act of the 21st Century............................ 102
21.3.6 The Food and Drug Administration (FDA)
Reauthorization Act of 2017 (FDARA) ................... 102
21.3.7 Federal Regulations................................................... 103
21.4 Part 807 of 21 CFR Subpart E: 510(k) or 510(k) Clause of
Medical Device Pre-market Notification................................ 104
21.5 The Quality and Kind of the Medical Device’s Clearance
510 (k) Application or Application for Clearance.................. 106
21.6 Quality Control of Medical Devices According to the FDA...... 107
21.7 Research Carried Out in the United States on Various
Medical Devices..................................................................... 108
x Contents

21.8 Quality Assurance and Control of Medical Equipment in

Europe.................................................................................... 109
21.9 Harmonisation of New European Regulation over CE
Certification............................................................................ 109
21.9.1 CE Certification......................................................... 109
21.10 Directive 2014/53/EU of the European Union for the
Legalisation of CE Certification............................................. 110
21.11 Radio Telecommunications (R&TTE) and Software
Development: Article 3 of the Act that Was Applied after
August 8, 2017, and the Regulation Conformance as per
Article 10 (10) of Directive 2014/53/EU................................. 110
21.12 Directive 90/385/EEC for Active Implantable Medical
Devices................................................................................... 111
21.13 The Directive 93/42/EEC for Medical Equipment................. 115
21.14 The Quality Assurance Measures of the Central Drugs
Standard Control Organisation (CDSCO) and the
Medical Equipment and Hospital Planning Division
Council (MHDC) of the Bureau of Indian Standards
Both Deal with Medical Devices........................................... 120
Bibliography...................................................................................... 120

Chapter 22 Regulation in Practising Telemedicine at the Edge of Data

Confidentiality and Medical Ethics................................................... 122
22.1 Introduction............................................................................ 122
22.2 Types of Telephone Consultations.......................................... 124
22.2.1 Provision of Health and Hygiene Education............. 124
22.2.2 Counselling or Advice............................................... 124
22.2.3 Prescribing Medication............................................. 125
22.3 The Use of Telemedicine Is Subject to the Consumer
Protection Act, 1986............................................................... 125
22.4 Telemedicine and the Drugs and Cosmetics Act, 1940
and the Drugs and Cosmetics Rules, 1945............................. 126
22.5 Telemedicine Practice and the Indian Medical Council
Act, 1956, and the Indian Medical Council (Professional
Conduct, Etiquette, and Ethics) Regulations, 2002................ 126
22.6 The Information Technology Act, 2000, Information
Technology 2011, the Information Technology
(Intermediaries Guidelines and Digital Media Ethics
Code) Rules, 2021, and Guidelines for Practicing of
Telemedicine, 2020................................................................. 127
22.7 Legal and Attributions of Section 79 of the Intermediary
Guideline by Ministry of Communications and
Information Technology......................................................... 129
Contents xi

