Industrial Pharmacy-II

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INDUSTRIAL PHARMACY-II
B.Pharma, Semester-VII
According to the syllabus based on ‘Pharmacy Council of India’
Dr. Ilango K B
Ph.D.
Principal & Professor
Shree Venkateshwara College of Paramedical Sciences, Erode
Dr. Vikesh Kumar Shukla

Ph.D. (Pharmaceutical Chemistry)
Associate Professor & Ph.D. Coordinator
AMITY Institute of Pharmacy, Noida
Dr. Sameer H. Lakade

M.Pharm, Ph.D.
Associate Professor
Rasiklal M. Dhariwal Institute of Pharmaceutical Education and
Research, Pune
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Industrial Pharmacy-II
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“Dedicated
to
my family”
- Dr. Ilango K B
“Dedicated
to
my father and father–in-law”
- Dr. Vikesh Kumar Shukla
“Dedicated
To
Almighty God
my Family
&
all who directly or indirectly
helped in writing this book.”
-Dr. Sameer H. Lakade
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Preface
It gives us immense pleasure to place before the B.Pharma Seventh Semester pharmacy
students the book on “Industrial Pharmacy-II”.
This book has been written strictly in accordance with the current syllabus prescribed by
Pharmacy Council of India, for B.Pharm a students. Keeping in view the requirements of
students and teachers, this book has been written to cover all the topics in an easy-to-
comprehend manner within desired limits of the prescribed syllabus, and it provides the
students fundamentals of different pilot plant scale up techniques and regulatory
requirements which are required by them during their pharmaceutical career.
All efforts have been made to keep the text error -free and to present the subject in a
student friendly and easy to understand. However, any suggestions and constructive
comments would be highly appreciated and incorporated in the future edition.
Please e-mail us at, thakurpublication@gmail.com
Website, www.tppl.org.in
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Acknowledgement
The inspiration to write a book came from my two mentors at UG & PG level Students.
My advisor, Professors, infected me with his enthusiasm for writing and showed me how
good writing is done. My profound gratitude also goes to my Professors, who have
supported me throughout my career.
As with any book, this text has been benefited from contributions of many people. My
students at UG & PG level ha ve been my primary audience, and I thank them for their
input and patience as the course and the book evolved. My colleagues have actively
participated in the development and teaching of the course, and I am grateful for their
ideas, suggestions and support.
The book has also improved as a result of extensive reviews provided by students from
many Institutions which have been very valuable in making the book suitable not just to the
needs of single University students, but also to students, teachers, andeaders
r elsewhere.
I wish to particularly thank the wonderful people at Thakur Publication Pvt. Ltd., whose
enthusiasm, commitment, professionalism, and patience made this a rewarding endeavor.
- Dr. Ilango K B
I am indebted to Prof. (Dr.) F. V. Manvi and Prof. V. S. Mastiholimath to bestow an
important impact on my thinking and my research and writing. My over -riding
indebtedness continues to go to my Parents, my wife Neelansha and Friends who
provided me with the time, support and inspiration needed to prepare this book.
I am thankful for the support and blessing received from my colleagues,Prof. G T Kularni,
Dr. Tanveer Naved, Dr. Satendra Rajput, Dr. Vinay Lather, Dr. Rajiv Kharab, Dr.
Ramanpreet Walia, Dr. Swati Gupta, Dr. Harikesh Kalonia, Dr. Rajendra Awasthi, Mr.
Nitesh Chauhanand my dear students whohave directly or indirectly put forward their ideas,
suggestions, moral support and encouragement at every step of the publication.
I acknowledge my heartfelt thanks to Founder President, Chancellor Sir, Vice Chancellor
mam and Management of AMITY University for providing all possible facilities for
completion of present work and Editorial
& publication team ofThakur Publication Pvt. Ltd.,
who have undertaken the publication of this book with personal interest.
- Dr. Vikesh Kumar Shukla
No work, big or small, fructify without help from different quarters. I always remember
the guidance of the people whose names I feel privileged to mention here. It is with a
sense of pride and pleasure that, I humbly look back to acknowledge, those who have
been source of encouragement in my entire endeavour.
The efforts are made to designed as a textbook on Industrial Pharmacy II for B. Pharma
students of VIIth semester as per the PCI syllabus. The book has total 5 modules. Each
module has sub content based on PCI syllabus pattern. All unit covers Pilot plant scale up
techniques, Technology development & transfer, Regulatory affairs & Regulatory
requirements for drug approv al, Quality management systems, Indian regulatory
requirements. The entire unit clears the basic understanding and elaborate information of
respective chapters. Hopefully the present information meet the desired requirement of
learners and found more useful and helpful to students and teachers of the profession.
I am very thankful to Thakur Publication Pvt. Ltd. , Ms. Tuhina Banerjee (Editor,
Pharmacy Department) and Mr. Anoop (Marketing Coordinator) for encouragement and
support.
-Dr. Sameer H. Lakade
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–6–
Syllabus
Module 01 10Hours
Pilot Plant Scale up Techniques
 General considerations - including significance of personnel requirements, space
requirements, raw materials, Pilot plant scale up considerations for solids, liquid
orals, semi solids and relevant documentation, SUPAC guidelines, Introduction to
platform technology.
Module 02 10 Hours
Technology Development and Transfer
WHO Guidelines for Technology Transfer (TT)
 Terminology, Technology transfer protocol, Quality risk management, Transfer
from R& D to production (Process, packaging and cleaning), Granularit y of TT
Process (API, excipients, finished products, packaging materials) Documentation,
Premises and equipment’s, qualification and validation, quality control, analytical
method transfer, Approved regulatory bodies and agencies. Commercialization .
 Practical aspects and problems (case studies), TT agencies in India - APCTD,
NRDC, TIFAC, BCIL, TBSE / SIDBI.
TT Related Documentation
 Confidentiality agreement, licensing, MoUs, legal issues.
Module 03 10 Hours
Regulatory Affairs
 Introduction, Historical overview of Regulatory Affairs, Regulator y authorities
 Role of Regulatory affairs department, Responsibility of Regulatory Affairs
 Professionals
Regulatory Requirements for Drug Approval
 Drug Development Teams, Non-Clinical Drug Development, Pharmacology, Drug
Metabolism and Toxicology.
 General considerations of Investigational New Drug (IND) Application,
Investigator’s Brochure (IB) and New Drug Application (NDA).
 Clinical research / BE studies, Clinical Research Protocols, Biostatistics in
Pharmaceutical Product Development.
 Data Presentation for FDA Submissions, Management of Clinical Studies.
Module 04 08 Hours
Quality Management Systems
 Quality management & Certifications.
 Concept of Quality, Total Quality Management, Quality by Design (QbD).
 Six Sigma concept.Out of Specifications (OOS).
 Change control.
 Introduction to ISO 9000 series of quality systems standards.
 ISO 14000, NABL, GLP.
Module 05 07 Hours
Indian Regulatory Requirements
 Central Drug Standard Control Organization (CDSCO) and State Licensing
Authority: Organization, Responsibilities, Certificate of Pharmaceutical Product
(COPP), Regulatory requirements and approval procedures for New Drugs.
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Contents
Chapter 1: Pilot Plant Scale Up Techniques
1.1. Pilot Plant Scale Up Techniques 13
1.1.1. Introduction 13
1.1.2. Rationale for Pilot Plant Studies 13
1.1.3. Significance of Pilot Plant Studies 13
1.1.4. Objectives of Scale Up 14
1.1.5. Steps Involved 14
1.2. General Considerations For Pilot Plant Scale Up 15
1.2.2. Reporting Responsibility 15
1.2.3. Personnel Requirements 15
1.2.4. Space Requirements 16
1.2.5. Raw Materials 17
1.2.6. Review of the Formula 17
1.2.7. Processing Equipment 17
1.2.8. Process Evaluation 17
1.2.9. Production Rates 18
1.2.10. Preparation of Master Manufacturing Procedure 18
1.2.11. Good Manufacturing Practice (GMP) Considerations 18
1.2.12. Transfer of AnalyticalMethods to Quality Assurance 19
1.3. Pilot Plant Scale Up Considerations for Solids 19
1.3.2. Material Handling 19
1.3.3. Dry Blending or Mixing 20
1.3.4. Granulation 21
1.3.5. Drying 22
1.3.6. Reduction of Particle Size 22
1.3.7. Blending 22
1.3.8. Dry Compaction 23
1.3.9. Direct Compression 23
1.3.10. Slugging 24
1.4. Pilot Plant Scale up Considerations for Liquid Orals 24
1.4.2. Steps of Liquid Manufacturing Process 25
1.4.3. Solutions 25
1.4.4. Suspensions 25
1.4.5. Emulsions 25
1.4.6. Formulation Aspects of Liquid Orals 26
1.4.7. Pilot Plant Scale Up Considerations for Semisolids 26
1.5. SUPAC (Scale Up and Post Approval Changes) Guidelines 27
1.5.2. Purpose of Guidance 28
1.5.3. Site Changes 28
1.5.3.1. Level 1 Changes 28
1.5.4. Changes in Batch Size (Scale Up or Scale Down) 30
1.5.5. Manufacturing 31
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1.5.5.1. Equipment 31
1.5.5.2. Process 32
1.5.6. In-vitro Dissolution 33
1.5.7. In-vivo Bioequivalence Studies 33
1.6. Platform Technology 34
1.6.2. Nanotechnology 34
1.6.3. Microsphere Technology 34
1.6.4. Liposomal Technology 35
1.6.5. Hot Melt Extrusion 35
1.6.6. Sustained Release Formulations Technology 35
1.6.7. Orally Disintegrating Formulations Technology 35
1.6.8. Inhalation Technology 35
1.6.9. Sprinklers 35
1.7. Summary 35
1.8. Exercise 37
Chapter 2: Technology Development and Transfer

2.1. Technology Development and Transfer 38
2.1.2. Need for Technology Transfer 38
2.1.3. Technology Transfer Process 39
2.2. WHO Guidelines for Technology Transfer (TT) 39
2.2.2. Terminology 40
2.2.3. Technology Transfer Protocol 43
2.2.4. Quality Risk Management (QRM) 44
2.2.4.1. Principles of Quality Risk Management 45
2.2.4.2. QRM Application in Pharmaceuticals 45
2.2.5. Development of Technology by R&D 47
2.2.6. Transfer from R&D to Production 47
2.2.6.1. Process 48
2.2.6.2. Packaging 49
2.2.6.3. Cleaning 49
2.2.7. Granularity of Technology Transfer (TT) Process 50
2.2.7.1. Active Pharmaceutical Ingredient (API) 50
2.2.7.2. Excipients 50
2.2.7.3. Finished Products 51
2.2.7.4. Packaging Materials 52
2.2.8. Documentation 52
2.2.9. Premises 53
2.2.10. Equipment 53
2.2.11. Qualification and Validation 54
2.2.12. Quality Control 54
2.2.13. Analytical Method Transfer 54
2.2.14. Exhibit 57
2.2.15. Approved Regulatory Bodies and Agencies 57
2.2.16. Commercialisation 59
2.2.17. Practical Aspects and Problems (Case Studies) 59
2.3. Technology Transfer Agencies in India 64
2.3.2. APCTT (Asian and Pacific Centre for Transfer of Technology) 64
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2.3.3. NRDC (National Research Development Corporation) 65

2.3.4. TIFAC (Technology Information, Forecasting and Assessment Council) 65
2.3.5. BCIL (Biotech Consortium India Limited) 66
2.3.6. TBSE (Technology Bureau for Small Enterprises) 67
2.3.7. SIDBI (Small Industries Development Bank of India) 68
2.4. Summary 68
2.5. Exercise 70
Chapter 3: Technology Transfer Related Documentation

3.1. Technology Transfer Related Documentation 71
3.1.2. Confidentiality Agreement 72
3.1.2.1. Ending of Obligations of Confidentiality 72
3.1.2.2. Duration of Obligations of Confidentiality 73
3.1.2.3. One Way and Two Way Agreements 73
3.1.2.4. Confidential Disclosure Agreement 73
3.1.3. Licensing 75
3.1.4. Memorandum of Understanding (MoUs) 75
3.1.5. Legal Issues 76
3.2. Summary 76
3.3. Exercise 77
Chapter 4: Regulatory Affairs

4.1. Regulatory Affairs (RA) 78
4.1.2. Objectives 78
4.1.3. Need of Regulatory Affairs 79
4.1.4. Historical Overview of Regulatory Affairs 79
4.1.5. Regulatory Authorities 81
4.1.5.1. Scope 83
4.1.5.2. Challenges 83
4.1.6. Role of Regulatory Affairs Department 83
4.1.7. Responsibility of Regulatory Affairs Professionals 84
4.2. Summary 87
4.3. Exercise 88
Chapter 5: Regulatory Requirements for Drug Approval-I

5.1. Regulatory Requirements for Drug Approval 89
5.1.2. Drug Approval Process in India 90
5.1.3. Drug Development Teams 91
5.1.4. Non-Clinical Drug Development 93
5.1.4.1. Pharmacology 95
5.1.4.2. Drug Metabolism 97
5.1.4.3. Toxicology 100
5.1.5. Data Presentation for FDA Submission 109
5.2. Summary 111
5.3. Exercise 112
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Chapter 6: Regulatory Requirements for Drug Approval - II

6.1. General Considerations of Investigational New Drug (IND) Application 113
6.1.2. Types 114
6.1.3. Content and Format of an IND Application 114
6.1.3.1. Cover Sheet and Table of Contents 114
6.1.3.2. Introductory Statement and General Investigational Plan 115
6.1.3.3. Investigator’s Brochure (IB) 115
6.1.3.4. Protocols 116
6.1.3.5. Chemistry, Manufacturing and Control (CMC) Information 117
6.1.3.6. Pharmacology and Toxicology Information 118
6.1.3.7. Previous Human Experience With the Investigational Drug 119
6.1.3.8. Additional Information 119
6.1.3.9. Relevant Information 119
6.2. General Considerations of Investigator’s Brochure (IB) 120
6.2.2. Information to be Included 120
6.2.2.1. Summary 121
6.2.2.2. Introduction 121
6.2.2.3. Physical, Chemical, & Pharmaceutical Properties & Formulation 121
6.2.2.4. Non-Clinical Studies 122
6.2.2.5. Effects in Humans 122
6.2.2.6. Summary of Data and Guidance for the Investigator 123
6.3. General Considerations of New Drug Application (NDA) 124
6.3.2. General Format of NDA 124
6.3.3. Archival Copy 124
6.3.4. Review Copy 125
6.3.5. Paper Size and Binding 125
6.3.6. Pagination 126
6.3.7. Volume Size and Identification 126
6.3.8. Packing Carton 127
6.4. Clinical Research 127
6.4.2. Designing Clinical Trials 127
6.4.3. Clinical Research Phase Studies 129
6.4.4. Investigational New Drug Process 130
6.4.5. Asking for FDA Assistance 130
6.4.6. FDA IND Review Team 131
6.4.7. Approval 131
6.4.8. Clinical Research Protocols 132
6.5. Bioequivalence Studies 135
6.5.2. Types of Bioequivalence Studies 135
6.5.3. Bioequivalence Study Parameters 137
6.5.4. Design of Single Dose Bioequivalence Study 138
6.5.5. Evaluation of Bioequivalence Data 141
6.6. Biostatics in Pharmaceutical Product Development 143
6.6.2. Experimental Design in Clinical Trials 144
6.6.3. Sensitivity and Cost 145
6.6.4. Random Sampling 145
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6.7. Management of Clinical Studies 146

6.7.2. A Trial Manager 146
6.7.3. Project Planning 147
6.7.4. Collaboration 147
6.7.5. Minimal Work for Investigators and Participants 148
6.7.6. Communication 148
6.7.7. Efficient Systems 148
6.8. Summary 149
6.9. Exercise 151
Chapter 7: Quality Management Systems

7.1. Quality Management 152
7.1.2. Certifications 152
7.1.3. Concept of Quality 153
7.1.3.1. Types of Quality 153
7.1.3.2. Quality Systems 154
7.2. Total Quality Management (TQM) 155
7.2.2. Concepts 155
7.2.3. Principles 156
7.2.4. Effect 159
7.2.5. Advantages 159
7.2.6. Disadvantages 159
7.3. Quality by Design (QbD) 160
7.3.3. Elements 161
7.3.4. Tools 162
7.3.5. Advantages 163
7.4. Six Sigma Concept 164
7.4.3. Methodologies 164
7.4.4. Implementation 166
7.4.5. Applications in Pharmaceutical Industry 167
7.5. Out of Specifications (OOS) 167
7.5.2. Phase I (or Laboratory) Investigation 168
7.5.2.1. Phase Ia Investigation 169
7.5.2.2. Phase Ib Investigation 169
7.5.3. Phase II Investigation 171
7.5.4. Phase III Investigation 175
7.5.5. Concluding the Investigation 175
7.6. Change Control 176
7.6.2. Benefits of Change Control System 176
7.6.3. Change Control Procedure 176
7.6.5. Change Control Process at Regulatory Submission Level 178
7.7. ISO 9000 Series for Quality Systems and Standards 178
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7.7.2. Principles 181
7.7.3. Working 182
7.7.4. Need for Obtaining ISO 9000 Certification 183
7.7.5. Importance 183
7.8. ISO 14000 184
7.8.2. History 184
7.8.3. Standards 184
7.8.4. Certification 185
7.8.5. Benefits of ISO 14000 Certification 185
7.9. GLP and NABL 186
7.9.2. Equipment 186
7.9.3. Chemicals and Reagents 187
7.9.4. Organisation and Personnel 187
7.9.6. Quality Control 187
7.9.7. Protocols and Conduct of a Laboratory Test 188
7.9.8. Records and Reports 188
7.9.9. Safety 188
7.9.10. Auditing Procedure 188
7.9.11. NABL (National Accreditation Board for Testing and Calibr ation 188
Laboratories)
7.10. Summary 189
7.11. Exercise 191
Chapter 8: Indian Regulatory Requirements

8.1. Indian Regulatory Requirements 192
8.1.2. Central Drug Standard Control Organisation (CDSCO) 192
8.1.2.1. Structure 193
8.1.2.2. Functions 193
8.1.3. State Licensing Authority (SLA) 194
8.1.3.1. Procedure for Obtaining Licenses 194
8.1.3.2. Organisation 195
8.1.3.3. Responsibilities or Functions 195
8.1.4. Certificate of Pharmaceutical Product (CoPP) 196
8.1.4.1. Aim 196
8.1.4.2. Scope 196
8.1.4.3. Inspection 197
8.1.4.4. Types of COPP 197
8.1.4.5. Certificate of a Pharmaceutical Product Model 198
8.1.5. Regulatory Requirements and Approval Procedures for New Drugs 201
8.2. Summary 203
8.3. Exercise 204
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Pilot Plant Scale Up Techniques (Chapter 1) 13
CHAPTER Pilot Plant Scale Up

1 Techniques
1.1. PILOT PLANT SCALE UP TECHNIQUES
1.1.1. Introduction
Pilot plant is a part of pharmaceutical industry in which a lab scale formula is
converted to a feasible product by developing a liable practical method for
manufacture. It can also be defined as a tech nique that involves development of a
practical procedure for manufacturing dosage forms that may result into
transformation of lab scale process into a viable product. The scale-up is helpful in
designing a prototype by utilising the information obtainedromf pilot plant model.
In this technique, a formula is examined and shifted to a most suitable

formulation by developing a reliable and useful manufacturing procedure which
affects the organised transition from laboratory to regular processing in a large -
scale production facility.
Pilot plant scale up studies is essential in pharmaceutical research for preventing

recurrence of long and expensive tests. It is important to collect sufficient
information during appropriately designed development and process optimisation
studies while scaling up the experimental formulation from the laboratory
through pilot to the production scale.
1.1.2. Rationale for Pilot Plant Studies

The basis for pilot plant studies are:
1) It examines a prod uct and processes on an intermediate scale before utilising
large amount of products and processes in full-scale production.
2) It helps in predicting the effects of a many-fold increase in scale.
3) It designs a large complex food processing plant from laboratory data alone.
1.1.3. Significance of Pilot Plant Studies

The following reasons have made the pilot plant studies important:
1) These studies are helpful in standardising formulations.
2) These studies are helpful in analysing different important manufacturing
equipments.
3) These studies are helpful in optimising and controlling production rate.
4) These studies provide information on equipment assembly used during the
scale up batches.
5) These studies identify the specifi c features of a product required to maintain
its quality.
6) These studies are helpful in maintaining suitable records and reports to
support GMP.
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14 Industrial Pharmacy - II
1.1.4. Objectives of Scale Up

Scale up technique works for the following objectives:
1) It improves various parameters required in the formulation and development
of physically and chemically stable therapeutic dosage forms.
2) It generates strategies for production and process control.
3) It enables handling of raw materials as per their specifications.
4) It determines the steps involved in raw material processing.
5) It develops the master manufacturing formula.
6) It develops pilot plant studies to form an identical examination of the formula
to tolerate batch scale.
7) It evaluates, validates, and finalises the production and process controls.
8) It allows any sort of modification in the process.
9) It properly evaluates and validates the developed product.
10) It modernises the manufacturing equipment.
11) It ensures physical and mechanical compatibili ty between the equipment and
preparation.
12) It makes the process more economical and less time consuming.
13) It develops modern marketing strategies.
14) It overcomes the problems in small -scale techniques by developing large -
scale techniques.
1.1.5. Steps Involved