22.8 Other Service Provider’s Regulations (“OSP

Regulations”) in Telecom Policy 1999................................... 130
22.9 The Clinical Establishments Act, 2010 for the
Registration and Regulation................................................... 130
22.9.1 Liability and Dispute................................................. 130
22.10 Civil Contempt in Negligence of Telemedicine Practice....... 131
22.11 Disciplinary Action by the MCI in Negligence of
Telemedicine Practice............................................................. 131
22.12 Criminal Liability in Negligence of Telemedicine Practice......132
22.13 Vicarious Liability in Negligence of Telemedicine Practice........133
22.13.1 The Consumer Protection Act (CPA)........................ 133
22.14 Category of Telemedicine and Regulation............................. 133
22.15 Types of the Telemedicine Practice Platform......................... 135
22.15.1 Consultation by Using Telemedicine Platform.......... 135
22.15.2 Consultation by Using Messaging Platform.............. 135
22.15.3 Consultation of Medical Practitioner to Medical
Practitioner by Telemedicine..................................... 135
22.15.4 Consultation by Cross-Border Opinion by the
Medical Practitioner.................................................. 136
22.16 Telemedicine Practices some Standpoint, Condition and
Guidelines............................................................................... 136
22.16.1 The Condition where the Physical Verification Is
Required.................................................................... 136
22.16.2 Patient and Medical Practitioner Identity
Disclosure before Consultation................................. 136
22.16.3 Emergency Situation and Telemedicine Practice...... 137
22.17 Consent from the Patient........................................................ 137
22.18 Consultation to Minors........................................................... 137
22.19 Format of Prescription............................................................ 137
22.20 Prescribing Medicines through the Telemedicine.................. 137
22.21 Limitation of Telemedicine.................................................... 138
22.21.1 Applicability.............................................................. 138
22.21.2 Security and Data Protection.................................... 138
22.21.3 Protection to Minors.................................................. 139
22.21.4 Prescribing Medicines............................................... 139
22.21.5 Telemedicine Practice within and Outside of the
Jurisdiction of India................................................... 139
22.22 Telemedicine Practicing in USA............................................ 140
22.23 Telemedicine Practicing in European Union.......................... 140
22.24 Legal Provision of Practicing Telemedicine in EU................ 141
22.24.1 Directive of Data Privacy (Article 8/1 and
Article 9/1)................................................................. 141
22.25 Apps-based and Website-based Telemedicine and
e-Commerce Business in India and European Union............ 142
xii Contents

22.25.1 Platform for App Application for Telemedicine

App............................................................................ 143
22.25.2 Legality of Third-Party App for Telemedicine App....143
22.25.3 Agreements of Legality of Third-Party App for
Telemedicine App...................................................... 143
22.25.4 Disclaimer, Terms of Use and Privacy
Agreements for Telemedicine App............................ 144
22.25.5 Designs and Trade Secrets of Telemedicine App...... 145
22.25.6 Telemedicine App Charges and Data Security......... 145
Bibliography ..................................................................................... 145

Chapter 23 Compressed Medical Gases: Regulations and Quality Control........ 148

23.1 Introduction............................................................................ 148
23.2 Categories of Medical Gas Production................................... 149
23.2.1 Air Separation Units (ASUs)..................................... 149
23.2.2 Transfers.................................................................... 149
23.2.3 Chemical Synthesisers.............................................. 150
23.3 Medical Gases Are in the Regulation.................................... 150
23.4 Challenges in Enforcement of the Act.................................... 150
23.5 Enforcement of the Violation of the Regulations................... 151
23.5.1 Dangerous Practices.................................................. 151
23.5.2 Protection of Action Taken in Good Faith................ 152
23.6 Regulations for Medical Gases in the USA............................ 153
23.6.1 Equipment Design, Size, and Locations................... 153
23.7 Quality Control of Medical Gases as per FDA Regulation.... 154
23.8 Labelling and Packaging, and Labelling as per FDA
Regulation............................................................................... 154
23.9 Testing and Release for Distribution of Medical Gas as
per FDA Regulation................................................................ 155
23.10 Component and Records of Medical Gas as per FDA
Regulation............................................................................... 155
23.11 Batch Production and Control Records of Medical Gas as
per FDA Regulation................................................................ 155
23.12 Laboratory Records of Medical Gas as per FDA Regulation.156
23.13 Mislabelling and Miscellaneous Provisions of Medical
Gas as per FDA Regulation.................................................... 156
23.14 Regulations of Medical Gas in Europe.................................. 156
23.15 British Compressed Gas Association (BCGA)....................... 156
23.16 Regulations of Medical Gas in India...................................... 156
23.17 Medical Gas Rule Enforced in India...................................... 157
23.18 Manufacturing of Medical Gases as per Regulations of
India........................................................................................ 158
23.19 General Requirements of Medical Gas Manufacturing as
per Regulations of India......................................................... 158
Contents xiii

23.19.1 Personnel................................................................... 158

23.19.2 Buildings and Premises............................................. 158
23.19.3 Production Area........................................................ 158
23.19.4 Quality Control Area................................................. 158
23.20 Manufacture Operations and Controls of Medical Gases
as per Regulations of India..................................................... 159
23.20.1 Equipment................................................................. 159
23.20.2 Records...................................................................... 159
23.20.3 Processing Records................................................... 160
23.20.4 Labels........................................................................ 160
23.20.5 Quality Check........................................................... 160
23.21 Quality Audit of Medical Gases............................................. 160
23.21.1 Product Containers and Closures.............................. 162
23.21.2 Distribution Records................................................. 162
23.21.3 Validation and Process Validation............................ 162
23.21.4 Product Recalls......................................................... 162
23.21.5 Complaints and Adverse Reactions........................... 163
23.21.6 Site Master File......................................................... 163
23.21.7 Transport of Medical Gases...................................... 163
23.22 Regulation on Quality Control of Compressed Gas
Cylinders as per Schedule I of Rule 3(1) of Gas
Regulation, 2004, Government of India................................. 163
23.23 Intervals between Periodic Inspection and Testing of
Compressed Gas Cylinder...................................................... 166
23.24 Inspection Intervals for Aluminium Alloy Liners of Gas
Cylinders................................................................................ 166
23.25 Inspection Intervals for Steel Liners of Gas Cylinders.......... 166
23.26 Inspection Intervals for Non-metallic Liners of Gas
Cylinder.................................................................................. 167
23.27 Inspection Intervals for cGas Cylinders without Liners........ 168
23.28 Procedures for Periodic Inspection and Testing of Gas
Cylinders................................................................................ 168
23.29 Heat Exposure of Gas Cylinders............................................ 168
23.30 Identification of Cylinder....................................................... 169
23.31 Permeability Testing of Cylinder........................................... 169
23.32 BIS Act of Compressed Medical Gas (1986).......................... 169
23.33 Medical Gases as per BIS Specification................................. 172
23.34 Instillation of the Liquid Medical Oxygen (LMO) Plant
in India................................................................................... 175
23.34.1 Regulatory Requirement for Installing of LMO....... 176
23.34.2 Quality Controls........................................................ 176
23.35 Pressure Swing Absorption (PSA) Oxygen Plant
Instillation in India................................................................. 178
Bibliography...................................................................................... 178
xiv Contents

Chapter 24 Regulation of Radiopharmaceuticals in the Preview of the

Drugs and Cosmetics Act, 1940........................................................ 180
24.1 Introduction............................................................................ 180
24.2 Classification of Radiopharmaceuticals................................. 180
24.3 The Manufacture of Radiopharmaceutical Preparations
in Accordance with GMP....................................................... 181
24.3.1 The Incorporation of Antibacterial Preservatives..... 181
24.3.2 Sterilisation............................................................... 181
24.3.3 Identity Tests............................................................. 182
24.3.4 Determination of the Half-life................................... 182
24.3.5 Radionuclide Purity................................................... 182
24.3.6 Radiochemical Purity................................................ 182
24.3.7 Chemical Purity of Radiopharmaceuticals............... 183
24.3.8 Bacterial Endotoxins/Pyrogens................................. 183
24.3.9 pH.............................................................................. 183
24.3.10 Labelling................................................................... 184
24.3.11 Storage....................................................................... 184
24.3.12 Safety of Critical Organ Exposure............................ 184
24.3.13 Other Important Data Requirements for
Approval of Radiopharmaceuticals in India............. 184
24.3.14 In vivo Study.............................................................. 185
24.3.15 Ex-vivo Testing of Radionuclides.............................. 186
24.3.16 Organ Biodistribution of Radionuclides.................... 186
24.3.17 Autoradiography of Tissue Sections for
Radionuclides............................................................ 187
24.3.18 Radio Metabolite Analysis........................................ 187
24.3.19 Plasma Protein Binding of Radionuclides................. 187
24.3.20 Toxicology of Radionuclides..................................... 188
24.3.21 Studies of Toxicity, Along with Dosage of
Radionuclides............................................................ 189
24.3.22 First Dose Calculation to be Given to a Human
Being (Also Known as the FIH Dose)...................... 189
24.3.23 Small-scale Dosimetry Models of Radionuclides..... 191
24.3.24 Dosimetry Phantoms and Models for Use with
Smaller Animals........................................................ 191
24.3.25 Extrapolation of Animal Dosimetry to Human
Dosimetry.................................................................. 191
24.3.26 In vivo Pharmacokinetic Data to Formation of
Time–Activity Curves of Radionuclides................... 192
24.3.27 Stability Assay Radiopharmaceuticals...................... 192
24.4 Role of Central Drug Standard Control Organization
(CDSCO) for Licensing and Approval Process of
Radiopharmaceuticals............................................................ 197
Contents xv