Scale up is the process of designing a prototype using the data acquired from the
pilot plant model. The steps of scale up are represented in figure 1.1:
Product economics are defined based on projected market
size and competitive selling, and guidance for allowable
manufacturing costs is provided.
Laboratory studies and scale up planning are conducted at

the same time.
Key rate-controlling steps are defined in the proposed

process.
Preliminary larger-than-laboratory studies with equipment to

be used in rate-controlling step to aid in plant design are
conducted.
A pilot plant including provisions for process and

environmental controls, cleaning and sanitising systems,
packaging and waste handling systems, and meeting
regulatory agency requirements are designed.
Pilot plant results (product and process) including process

economies are evaluated to make any corrections and
whether or not to proceed with a full scale plant development
is decided.
Figure 1.1: Steps in Scale Up
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1.2. GENERAL CONSIDERATIONS FOR

PILOT PLANT SCALE UP
1.2.1. Introduction
In pilot plant, a feasible and strong product is made by the conversion of a
formula through development of a dependable manufacturing procedure, which
affects the orderly transition from laboratory to regular processing in a large -
scale production facility ; whereas the scale up involves designing a prototype
making use of the data acquired from the pilot plant model.
Pilot plant studies should involve a close investigation of formula to find its
ability to resist batch -scale and p rocess modifications. It should also involve
reviewing a wide variety of significant processing equipment, and evaluating and
finalising availability of raw materials fulfilling the product requirements during
the scale up efforts in the pilot plant produc tion and process control.
Additionally, proper records and reports should be issued to support GMPs and
to deliver historical development of the product formulation, process, equipment
training, and conditions . A manufacturer’s choice to scale up or scale down a
process is based on the economics of the production procedure, i.e., in the
material cost, personnel, equipment related to the procedure, and its regulation.
1.2.2. Reporting Responsibility

In reality, the pilot plant function can be a part of the R&D or operation-oriented
groups. If it is a part of R&D, there is a need of separate staff and importance is
also given on consideration of hierarchy of responsibility to scale -up
formulations manufactured by the R&D department and that emerges as the
product. On the other hand, the formulator of the product can provide support
even after transition into production.
Some industries chose to have the pilot plant as a technical service group that is
operation-oriented. Such a group is beneficial as the pilot plan t is more
substantial and accessible to operations. Some industries implem ent a
combination of the R&D and the operation -oriented systems to achieve the best
qualities of both . The goal of the pilot plant is to assist the transfer of a product
from the laboratory to the production, irrespective of the approach adopted by the
industry. The pilot plant’s efficiency is estimated by the simplicity with which
new products or processes are taken into regular production. This can be attained
by good management bet ween various departments such as R&D, packaging,
processing, engineering, quality assurance, quality control, administration , and
marketing.
1.2.3. Personnel Requirements

A pilot plant organis ation needs a team of personnel, each having a good
theoretical and practical knowledge of pharmacy, good communication skills and
designing ability to merge new processes with the existing facility. The team is
also bound to define equipment specifications and the physical association of
process operations for complying with regulatory standards.
* *
The personnel should be aware of the appropriate scale up conditions to be used

as their misuse can result in variances in the performance of bench-top and
manufacturing plant scales. Hence, stepwise scale up is suggested. Additi onally,
for successful scale up, the manufacturing personnel should be trained on process
requirements and GMPs to provide an effective transition into commercial
production within a short time period.
Experience of formulation process and equipment in th e production environment
is also important . Pilot plant personnel should know the objective of the
formulator and also recognise the view point of production personnel. Due to
these reasons, pilot plant organisations include scientists having experience in
both areas.
1.2.4. Space Requirements

The space requirements of a pilot plant are as follows:
1) Administration and Documentation: The data from every experiment and
trial p erformed in a pilot plant scale up of a product are recorded and
documented. The document ation area should be near to the work area, but
should be located remotely so that the people can work without any
interruptions. The administration and documentation area comprises of:
i) Space for discussing issues with the group members working in different
departments of research and production stages,
ii) Computer terminal for entering data, and
iii) Stores for historical files, books, stability data protocols, and journals.
2) Physical Testing Area : A sufficient working area should be available for
analysis and physical testing of samples (in -process quality control analysis)
to assist in timely identification of production error. The physical testing area
should have a bench top space for physical testing instruments that are used
regularly, like balances, pH meters, viscometers, etc.
3) Standard Pilot Plant Equipment Floor Space: All the important equipment
employed in the pilot plant scale up techniques is kept in this area. Variably
sized equipment should be available to all the members of production unit.
This arrangement is helpful for ensuring the quality of the scale up data
collected, and being discreet to expensive materials.
Medium and large -sized or full scale production equipment are used for
estimating the effects of scale up on research formulations and p rocesses.
Wherever possible, the equipment should be made portable as the pilot plant
equipment is rarely used depending on project assignments. The pilot plant
equipment floor space is best used when is sub -divided into different areas
for different dosage forms (solid, semi-solid, liquid and sterile products).
4) Storage Area : A separate area should be made available for storing active
ingredients and excipients. Diverse areas should be provided for storing in -
process materials, finished bulk products from t he pilot plant , and materials
from the experimental scale-up batches made in the production. Storage area
should also be provided for packaging materials.
* *
1.2.5. Raw Materials

The pilot plant operation approves and authenticates the active and excipient raw
materials used in formulating pharmaceutical products. The raw materials used
for small scale formulation trials may not be appropriate for large volume
shipments of materials used in a large manufacturing scale. The active
ingredients used in a laboratory scale should also fulfil the increasing demands of
the product when subjected to scale up. There may be changes in part icle size,
shape, or morphology, and these changes result in various handling properties or
differences in density, solubility rate, static charges, flow properties , etc., of the
active/inert ingredients as the batch size increases.
1.2.6. Review of the Formula

A review of every formulation aspect should be done during the scale up process.
The use and role of every ingredient in the final product manufacturing on small
scale laboratory equipment should be known. Then , the outcomes of scale up
using equipment should be determined on a large scale, which may have
undergone different types of stresses.
1.2.7. Processing Equipment

It is known that almost all formulation development work has been done using
small and sim ple equipment. In further scale up of the same, alternative
equipment that is economical, effective, simple , and most efficiently produces
the product within the suggested conditions should be assessed. The equipment
size should be appropriate for conducting experimental trials that are significant
to the production size batches. The method developed will not scale up well if the
pilot plant equipment is very small, and additional costs will be incurred if the
equipment is very large; new and costly active ingredients will also get wasted in
large quantities.
Upon development of a practical process on the pilot plant equipment, medium -

sized and economical experiment should be carried out. If the equipment is not
present in-house, one can reach out to equipment vendors. Choice of equipment
depends on the ease of cleaning, especially if multiple products are manufactured
in the same equipment. The time needed to break down the equipment for
cleaning and changing from one product to another should be estimated. Trials
should be conducted at the vendor’s facility for assessing these parameters. This
aids in establishing the real capabilities of the equipment and the quality of
technical support available from the vendors.
1.2.8. Process Evaluation

Understanding the outcome of key processes such as mixing speed, time, rate of
addition of granules, granulating agent, solution of drugs, solvents, heating and
cooling rates, etc., is a major requirement for optimising and verifying the quality
of in-process and finished product. The aim of process validation is to check
whether the chosen manufacturing method ensures the product quality at
numerous critical stages in the process and in the finished form. This can be
achieved by monitoring the within-batch variation of measurable parameters, and
* *
the data acquired shows if the process is performed as planned and where
problem areas could be found. Review of the manufacturing process and quality
control data should be done annually, and if required, some revalidation studies
should be performed to confirm that alterations have not ensued.
1.2.9. Production Rates

While estimating the production rates and the type/sizes of production equipment
to be used in the production, th e current and future market demands of a product
should be kept in mind. The equipment size should be proportional to its
utilisation. The selection of equipment and process to be used depends on the loss
of product in equipmen t during manufacturing , time needed for cleaning the
equipment between batches, and the number of batches required for testing.
1.2.10. Preparation of Master Manufacturing Procedure

The master process records are made for the optimised formulation, in which the
manufacturing directions , chemical weigh sheet and in -process and finished
product specifications are recorded. The processing steps should be accurate and
written in a style which uses language and terms well known to the operators. For
writing the manufacturing procedures, sufficient input should come from the
operators or from someone having knowledge and experience in the modern
weighing and processing areas.
The batch record steps should include specification for mixing time, addition
rates, mixing speed, temperat ure, heating and cooling rates. The record should
also bear proper r anges. The batch process record should follow the master
process record instructions. The manufacturing process and quality control data
should be reviewed annually and if required, some revalidation studi es should be
performed to make sure that alterations have not ensued.
The a ccurate time, speed, and temperature used in batch process should be
recorded. These can be monitored and recorded using suitable controller recorders.
GMPs, periodic revalidation , and monitoring of finished product test results
through control chartsare required for maintaining constant product quality.
1.2.11. Good Manufacturing Practice (GMP) Considerations

The following list includes items which should be a part of GMP for scale up of a
new product or process introduction:
1) Equipment qualification,
2) Process validation,
3) Regularly scheduled preventative maintenance,
4) Regular review and revalidation of the process,
5) Relevant written standard operating procedures,
6) Use of technically qualified personnel,
7) Adequate facilities for personnel training,
8) A well-defined technology transfer system,
9) Validated cleaning procedures, and
10) A systematic arrangement of equipment for easy material flow and
*
prevention of cross contamination. *
1.2.12. Transfer of Analytical Methods to Quality Assurance

The analytical test procedures developed in research during scale up of a new
product should be moved to the quality assurance department. The staff of this
department should assess the process to ensure that proper analytic al
instrumentation is present and personnel are trained to do the assigned activities.
Research personnel should analyse the assay method and the data acquired
during the validation studies for confirming that the analytical procedures have
not been changed in a way that may alter the reliability and accuracy of the tests.
1.3. PILOT PLANT SCALE UP

CONSIDERATIONS FOR SOLIDS
1.3.1. Introduction
In scaling up the production of solid dosage forms (like tablets and capsules )
from experimental laboratory batch sizes to m edium- and large-scale production,
every operation step should be considered suitably. A method using the same
type of equipment produces different results when the equipment size and the
material quantity are changed considerably. Following are the consid erations for
the pilot plant scale up of solid dosage forms:
1) The major responsibility of the pilot plant staff is tomake sure that the recently
formulated tablets manufactured by the product development personnel are
efficiently, economically, and regularly reproducible on a production scale.
2) Design and building of the pharmaceutical pilot plant for tablet manufacture
should include all the necessary features to assist maintenance and cleanliness.
3) The tablet manufacturing area should be present on the gro und floor to
facilitate handling and transportation of supplies.
4) The following specifications should be included in the pilot plant design to
avoid microbiological contamination:
i) Fluorescent lighting fittings should be the ceiling flush type.
ii) The operating areas should have floor drains for simplifying cleaning.
iii) The area should be air-conditioned and humidity controlled.
iv) The floors should be of high-density concrete.
v) The walls of the processing and packaging areas should have enamel
cement finish on concrete.
5) Equipment used in the pharmaceutical pilot plant for manufacture of tablets
should be similar to that used by production division.
1.3.2. Material Handling

On a laboratory scale, materials can be handled through scooping, dumping, or
pouring by hand. These manual handling practices may prove satisfactory for small
or intermediate -scale productions, but for large -scale productions, mechanical
devices are required. The simple forms of material handling procedures include post
hoist devices, devices for liftin g and tilting drums; while the modern procedures
include vacuum loading systems, screw feed system
*
, and meter pumping systems. *
The material characteristics (like density and static change ) influences the
selection of a definite system. There should be min imal or no material loss in
material handling system. Lengthy transfer processes facilitate material loss.
Validated cleaning procedures prevent cross-contamination during the transfer of
more than one material by a single system. Every material handling s ystem
should supply ingredient to the formulation in precise quantity.
1.3.3. Dry Blending or Mixing

The dry blending process utilises a binary cohesive powder mixture containing
particles of two different sizes; the finer particles stick to the surface of the
coarse particles. This mixture is also known as interactive mixture (figure 1.2).
Mechanical Mill
Interactive mixture
Figure 1.2: Dry Blending Method
The agglomerates of fine and coarse powders break down when the fine and coarse
particles are blended. During blending, the particles interact and collide with each
other, thus, generating an electric charge. This process is irreversible, i.e., the fine
and coarse particles do not return to their agglomerate states. New agglomerates,
containing finer particles that stick to the coarse particles’ surface, are producedas
a result of blending. However during the first step, the coating particles stick
randomly on the core particles’ surface. Processes like screening and/or milling are
performed initially to make blending more dependable and reproducible.
Problems Associated with Improper Blending

1) Flow problem through the equipment,
2) Non-reproducible compression, and
3) No content uniformity.
Equipment Required for Blending

1) V-blender,
2) Double cone blender,
3) Ribbon blender,
4) Slant cone blender,
5) Bin blender, and
6) Orbiting screw blenders vertical and horizontal high intensity mixers.
Parameters to be Considered for Improving the Blending Process

1) Blending time,
2) Blender loading, and
3) Blender size.
* *
1.3.4. Granulation
The process of granulation involves agglomeration of smaller particles in to
larger ones , in which the original particles can still be recognised.
Pharmaceutical granulation involves enhancing the surface area and dissolution
of API by rapidly breaking down the agglomerates. Granulation process is a form
of particle designing.
Functions of Granulation Process

1) It facilitates uniform drug distribution throughout the product.
2) It increases material density.
3) It improves flow rates and rate uniformity.
4) It aids in metering or volumetric dispensing of drugs.
5) It reduces dust production.
6) It enhances product appearance.
Types of Granulation Methods
1) Wet granulation method, and
2) Dry granulation method.
Table 1.1 enlists different drying techniques involved in wet and dry granulation
methods:
Table 1.1: Drying Techniques for Granulation
Granulation Techniques Drying Techniques
Wet Granulation Method Tray or fluid-bed dryer
Vacuum/gas stripping/microwave
Spray dryer
Extrusion/spheronisation/pelletisation
Dry Granulation Method Direct compression
Slugging mill
Roller compactor
Different processes involved in granulation mechanism are wetting,

nucleation, coalescence (or growth), consolidation, and attrition (or breakage).
Spray rate (or fluid distribution) and feed formulation properties affect the initial
wetting of feed powder and the existing granules by the binding fluid.
Table 1.2 enlists the different parameters and methods utilised for characterising
granules:
Table 1.2: Different Parameters and Methods for Characterisation of Granules
Parameters Methods
Panicle morphology Optical microscopy
Particle size distribution Sieve analysis and laser light scattering
Nature Powder X-ray diffraction
Thermal analysis DSC, TGA, and DTA
Identification Near-Infrared (NIR) spectroscopy
Surface area Gas adsorption
Granule porosity Mercury intrusion methods
Granule strength Development of a formulation
Granule flowabilityand density Mechanical method, hopper method, density apparatus
* *
1.3.5. Drying
Circulation of granules in a hot air oven (heated by either steam or electricity) i s
one of the most commonly used methods for drying granules. Factors like air
flow, air temperature, and depth of granulation on trays are consid ered as
essential part of scale up in an oven drying operation. The drying process will
be unproductive if the granulation bed is too deep or too dense, or if the soluble
dyes (present in granules) migrate to the surface. Each and every product or a
particular oven load should have a specific and definite air flow rates, and drying
times and temperatures.
An alternative to circulating hot air oven is fluidised bed dryer. Optimum loads,
air flow rate, inlet air temperature, and humidity are the factors that play an
important role in scale up of a fluidised bed dryer.
1.3.6. Reduction of Particle Size

Particle size indic ates the product quality and performance. It also affects the
other properties associated with particulate materials . The flow rate of larger and
spherical particles is more than that of the smaller or high aspect ratio particles.
Dissolution of smaller pa rticles occurs more rapidly (forming suspensions of
higher viscosities) than that of the larger particles. Therefore, control and
measurement of the particle size distribution of several products is necessary.
Problems Produced by Improper Particle Size
1) Weight variation of tablets occurs because of inadequate filling of the die
cavity due to large-sized particles.
2) Weight variation of tablets may also occur due to flowability problems of
very fine particles.
3) Chances of mottling increases if the coloured granules are coarser.
4) Capping may occur as a result of augmented press speed.
Equipment Involved in Particle Size Reduction

1) Oscillating granulator (for not too hard oversize granulation),
2) Hammer mill,
3) Mechanical sieving device, and
4) Screening device.
1.3.7. Blending
Two main purposes of blending in solid dose manufacturing are:
1) Achieving blend uniformity, and
2) Distributing the lubricant.
According to objective 1, blending should attain uniform size distribution of all

the components before final blending with t he lubricant ( objective 2 ). Several
features like particle size, moisture content, structure, bulk density, and flow
characteristics may create problems in powder blending. The particle shape for
most oral solid dosages should lie within the range of 40 -180 mesh; it is the first
step in attaining expectable results in a blend. The other step involves completing
the pre-blending steps by carefully and sequentially adding the ingredients.
* *
The blending equipment used for scale up differs from that used in lab oratory.
Particle size, shape, hardness, density, and d ynamics of mixing action affect the
blending process involving simultaneous occurrence of segregation and mixing.
Use of high shear mixers with spiral screws or blades causes particle abrasion.
Blending of low dose API involves sandwiching the ingredient between two
portions of directly compressible excipients. Thus, API loss to the blender
surface is prevented.
1.3.8. Dry Compaction

In dry compaction granulation process, materials are compressed by applyi ng
pressure (up to 10 tons per linear inch) on the powder passing between two
rollers. Sufficient bulk density required for tablet encapsulation or compression
can be attained by subjecting low density materials to roller compaction process.
Densification of alumin ium hydroxide is one of the best examples of this
process. It is the responsibility of the pilot plant personnel to determine whether
or not the effectiveness of this API compaction technique for yielding
granulation (exhibiting the desired tablet ing or encapsulation characteristics) is
more as compared to other commonly used conventional processes.
1.3.9. Direct Compression

This process involves direct compression of powder mixture of API and other
excipients into tablets . The Wet or dry granulation pr ocess requires no pre -
treatment of powder blend. Compression of granules on a high speed tablet press is
a crucial test performed to ensure proper tablet formulation and granulation
process. Compression features of a formulation are evaluated by keeping the press
speed equal to that to be used in normal production during lengthy trial runs. This
will be helpful in detecting the problems, like sticking to the punch surface, tablet
hardness, capping, and weight variations. High speed tablet compression is
determined by the capacity of the press to interact withthe granules.
In the die feed system, the die is passed under the feed frame during which the
die cavities are filled effectively within a short period. Uniform filling of smaller
tablets utilising a high press speed is more difficult. Induced die feed systems are
necessary for high speed machines. These machines are provided with variable
speed capabilities and a variety of feed paddles to achieve optimal feed for every
step of granulation.
Drug + Excipients
Drying of material Milling Mixing Compression

Figure 1.3: Manufacturing Steps for Direct Compression
Granulation compression is a single step involving passage of granules between
the lower and upper punches and pressure rollers. The punches are thus allowed
to penetrate the die to a pre -set depth and produce compact granulation with
* *
thickness equal to the gap set between the punches. The creation of bonds within
the compressible material during compression of granulation results in sticking,
thus, forms tablets. Soft tablet may occur due to utilisation of high level of
lubricant or over blending which may result in decreased powder wettability with
prolonged dissolution time. Utilisation of die with 0.001 -0.005 inch wider upper
portion than the center (to relieve pressure during ejection) prevents binding of
granules to die walls. This operation is usua lly carried out by high speed rotary
machine, multi rotary machine , double rotary machine , upper punch and
lower punch machine, and single rotary machine.
1.3.10. Slugging
This process is utilised to produce granules for moisture- and heat-sensitive APIs,
and when APIs exhibit sufficient binding or cohesive properties. The method of
slugging is also known as dry granulation , pre-compression, or double
compression. The APIs, diluents, and a portion of lubricants are mixed together
to form a blend. It is essential that either the API or the diluents should be
cohesive in nature.
Pressure is applied to remove significant amount of air present in powdered
material to produce a dense product. The tablet or slug quality improves with
increase in time allowed for the air to escape. This process is performed on a tablet
press that functions at pressures of 15 ton which is much higher than the 4 tons
pressure utilised in normal tablet press. The material that can be easily slugged
produce slugs of 1 inch diameter, while t he materials difficult to be compressed
and require more pressure per unit area can produce slugs of ¾ inch diameter.
Roller compaction process is utilised for compacting very low density materials
so that bulk density sufficient enough for encapsulation or compression is
achieved, e.g., densification of aluminium hydroxide.
1.4. PILOT PLANT SCALE UP

CONSIDERATIONS FOR LIQUID ORALS
1.4.1. Introduction
Liquid dosage forms comprise of non -sterile solutions, emulsions , and
suspensions. Scale up of these pharmaceutical s involves various processing
problems that should be evaluated and optimised in a pilot plant scale up study.
The considerations for pilot plant scale up of liquid orals are as follows:
1) The physical form of a pourable drug product shows Newtonian or pseu do
plastic flow behaviour and takes the shape of its container at room
temperature.
2) Liquid orals may be solutions or dispersed systems.
3) Two or more phases , with one phase distributed in another, are present in
dispersed systems.
4) A homogeneous mixture of two or more substances is referred to as solution.
* *
1.4.2. Steps of Liquid Manufacturing Process

Liquid manufacturing process involves the following steps:
1) Planning of material requirements,
2) Liquid preparation,
3) Filling and packing, and
4) Quality assurance.
1.4.3. Solutions
Scale up of simple solutions is easy , but require tanks of sufficient size and
mixing capacity. Generally, the equipment should have good heating and cooling
properties to result in rapid dissolution of system components. Suitable transfer
systems and filtration equipment are needed and should be observed to make sure
they can clarify the product without removing the active or adjuvant ingredients.
1.4.4. Suspensions
Scale up of s uspensions needs more care than that of simple solutions due to the
additional processing requirements. Addition and distribution of suspending
agents on a laboratory scale may include sprinkling the material in th e liquid
vortex and need to use vibrating feed system or other new approach. Suspending
agents which cannot be easily dispersed are combined by making slurry with a
part of the vehicle during scale up studies. In a concentrated slurry, the suspending
agent can be easily made wet and dispersed by using a high-shear mixer in a small
volume of vehicle. Such slurry assists in fast and complete hydration of the
suspending agent when mixed with a large part of vehicle. The temperature and
time needed for hydrating the suspending agents are generally critical.
The active ingredients in a suspension should be equally dispersed in the batch.