24.5 The Responsibility of the Atomic Energy Regulatory

Board (AERB) in the Process of Authorizing the Use of
Radiopharmaceuticals............................................................ 198
24.6 The Indian Pharmacopoeia and the Official Monograph
for Medicines and Radiopharmaceuticals.............................. 199
24.7 The Regulatory Framework for Radiopharmaceuticals in
the United States.....................................................................200
24.8 Radiopharmaceuticals and the United States’ National
Legislation..............................................................................200
24.9 Implementation of Good Manufacturing Practice for
Radiopharmaceuticals............................................................ 201
24.10 GMP for Positron Emission Tomography (PET) Drugs......... 203
24.11 Europe’s Regulatory Framework for the
Radiopharmaceutical Industry............................................... 203
24.12 Other Countries’ Approaches to the Regulation of
Radiopharmaceuticals............................................................204
24.13 Assessment of the Radiopharmaceuticals’ Safety Prior to
Clinical Use in Other Countries.............................................205
24.14 The European Union Needs Preclinical Studies for
Radiopharmaceuticals as Experimental Medicinal Products..... 205
24.15 Radiopharmaceuticals for “Micro-dosing” and
Evaluation of Non-clinical Safety Studies..............................206
24.16 eIND vs. IND: Comparing Radiopharmaceuticals and
Regulation in the United States..............................................206
Bibliography......................................................................................208

Chapter 25 Abbreviated New Drug Application (ANDA) or Generic Drug

Approval Process............................................................................... 210
25.1 Introduction............................................................................ 210
25.2 The Hatch-Waxman Act (HWA)............................................ 210
25.2.1 The Hatch-Waxman Act’s Significance.................... 212
25.3 Regulation of Shortened New Drug Applications in India.... 212
25.4 Documents Needed in India for the Approval of a Brief
New Medication/Drug Application........................................ 213
25.5 Approval of Bioequivalence (BE) Study................................ 214
25.6 Submissions of ANDA in the US........................................... 215
25.7 Approval of Common Technical Document (CTD) for
ANDA..................................................................................... 216
25.8 European Union ANDA Approval (EU)................................ 226
Bibliography...................................................................................... 226

Chapter 26 Biological Licence Application (BLA) Procedures.......................... 228