The selection of dispersion method to be used for the production of suspensions
relies on the physical characteristics of the active ingredient. If the active
ingredients get wet and do not agglomerate, the chemicals are added at a suitable
stage of the manufacturing process. If the y do not get wet easily and form
agglomerates, other procedures for adding these ingredients shoul d be pursued.
One method could be preparing a slurry with a wetting agent and high -shear
mixing equipment. Another method could be pre-treating the hard -to-wet
material by mixing it with one or some other liquid ingredients (probably a
surfactant) in a high-shear powder blender.
The type of mixers, pumps, mills, and the horsepower of the motors should be
properly chosen based on scale up performance in the process of manufacturing
suspensions. During the manufacturing procedure, the equipment should be
chosen based on the batch size and the maximum viscosity of the product.
1.4.5. Emulsions
Emulsions are also dispersed systems, but their dispersed phase is a finely divided
immiscible liquid (and not a solid). The dispersed phase is made up of oils and
waxes, which may exi st in a liquid or solid state. For m anufacturing liquid
emulsions, specific proceduresare used and thus, scale up into production equipment
* *
involves process devel opment and validation. Homogenising equipment,

temperature, in-process or final product fillers, mixing equipment, filling equipment,
and screen pumps are the processing parameters that should be regulated and
controlled for various types of emulsions. The physical properties (appearance and
viscosity) and the physical stability of ethemulsion is affected by the degree to which
the emulsion is refined by reducing the globule size of the internal phase.
Manufacturing systems which use high-shear mixtures have more probability of
air entrapment and adversely affecting the physical and chemical stability. The
problem of undesirable aeration can be stopped by using vessels which can be
operated with the contents under a controlled vacuum. Emulsions are filtered to
remove the particles of raw materials used during processing, as these par ticles
can affect the product quality. The most efficient way to remove the undesirable
particles is to separately filter the oil and water phases before emulsification.
1.4.6. Formulation Aspects of Liquid Orals

The different formulation aspects of solutions, s uspensions and emulsions are
given in tables 1.3, 1.4, and 1.5:
Table 1.3: Formulation Aspects of Solutions
Purposes Agents
Protecting the API Buffers, antioxidants, and preservatives.
Maintaining the appearance Colouring agents , stabilisers, co -solvents, and
antimicrobial preservatives.
Masking the unpleasant taste or odour Sweeteners and flavouring agents.
Table 1.4: Formulation Aspects of Suspensions
Purposes Agents
Facilitating the binding between API Wetting agents and salt formation ingredients.
and vehicle
Protecting the API Buffers, polymers, and antioxidants.
Maintaining the suspension appearance Colouring agents , suspending agent s, and
flocculating agents.
Table 1.5: Formulation Aspects of Emulsions
Purposes Agents
Particle size Solid and droplet particles.
Protecting the API Buffers, antioxidants, and polymers.
Maintaining the appearance Colouring agents , emulsifying agents,
penetration enhancers, and gelling agents.
1.4.7. Pilot Plant Scale Up Considerations for Semisolids

Pastes, ointments, gels, and creams have high viscosities. High viscosity makes
some characteristics of the scal e up of semisolid products more critical. For such
products, the mixing equipment should constantly move the semisolid mass from
the outside walls of the mixing equipment to the centre and from the bottom to
the top of the equipment. This is necessary for distributing the ingredients and for
fast and effective heat transfer to and from the product during the heating and
cooling stages.
* *
The power required to perform mixing changes greatly during the manufacturing
and depends directly on the changes in product viscosity. Motors used to run the
mixing system of semisolid manufacturing equipment should have a specific size
to handle the product even at the highest viscous stage. Most semisolid
equipment offer variable mixing speed for working with low- and high- viscosity
semisolid formulations. The processing stages like mixing of oil and water
phases during emulsification, component homogenisation, addition of active
ingredient, and product transfer are performed at predetermined temperatures.
The operatin g temperature range at which these operations are performed is
important for the final product quality.
Several cream formulations and gel products are shear -sensitive. Handling the se
products while transfer ring from the manufacturing equipment to holding times
or to the filling lines need that attention is given to the amount of shear the
products will go through. Variations in measured viscosity occur when viscous
products are pumped through long transfer lines or when filtered for removing
unwanted particles. For this, the relationship between shear stress and the
measured product viscosity should be known.
Transfer pumps for semisolid products should be capable of moving viscous

material without applying extreme shear and without incorporating air. Product
viscosity, product compatibility with the pump surfaces, preferred pumping rate,
and pumping pressure should be considered while selecting the size and type o f
pump for a specific operation.
The most serious processing steps which need to be properly evaluated during the
manufacture of a cream are the emulsification of the two phases and the
dispersion of any suspended active ingredient . Pharmaceutical equipment used
for homogenising the emulsion and dispersing of suspended active ingredients
include high-shear mixers, homogenisers, and colloid mills.
1.5. SUPAC (SCALE UP AND POST

APPROVAL CHANGES) GUIDELINES
1.5.1. Introduction
Scale Up and Post Approval Changes (SUPAC) involve the scale up process es
and the changes made after approval in the composition, manufacturing process,
manufacturing equipment, and changes of site. Changes are made in the
manufacturing process and chemistry of a drug product after approval.
Based on the predicted or unpredicted needs, there can be variations in the raw
materials, process, equipment or manufacturing site, and batch siz e that
eventually affect the drug or finished product quality. Hence, there is a
requirement to foresee and evaluate the impact of any alteration on the drug or
finished product quality. The intensity of adverse effect produced by a particular
change depends on the type of dosage form.
* *
1.5.2. Purpose of Guidance

SUPAC guidelines provide instructions to sponsors of New Drug Applications
(NDAs), Abbreviated New Drug Applications (ANDAs), and Abbreviated Antibiotic
Applications(AADAs) who wantto change the following,after post approval:
1) The components or composition,
2) The manufacture site,
3) The scale up or scale down of manufacture, and
4) The manufacturingprocess & equipmentof an immediate release oral formulation.
SUPAC guidelines or guidance defines the following (figure 1.4):
1) Levels of change,
2) Recommended chemistry, manufacturing, and control tests for each level of
change,
3) In vitro dissolution tests and/or in vivo bioequivalence tests for each level of
change, and
4) Documentation supporting each level of change.
Thus, this guidance brings forward the application information which should be
given to CDER for ensuring constant product quality and performance features of
an immediate release solid oral dose formulation for stated post approval changes.
Level of 1) Minor change

changes 2) Moderate change
3) Major change
1) Application/Compendial Tests
Tests 2) In vitro Dissolution/Release
3) In vivo
1) Annual Report
Filling 2) Changes Being Effected Supplement
3) Prior Approval Supplement
Figure 1.4: SUPAC Guidelines
1.5.3. Site Changes

Site changes include changes in location of the manufacturing site for company
owned and contract manufacturing facilities; however, any alterations in scale up
process, manufacturing process and/or equipment , or in components or
composition are not included . New manufacturing locations should have an
acceptable Current Good Manufacturing Practice (CGMP) inspection.
1.5.3.1. Level 1 Changes

Level 1 changes include site changes in a single facility where identical
equipment, Standard Operating Procedures (SOP s), environmental conditions
(temperature and humidity) and controls, and personnel common to both
manufacturing sites are utilised, and where manufacturing batch records are not
changed, excluding administrative information and the facility location. Common
is defined as the employees wor king i n the campus and having acceptable
experience in the manufacturing process.
* *
Test Documentation
1) Chemistry Documentation: None beyond application/compendial release
requirements.
2) Dissolution Documentation: None beyond application/compendial release
requirements.
3) In Vivo Bioequivalence Documentation: None.
Filing Documentation: Annual report.

Level 2 changes include site changes in an adjoining campus or between facilities
in adjacent city blocks, where the identical equipment, SOPs, environmental
conditions (temperature and humidity) and controls, and personnel common to
both manufacturing sites are utilised, and where manufacturing batch records are
not changed, excluding administrative information and the facility location.
Test Documentation
1) Chemistry Documentation: Location of new site and updated batch records.
None beyond application/compendial release requirements.
2) Stability Testing: One batch on long -term stability data reported in annual
report.
3) Dissolution Docume ntation: None beyond application /compendial release
requirements.
Filing Documentation: Changes being effected supplement; annual report (long
term stability test data).

Level 3 changes include a change in manufactu ring site to a different campus,
which is the one that is not on the same original adjoining site or in which the
services are not in adjacent city blocks. To be included in a level 3 change, the
same equipment, SOPs, and environmental conditions and controls should be
utilised in the manufacturing process at the new site, and the manufacturing batch
records should not be changed, excluding the administrative information,
location, and language translation.
Test Documentation
1) Chemistry Documentation: Location of new site and updated batch records.
Application/compendial release requirements.
2) Stability Testing: Significant body of data available; o ne batch with three
months accelerated stability data reported in supplement; one batch on long -
term stability data reported in annual report. Signifi cant body of data not
available; u p to three batche s with three months accelerated stability data
reported in supplement; up to three batches on long -term stability data
reported in annual report.
* *
3) Dissolution Documentation Case B: Multipoint dissolution profile should

be performed in the application/compendia medium at 15, 30, 45, 60 and 120
minutes or until an asymptote is reached. The dissolution profile of the drug
product at the current and proposed site should be similar.
1.5.4. Changes in Batch Size (Scale Up or Scale Down)

Additional information is required to be submitted in the application for post -
approval changes in the batch size from the pivotal/pilot scale biobatch material
to larger or smaller production batches. Scale down below 1,00,000 dosage units
does not come under this guidance . All scale up changes should be suitably
validated and inspected by suitable agency personnel (if need so).

Definition of Level: Changes in batch size up to and including a factor of 10
times the size of the pilot/biobatch, where:
1) The equipment used for producing the test batch is of identica l design
working principles.
2) The batch is manufactured by following the CGMP guidelines.
3) The same SOPs, controls, and formulation and manufa cturing methods are
used on test batch as well as on full-scale production batch.
Test Documentation
1) Chemistry Documentation : Application/compendial release requirements.
Notification of change and submission of updated batch records in ann ual
report.
2) Stability Testing: One batch on long-term stability reported in annual report.
3) Dissolution Documentation : None beyond application/compendial release
requirements.
4) In Vivo Bioequivalence: None.
Filing Documentation: Annual report (long-term stability data).