26.1 Introduction............................................................................ 228
xvi Contents

26.2 Considerations Relevant to Molecular Biology...................... 229

26.2.1 Clearly Specify the Strain(s) of Bacteria Used in
the Production........................................................... 229
26.2.2 Recombinant Products.............................................. 230
26.2.3 Biological Characterisation....................................... 230
26.3 Preclinical Toxicity Study Requirement for a Biological....... 233
26.3.1 Species Selection....................................................... 233
26.3.2 Immunogenicity........................................................ 235
26.4 Safety Pharmacology Studies of Biological Products............ 235
26.5 Carcinogenicity Studies of Biological Product...................... 237
26.6 Compliance of Purity of Excipients from Animal or
Human Origin......................................................................... 237
26.7 Validation Studies (Analytical Methods) of Biological
Products.................................................................................. 237
26.7.1 Limit of Detection and Limit of Quantification........ 238
26.7.2 Linearity.................................................................... 238
26.7.3 Accuracy.................................................................... 238
26.8 Stability Studies of Biological Products................................. 238
26.9 Accelerated Stability Studies of Biologicals.......................... 238
26.10 Information on Biological Drug Product for Approval.......... 239
26.11 Importance Form 29 for Approval of Biological Products....240
26.12 Protocol of Clinical Trial of Biological Products................... 241
26.12.1 Trial Objective........................................................... 241
26.12.2 Study Design and Duration of the Trial.................... 241
26.12.3 Total Number of Sites and Multicentric Trial........... 241
26.12.4 List of Investigators................................................... 241
26.12.5 Sample Size and Patient Population.......................... 241
26.12.6 Inclusion and Exclusion Criteria............................... 241
26.12.7 Drug Formulation...................................................... 242
26.12.8 Dosage Regimen........................................................ 242
26.12.9 Data Generation........................................................ 242
26.12.10 Risk Management.................................................... 242
26.12.11 Consent from the Volunteer..................................... 242
26.12.12 Discontinuation Criteria.......................................... 242
26.12.13 Efficacy Variables and Safety Variable Analysis..... 242
26.12.14 Statistical Analysis................................................... 243
26.13 Accelerated Clinical Trial of Biological
Products.................................................................................. 243
26.14 Marketing Authorisation of the Biological Products.............. 243
26.15 Post-approval Changes to Biological Products....................... 243
26.16 Import Licence of Biological Products...................................244
26.17 Biological Registration for Manufacturing
and Import.............................................................................. 245
Bibliography......................................................................................246
Contents xvii

Chapter 27 Regulatory Approval of Biosimilars Including Nucleic Acid-

based Recombinant Products, Recombinant Therapeutic
Enzymes, and Protein........................................................................ 247
27.1 Introduction............................................................................ 247
27.2 Waiver Provisions of the Safety and Efficacy Data................248
27.3 Product Characterisation........................................................248
1. Structural and Physicochemical Characterisation...........248
2. Biological Activity........................................................... 249
3. Immunological Properties............................................... 249
4. Purity and Impurities....................................................... 249
5. Quality Comparability of Biosimilar to Reference
Biological����������������������������������������������������������������������� 249
27.4 Characterisation, Both Physicochemical and Biological,
of Nucleic Acid-based Recombinant Products (Including,
But Not Limited to, Vectors for the Production
of Recombinant Proteins, siRNA and
snRNA, etc.)........................................................................... 250
1. The structure of the active substance is to be
mentioned.����������������������������������������������������������������������250
2. Product-related Impurities............................................... 251
3. Process-related Impurities............................................... 251
4. Biological Characterisation (Functional and
Biological Activity)�������������������������������������������������������� 251
5. Efficacy (in vitro/in vivo)................................................. 251
6. Expression of Small Interfering RNA (siRNA)/
(Small Nuclear RNA(snRNA) in Vector������������������������� 252
27.5 Physicochemical and Biological Characterisation of
Recombinant Therapeutic Proteins........................................ 252
1. Primary Structure Analysis............................................. 252
2. Secondary Structure Analysis......................................... 252
3. Tertiary Structure Analysis............................................. 253
4. Isoforms of Active Substance.......................................... 253
5. Host- and Process-related Impurities............................... 253
6. Drug Product Characteristics.......................................... 253
7. Product-related Impurities............................................... 253
8. Functional and Biological Activity.................................. 254
27.6 Physicochemical and Biological Characterisation of
Recombinant Therapeutic Proteins........................................ 254
1. Primary Structure Analysis............................................. 254
2. Secondary Structure Analysis......................................... 254
3. Tertiary Structure Analysis............................................. 254
4. Isoforms of the Active Substance.................................... 254
5. Product-related Variants and Impurities......................... 255
6. Process-related Impurities............................................... 256