Definition of Level: Changes in batch size beyond a factor of 10 times the size
of the pilot/biobatch, where:
i) The equipment used for producing test batch is of identical design and
working principles.
ii) The batch is manufactured by following CGMP guidelines.
iii) The same SOPs, controls, and formulation and manufacturing methods are
used on test batch as well as on full-scale production batch.
Test Documentation
Notification of change and submission of updated batch records.
* *
2) Stability Testing: One batch with three months accelerated stability data and
one batch on long-term stability.
3) Dissolution Documentation: Case B testing.
4) In Vivo Bioequivalence: None.
Filing Documentation: Changes being effected supplement; annual report (long-
term stability data).
1.5.5. Manufacturing
The equipment used in the manufacturing process as well as the process may be
influenced by the manufacturing changes.
1.5.5.1. Equipment
Level 1 Changes
This category involves:
1) Changes from non-automated or non -mechanical equipment to automated or
mechanical equipment to transfer constituents, and
2) Changes to alternative equipment of similar design and working principles of
similar or dissimilar capability.
Test Documentation
1) Chemistry Documentation: Application/compendial release requirements.
2) Stability Testing: One batch on long-term stability.
3) Dissolution Documentation : None beyond application/compendial release
requirements.
4) In Vivo Bioequivalence Documentation: None
Filing Documentation: Annual report (long-term stability data).
Level 2 Changes
This category involves changes in equipment to a different design and working
principles.
Test Documentation
1) Chemistry Documen tation: Application/compendial release requirements.
2) Stability Testing: Significant body of data available ; o ne batch with three
months accelerated stability data reported in supplement; one b atch on long-
term stability data reported in annual report. Signifi cant body of data not
available; u p to three batches with three months accelerated stability data
3) Dissolution Documentation: Case C dissolution profile.
Filing Documentation: Prior approval supplement with justification for change;
annual report (long-term stability data).
* *
1.5.5.2. Process
Level 1 Changes
This category involves process changes comprising of changes in mixing time
and speed of operation within application/validation ranges.
Test Documentation
1) Chemistry Documentation : None beyond application/compendial release
requirements.
2) Dissolution Do cumentation: None beyond application/compendial release
requirements.
Filing Documentation: Annual report
Level 2 Changes
This category involves process changes comprising of changes in mixing time
and speed of operation beyond application/validation ranges.
Test Documentation
2) Stability Testing: One batch on long-term stability.
3) Dissolution Documentation: Case B dissolution profile.
Filing Documentation: Changes being affected supplement; annual report (long-
term stability data).
Level 3 Changes
This categoryinvolves changes in the type of manufacturingprocess for the product,
like an alteration from wet granulation to direct compression of dry powder.
Test Documentation
2) Stability Testing: Significant body of data available; on e batch with three
months accelerated stability data reported in supplement; one batch on long -
term stability data reported in annual report. Significant body of data not
available; u p to three batches with three months accelerated stability data
3) Dissolution Documentation: Case B dissolution.
4) In Vivo Bioequivalence Documentation: The bioequivalence study may be
waived if a suitable in vivo/in vitro correlation has been verified.
Filing Documentation : Prior approval supplement with justification; annual
report (long-term stability data).
* *
1.5.6. In-vitro Dissolution

Among several methods investigated for dissolution profile comparison, f 2 is the
simplest. Moore and Flanner projected a model -independent mathematical
approach to compare the dissolution profile using f1 and f2 factors.
f1  [ t 1 n R t  Tt ] /[ t 1nR t ]100
f2  50  log[1  (1/ n)t 1n(R t  Tt )2]  0.5 100
Where, R t and T t = Cumulative percentage dis solved at each of the selected n
time points of the reference and test product, respectively.
f1 factor value = 0 to 50 (Differential factor)
f2 factor value = 50 to 100 (Similarity factor)
1.5.7. In-vivo Bioequivalence Studies

In-vivo bioequivalence study is a guide and the design of actual study may change
based on the drug and dosage form. The overall summary of a study is given below:
1) Objective: To compare the rate and amount of drug absorption for which the
manufacture has been altered, as defined in this guidance, to the drug product
manufactured before the alteration.
2) Design: The study design should be a single dose, two -treatment two-period
crossover with sufficient washout period between the two phases of the
study. Equal numbers of subjects should be randomly allotted to every two
dosing sequences.
3) Selection of Subjects: The number of subjects involved in the
bioequivalence study should be statistically determined to justify the
intrasubject variations and to achieve the current bioequivalence interval.
4) Procedure: The following two treatments should be given to every subject:
Treatment 1: Product manufactured with the proposed change.
Treatment 2: Product manufactured before the proposed change.
After an overnight fast of minimum 10 hours, the subjects should get any of
the two treatments with 240ml water. Food should not be given till 4 hours
after dosing. After an hour of dosing, water can be given. Standardised meals
should be given to the subjects beginning at 4 hours during the study.
5) Restrictions: Before and during each study phase, water may be given as
necessary excluding the 1 hour period before and after drug administration. The
subject should be given standardised meals and beverages at specific times. No
alcohol, xanthine- or caffeine-containing foods and beverages should be given
for 2 days before every study and till the last blood sample is collected.
6) Blood Sampling: Blood samples should be taken in appropriate volume for
analysing the parent drug and its active metabolites(s)
. The sampling time should
be selected in way that it should find out the Cmax and tmax during the absorption
period. Sampling should be done for a minimum three terminal elimination half -
lives for parent drug and active metabolite(s). Whole blood, plasma or serum
(whichever is suitable for the analytes ) should be harvested and samples
*
should be frozen at –20C or –70°C for maintaining sample stability. *
7) Analytical Method: The chosen assay method should confirm the

specificity, interday and intraday precision, linearity of standard curves,
accuracy, sensitivity, recovery, and stability of the samples under the storage
and handling conditions related to the analytical procedure.
8) Pharmacokinetic Analysis: AUC0-t, AUC0-infinity, Cmax, tmax, K el, and t 1/2
should be determined using the plasma drug concentration-time data.
9) Statistical Analysis: Study of variation suitable for a crossover design on the
pharmacokinetic parameters using the linear model methods of SAS or a
similar program should be carried out, with analysis of period, sequence and
effects of treatment. The 90% confidence intervals for evaluations of the
difference between the test and reference least squares means for the
pharmacokinetic parameters (AUQ0-t, AUC o-infinity, C max, and tmax) should be
calculated using the two one-sided t-test procedure.
1.6. PLATFORM TECHNOLOGY
1.6.1. Introduction
A platform is a group of technologies that acts as a base for the development of
other applications, methods , or tech nologies. Platform technologies are a
beneficial tool for improving the productivity and quality of drug product
development. The basic thought is that a platform , along with a risk -based
approach, is the most efficient method for leveraging previous understanding for
a new molecule.
Moreover, suc h a platform allows a constant development through addition of
data for each new molecule produced using this approach, thereby increasing the
robustness of the platform. Following a re some commonly used platform
technologies:
1) Nanotechnology, 2) Microsphere technology,
3) Liposomal technology, 4) Hot melt extrusion,
5) Sustained release formulations technology,
6) Orally disintegrating formulations technology,
7) Inhalation technology, and 8) Sprinklers.
1.6.2. Nanotechnology
Nanotechnology is utilised for developing targeted therapies for diseases, such as
cancer. It uses nano-sized particles for delivering d rugs to particular cell types ,
like cancer cells. Th e particles are made such that they attract to the diseased
cells and ensure their direct treatment. The objective is to avoid undesired
toxicity because of broad distribution, to increase patient compliance , and to
generate positive clinical outcomes.
1.6.3. Microsphere Technology

Microsphere technology is used for developing distinguished formulations for
targeted delivery. This technology is utilised for a site-specific action to eradicate
problems of repeated injections and to reduce toxic side effects.
* *
1.6.4. Liposomal Technology

Liposomal technology is also used for improving drug delivery. Liposomes provide
an exceptional chance to target specific drugs, and thisenhances the pharmacokinetic
parameters andpharmacological effects, and decreases the toxicity of drugs.
1.6.5. Hot Melt Extrusion

Hot melt extrusion technology is used for producing solid molecular dispersions
which are better than solvent-based processes, like spray drying and co-precipitation.
This technologyis used forattaining sustained, modified and targeted drug delivery.
1.6.6. Sustained Release Formulations Technology

For delivering o nce-daily tablets and for developing sustained r elease
formulations technology, an advanced technology of Osmotic -controlled Release
Oral delivery System (OROS) is used. This technology utilises osmotic pressure
for de livering the drug in multiple therapeutic areas. It results in better safety
profile, stable drug concentrations, uniform drug effects , and low dosing
frequency. OROS technology allows the use of an effective starting dose and
abolishes the requirement for dose titration. This enables control of symptom s
much earlier than the immediate-release tablets.
1.6.7. Orally Disintegrating Formulations Technology

This technology is utilised for ma nufacturing orally disintegrating tablets which
disintegrate on placing over the tongue and thus show faster onset of action.
1.6.8. Inhalation Technology

Inhalation technology includes:
1) Metered-dose inhalers,
2) Dry powder inhalers,
3) Autohalers, and
4) Nasal sprays.
1.6.9. Sprinklers
Sprinklers are primarily used for paediatric patients. They are sprinkled over a
child’s food for making the drug palatable. This formulation remo ves the
problems related to compliance, which is a key challenge in paediatric therapy.
1.7. SUMMARY
The details given in the chapter can be summarised as follows:
1) Pilot plant is a part of pharmaceutical industry in which a lab scale formula
is converted to a feasible product by developing a liable practical method for
manufacture.
2) Pilot Plant Scale Up Technique can also be defined as a technique that
involves development of a practical procedure for manufacturing dosage forms
*
that may result into transformation of lab scale process into a viable product. *
3) A pilot plant organisation needs a team of personnel, each having a good

theoretical and practical knowledge of pharmacy, good communication skills
and designing ability to merge new processes with the existing facility.
4) The pilot plant operation approves and authenticates the active and excipient
raw materials used in formulating pharmaceutical products.
5) Understanding the outcome of key processes such as mixing speed, time, rate
of addition of granules, granulating agent, solution of drugs, solvents, heating
and cooling rates, etc., is a major requirement for optimising and verifying
the quality of in-process and finished product.
6) The batch record steps should include specification for mixing time,
addition rates, mixing speed, temperature, heating and cooling rates.
7) The tablet manufacturing area should be present on the ground floor to
facilitate the handling and transportation of supplies. Fluorescent lighting
fittings should be the ceiling flush type.
8) The operating areas should have floor drains for simplifying cleaning. The
area should be air-conditioned and humidity controlled.
9) The dry blending process utilises a binary cohesive powder mixture containing
particles of two different sizes; the finer particle s stick to the surface of the
coarse particles. This mixture is also known asinteractive mixture.
10) The process of granulation involves agglomeration of smaller particles into
larger ones, in which the original particles can still be recognised.
11) The drying process will be unproductive if the granulation bed is too deep
or too dense, or if the soluble dyes (present in granules) migrate to the
surface.
12) Direct compression process involves direct compression of powder
mixture of API and other excipients into tablets.
13) Slugging process is utilised to produce granules for moisture- and heat -
sensitive APIs, and when APIs exhibit sufficient binding or cohesive
properties.
14) The method of slugging is also known as dry granulation , pre-
compression, or double compression.
15) New manufacturing locations should have an acceptable Current Good
Manufacturing Practice (CGMP) inspection.
16) Levels are changes in batch size up to and including a factor of 10 times the
size of the pilot/bio batch.
17) Moore and Flanner projected a model -independent mathematical approach
to compare the dissolution profile using f1 and f2 factors.
18) In vivo bioequivalence study is a guide and the design of actual study may
change based on the drug and dosage form.
19) AUC0-t, AUC0-infinity, Cmax, T max, K el and t 1/2 should be determined using the
plasma drug concentration-time data.
20) Nanotechnology is utilised for developing targeted therapies for diseases,
*
such as cancer. *
21) Microsphere technology is used for developing distinguished formulations

for targeted delivery.
22) Liposomal technology is also used for improving drug delivery.
23) Hot melt extrusion technology is used for producing solid molecular
dispersions which are better than solvent -based processes, like spray drying
and co-precipitation.
24) For delivering once -daily tablets and for developing sustained release
formulations technology, an advanced technology of Osmotic-controlled
Release Oral Delivery System (OROS) is used.
25) Sprinklers formulation removes the problem related to compliance, which is
a key challenge in paediatric therapy.
1.8. EXERCISE
1.8.1. Very Short Answer Type Questions

1) Define pilot plant scale up technique.
2) Define dry blending method.
3) What is wet granulation?
4) Enlist steps of liquid manufacturing process.
5) Write full form of SUPAC and ANDAs.
6) Give the test documentation of level 1 site changes.
7) Mention the test documentation of level 2 site changes.
8) Enumerate types of platform technologies.
1.8.2. Short Answer Type Questions

1) Give significance of pilot plant studies.
2) Write a note on space requirement for pilot plant scale up.
3) Enlist items which should be a part of GMP for scale up of a new product.
4) Enlist the different parameters and methods utilised for characterising granules.
5) Discuss about direct compression.
6) Write an illustrative note on granulation.
1.8.3. Long Answer Type Questions

1) What are the objective and steps involved in scale up process?
2) Give any seven general considerations for pilot plant scale up.
3) Briefly discuss about pilot plant scale up consideration for solids.
4) Mention the formulations aspects of liquid orals.
5) Write a detail note on levels of site changes and batch size changes.
6) Write an illustrative note on in-vitro dissolution and in-vivo bioequivalence studies.
7) Enumerate different type of platform technology and explain it.
* *
CHAPTER Technology Development

2 and Transfer
2.1. TECHNOLOGY DEVELOPMENT AND

TRANSFER
2.1.1. Introduction
The process of technology transfer involves transfer of scientific information
among different organisations to promote their development and enhance the
availability of novel products (like medicines, educat ional tool, electronic
devices, safety equipment, and health services) to the public. Different
organisations dealing in business, science, engineering, law, and government are
interconnected through technology transfer.
Technology transfer plays an important role in the drug discovery and

development of novel medicinal products. Technology transfer is necessary for
explaining essential information and transferring it from R&D (Research &
Development) to PDL (Product Development Laboratory).
It is also helpful in the development of an existing product to the production for

commercialisation. Technology transfer provides an efficient process, maintains
product quality, helps in attaining standardised process, and al so facilitates time
and cost effective production. Therefore, it is extremely helpful in developing
dosage forms.
2.1.2. Need for Technology Transfer

The technology transfer in pharmaceutical industry refers to the processes
required for successful progress from drug discovery to product
development, to clinical trials to full scale commercialisation . It is also
referred to as the process by which a technology developer makes its
technology available to commercial partner to promote its use.
The preparation of dosage form in pharmaceutical industry needs improvement in

several stages. For example , a 0.5 -2kg batch produced by a small -scale
laboratory can be improved up to 5 -10kg batch and then to 20 -100kg on a pilot
scale. Production level lies in the range of 200-1000kg or greater.
Usually, scale -up involves transferring the technology and information gained
during the small scale development of products and processes. Good
communication plays an important role in successful transfer of formulation and
process. Every researcher or technology developer should ensure the availability
of the technology to another person to promote its development in different fields
* *
Technology Development and Transfer (Chapter 2) 39
of applications, and also allow its exploitation by organisations having better

manufacturing, marketing, and commercial capabilities. The commercialisation
of a pharmaceutical product in pharmaceutical industry is usually attained
through transferring technology to other departments and organisations.
2.1.3. Technology Transfer Process

Technology transfer pla ys an important role in drug discovery and development
of novel medicinal products. The financial conditions are responsible for
deciding the flow of product transfer between the manufacturing sites. The data
collection, data review, regulatory impact with particular emphasis on any
change approvals, analytical validation, pilot or full -scale process batch, and
stability set down (if required) are some of the stages involved in technology
transfer. Figure 2.1 presents the different technology transfer process.
QA
Formulation Manufacturing
Development Production
Technology
Analytical Transfer
QC
Development Process
Department
Packing
Packing Production
Development
Engineering
Department
Figure 2.1: Technology Transfer Flow Chart
2.2. WHO GUIDELINES FOR TECHNOLOGY

TRANSFER (TT)
2.2.1. Introduction
The WHO defined transfer of technology as “ a procedure that controls the
transfer of any process together with its documentation and professional
expertise between development a nd manufacture or between manufacture
sites”.
The WHO guiding principles on technology transfer act as a framework that can
be used in an adjustable manner instead of a strict rigid guidance. Focus has been
kept on the quality, in accordance with WHO’s instruction.
Technology transfer does not involve a single way. Collaboration of many

individuals is desired for the conversion of pharmaceutical prototypes (like
tablet, a transdermal patch, a topical ointment, or an injectable) into a successful
product. The problems or insights arising at the production level can give rise to
* *
new ideas that may contribute to the further basic advancement of process.
Therefore, the typical vision of a flow from basic to applied technology is
occasionally considered as a gr eat generalisation. The competitiveness and
development in some sectors occur because of the close connections formed
among the basic researchers, manufacturing experts, and marketing personnel.
Figure 2.2 presents the different stages involved in process technology.
Research and Analytical Development
Development and Validation
Product Development Quality Assurance and

Laboratory Quality Control
Setting Parameters Production and

and Documentation Commercialisation
Figure 2.2: Representation of Technology Transfer Process
2.2.2. Terminology
The following definitions apply to the terms used in the WHO guidelines for
technology transfer and may have different meanings in other perspectives:
1) Acceptance Criteria : Assessable terms under which the outcome o f a test
will be acceptable.
2) Active Pharmaceutical Ingredient (API) : It is a substance or a mixture of
substances that is used for manufacturing a pharmaceutical dosage form , or
that which when used acts as an active ingredient of that pharmaceutical
dosage form . The se substances provide pharmacological activity or other
direct effect in the diagnosis, mitigation, cure, treatment, or prevention of
disease or affect the body structure and function.
3) Bracketing: It is an experimental d esign for testing the lim its of dosage
strength. The design presumes that the limits will represent all the samples
within the limits.
4) Change Control (C/C) : It is a system through which the qualified
representatives of suitable disciplines review the suggested or actual changes
that may affect a validated status. The intention is to establish the necessity
of an action that would confirm that the system is in a validated state.
5) Commissioning: It is the process of setting up, adjusting, and testing of
equipment or a system to make s ure that it fulfils every requirement, as
mentioned in the user requirement specification, and capacities as mentioned
by the designer or developer. Commissioning is performed prior to
qualification and validation.
* *
6) Control Strategy : It is an intended set of controls, obtained from current

product and knowledge of process which guarantees process performance
and product quality. The controls comprise of parameters and attributes
associated to materials and components related to drug substances and drug
product materials and components, in -process controls , finished product
specifications, facility and equipment operating conditions, and the related
methods and regularity of control and monitoring.
7) Corrective Action (C/A) : It is an action required to be tak en when the
outcomes of monitoring at a critical control point shows a loss of control.
8) Critical: It is the capability to affect product quality or performance in a
substantial way.
9) Critical Control Point (CCP) : It is a point at which control can be applie d
and is important for avoiding or eliminating a pharmaceutical quality hazard
or for reducing it to an acceptable level.
10) Design Qualification (DQ) : It is a d ocumented evidence to show that the
premises, utilities, supporting systems, equipment , and processes have been
developed in compliance with the requirements of GMP.
11) Design Space: It is a multidimensional combination and interaction of input
variables (e.g., material attributes) and process parameters which have been
established to guarantee the quality.
12) Drug Master File (DMF) : It is an elaborate information related to a
particular facility, process or product submitted to the medicines regulatory
authority, proposed for incorporation into the application for marketing
authorisation.
13) Finished Pharmaceut ical Product (FPP) : It is a product which has gone
through every production stage, including packaging in its last container and
labelling. An FPP may contain one or multiple APIs.
14) Gap Analysis : It is the i dentification of critical components of a process
which are present at the SU but not present at the RU.
15) Good Manufacturing Practices (GMP) : It is that part of quality assurance
that confirms that pharmaceutical products are constantly produced and
controlled to the quality standards suitable to their pro posed use and as
needed by the marketing authorisation.
16) In-Process Control (IPC) : It involves the c hecks performed during
production for monitoring and adjusting the process to make sure that the
product conforms to its specifications. The environment or equipment control
can also be considered as a part of IPC.
17) Installation Qualification (IQ): It involves the tests that make sure that the
installations (like machines, measuring devices, utilities , and manufacturing
areas) utilised in a manufacturing procedure are suitably chosen and properly
installed, and are working according to the recognised specifications.
18) Intercompany Transfer: It is a t echnology transfer within sites of different
*
companies. *
19) Intracompany Transfer: It is a t echnology transfer within sites of the same

group of companies.
20) Operational Qualification (OQ) : It is a d ocumented confirmation that the
system or sub-system performs as anticipatedthrough all the operating ranges.
21) Performance Qualification (PQ) : It is a d ocumented confirmation that the
equipment or system works steadily and provides reproducibility within the
established specifications and parameters for extended periods.
22) Process Validation: It is a documented evidence that offers a high amount
of assurance that a particular p rocedure will regularly result in a product that
fulfils the predetermined specifications and quality aspects.
23) Qualification: It is the act of verifying and documenting that any premises,
systems and equipment are installed appropriately, working correctly, and are
giving desired outcomes. Qualification is the initial stage of validation, but
the specific qualification stages alone do not create process validation.
24) Qualification Batches : These are the batches produced by the RU for
showing its capability of reproducing the product.
25) Quality Assurance (QA) : It is a broad concept that covers all matters that
specifically or collectively affect the product quality. It is the entirety of the
arrangements made with the aim to confirm that the quality of
pharmaceutical products is as desired for their proposed use.
26) Quality Control (QC): It includes all the actions taken (including the setting
of specifications, sampling, testing , and analytical clearance ) to confirm that
the starting materials, intermediates, pack aging materials , and finished
pharmaceutical products meet all the established specifications for identity,
strength, purity, and other features.
27) Quality Planning : It is a part of quality management that focuses on
establishing quality objectives and impor tant operational processes and
associated resources to accomplish the quality objectives.
28) Quality Policy: It involves all the purposes and direction of an organisation
associated to quality as officially expressed by senior management.
29) Quality Risk Manage ment (QRM): It is a stepwise process for assessing,
controlling, communicatin g, and reviewing the risks to the quality of
pharmaceutical product through the product shelf-life.
30) Receiving Unit (RU) : It involves the disciplines of an organisation where a
designated product, process or procedure is anticipated to be transferred.
31) Sending Unit (SU): It involves the disciplines of an organisation from where
a designated product, process or procedure is anticipated to be transferred.
32) Spiking: It is the addition of a known quantity of a compound t o a standard
sample or placebo for ensuring the performance of an analytical procedure.
33) Standard Operating Procedure (SOP) : It is an approved written process
giving directions to perform operations not specific to a partic ular product or
material (e.g., equipment operation, maintenance and cleaning, sampling and
* *
inspection, validation, cleaning of premises and environmental control).

Some specific SOPs may be used for complementing product-specific master
and batch production documentation.
34) Technology Transfer Report : It is a documented outline of a specific
technology transfer project mentioning all the procedures, acceptance criteria,
results, and conclusions. Any deviationshould be discussed and justified.
35) Validation: It is the act of proving and documenting that any process,
method or procedure leads to anticipated results.
36) Validation Master Plan (VMP): It is a high-level document which creates a
validation plan for the whole project and reviews the manufacturer’s overa ll
philosophy and approach, to be employed for establishing performance
competence. It provides information on the manufacturer’s validation work
programme and describes details of and timescales for the validation work to
be performed, including an account of the responsibilities of those executing
the plan.
37) Validation Protocol (or Plan) (VP): It is a document providing the details
about the activities to be carried out in a validation, including the acceptance
requirement for the approval of a manufacturing process.
38) Validation Report (VR) : It is a document which has the assembled and
summarised records, results and evaluation of a completed validation programme.
It may also contain suggestions for improving the procedures and equipment.
2.2.3. Technology Transfer Protocol

The technology transfer protocol is written by the originating lab with review and
approval by both the labs . Sometimes, the receiving labs have their own SOP
which should be followed , especially if a contra ct manufacturer/laboratory is
involved. Since the contractor deals with multiple customers, they may have their
own nee ds which are less adjustable tha n the originating lab. In cases when a
method is being transferred from an API supplier, the manufacturin g site
laboratory may write a protocol in which the transfer will depend on repetition of
the method validation or testing multiple batches and comparing the results
generated with the supplier’s Certificates of Analysis (COAs).
The sections in technology transfer protocol are described below:
1) Objective: It indicates the project involved in addition to the laboratories
involved in the technology transfer.
2) Scope: It defines the methods that will be transferred and the methods which
do not require transfer.
3) Materials, Methods and Equipment: It e nlists the batch numbers (which
will be used), reference standard lot number , and method references. Sample
age and uniformity is also described here. For example , if a product
degrades on stability, the protocol should consider this by having both labs
test equally aged products, e.g., the release results from the originating lab
should not be used and compared to 6 -month stability samples at the
receiving lab. Equipment should also be defined.
* *
4) Experimental Design: It d efines the procedure which will be followed

including the number of batches, analysts, replicates, instruments, and any
additional detail not given in the procedure but is important for the transfer ,
like sample and standard preparation, number of inje ctions for each, number
of samples that can be injected between standards, dissolution process, time
range for finishing all testing once the samples are received (like 30 days).
5) Data and Data Report Forms: The protocol should designate which lab
will file the raw data , and how and to whom the final results will be
conveyed. The originating lab receives the results on a data report form and
adds it to the transfer protocol or send s their Laboratory Information
Management System (LIMS) or results report and all required data.
6) Data Analysis and Acceptance Criteria: It specifies who will perform the
analysis and what acceptance criteria have been set. The criteria can be
totally different between the labs or statistically derived.
7) Deviations and Investigation s: It defines how deviations and investigation
will be handled in accordance with the lab’s SOP ( e.g., incorrect mobile
phase, weighing error, equipment malfunction, glassware breakage, etc.).
Examinations will infer a procedure problem, like standard not dissolving, or
system suitability criteria not fulfilled at the receiving lab in which case the
transfer team are involved to obtain a satisfactory solution.
2.2.4. Quality Risk Management (QRM)

Quality risk management is defined as “ a systematic process for the
identification, assessment and control of risks to the quality of
pharmaceutical products across the product lifecycle”.
Initiate Quality Risk Management
Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management Tools
Unacceptable
Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output/Result of the Quality Risk

Management Process
Risk Review
Review Events
Figure 2.3: Overview of a Typical Quality Risk Management Process

* *
2.2.4.1. Principles of Quality Risk Management

The two primary principles of QRM are:
1) Evaluation of quality risk should depend on scientific knowledge and related
to the protection of the patient, and
2) The amount of effort, formality and documentation of the QRM process
should be proportionate to the amount of risk.
Apart from these, the following principles are also a constituent of QRM procedure:
1) When applied, processes employing QRM procedures should be dynamic,
repetitious, and open to change, and
2) The ability for continuous improvement should be included in the QRM
process.
2.2.4.2. QRM Application in Pharmaceuticals

Some applications of QRM in pharmaceuticals are given below:
1) Training and Education : Training of import ant employees in industry,
MRAs, and universities in QRM principles and applications is crucial for its
efficient application. Industry employees should know about QRM, should
have skil ls required for applying it correctly, and should be sufficiently
resourced to allow effective practice of the QRM principles.
In developing the training programme for supporting QRM activities,
working guidelines and methods should be written to clear the strategy and
describe the work of everyone involved . Particular training should be given
as needed f or increasing awareness. The staff with the task to manage and
review risks should get formal training in the important processes.
2) Responsibilities: Effective implementation of QRM is based on proper
knowledge of duties for all the staff involved in QRM ac tivities. It is
suggested that a cross-functional matrix of allotted duties and responsibilities
is made and shared with all important personnel. For example , one may
think a bout using techniques , like RACI (Responsibility/Accountability/
Consulted/ Informed) grids to demonstrate the communication pathways more
thoroughly.
3) QRM Application during Product Development : Use of QRM processes
advances through several phases of product development. It is necessary to
detect risks in the initial phases of product development which may challenge
the accomplishments of the Quality Target Product Profile (QTPP). The first
QRM exercise should be done once QTPP has been described and
preformulation work has been completed on the drug. There should be major
gaps in knowle dge for this phase of a project. Hence, it will be necessary to
use the following risk tools which are suitable for such a condition:
i) Cause and effect diagrams (also known as Ishikawa or Fishbone diagrams),
ii) Flowcharts [e.g., Input-Process-Output (IPO)],
iii) Decision trees,
iv) Fault-tree analysis, and
v) Relationship matrices.
* *
As the product advances to next phases of development, a more informative

estimation of risks related to the API and FPP becomes a necessity. Risks
would cover problems related to stability, bioavailability, patient safety, and
any problems due to the manufacturing procedure ( for example, API form
conversion under specific processing conditions).
4) QRM Application during Validation and Qualification : Based on the
principles of QRM, the process v alidation contains the product life cycle.
Therefore, process validation activities should include the development and
estimation of data throughout the full-scale production procedure, which will
give a science-based declaration of regular delivery of best quality product.
An essential highlight is that the building of scientific affirmation starts early
in development. It is generated through rational design of experiments and
estimation of data during the product/process development through the large-
scale production phase during which the API and drug product Critical
Quality Attributes (CQAs) are well -known and controlled. In this case,
validation or conformance batches reinforce the science - or risk -based
choices made as product development progresses and should control all the
known sources of variability. Any unintended change s within a batch or
between batches should be examined using appropriate statistical tools, e.g.,
trend analysis, for checking process control.
When suitable the principles of QRM should also be employed for
qualification activities.
Qualification comprises of four stages [design qualification (DQ), installation
qualification (IQ), operational qualification (OQ) , and performance
qualification (PQ)]; but generally, only IQ, OQ, and PQ are done by the
manufacturers. QRM principles can be employed for narrowing the scope of
IQ, OQ and PQ to cover the important elements that may affect the quality of
product. It can also be employed for obtaining the best schedule for
maintenance, monitoring, calibration, and requalification.
5) QRM Application during Commercial Manufacturing : QRM principles
used as a procedure assists science -based and practical decisions when used
in commercial manufacturing. Generally, using QRM should not remove a
manufacturer’s responsibility of following regulatory expectations ( e.g.,
regulatory requirements, regulatory filings, inspection obligations, etc.). All
QRM activities should be organised in a manner that allows growth of risks
to the suitable management level in an organisation. Special attention should
be placed on the risk assessment and risk control of:
i) Product quality risks,
ii) Adverse impact on patient health based on product quality defects,
iii) Product supply interruption to patients,
iv) GMP and regulatory compliance risks,
v) Multisite risks,
vi) Multiproduct risks, and
vii) New facility and changes to existing facility,e.g. start-ups, new commercial
manufacturing processes, technology transfers , and product discontinuation.
* *
After finishing the risk assessment and ri sk control activities , the results
should be documented in a fresh or previous report or may be added as a part
of another documen t approved by suitable decision -makers ( e.g., site or
functional management, system owner, quality unit, etc.). A risk review is
necessary if new risks or changes to the prevailing risk levels are detected
through planned or unplanned events like routine operation, complaints,
changes, discrepancies/deviations, product returns, trends, data monitoring,
inspections/audits, changes in regulatory environment, etc.
Risk review may also include the estimation of:
i) Effectiveness of risk control activities and actions, and
ii) Changes in observed risk levels or the existing controls.
2.2.5. Development of Technology by R&D

This step involves the following:
1) Design of Procedure and Selection of Excipients by R&D: Based on the
features of the innovator product, R&D designs procedures and selects
excipients.
2) Identification of Specification and Quality by R&D: Whether or not the
product quality complie s with the specifications of the innovator product is
evaluated by R&D by performing stability studies for the innovator product
and the product to be manufactured.
2.2.6. Transfer from R&D to Production

Technology Transfer Dossier (TTD) is a document presented by R&D to
product development laboratory and includes the information (given below)
related to the formulation and drug product:
1) Master Formula Card (MFC): It provides information on the product
name, generic name, strength, MFC number, page number, effec tive date,
shelf-life, and market.
2) Master Packaging Card: It provides information regarding the type of
packaging, material used for packaging, stability profile of packaging, and
packaging shelf-life.
3) Master Formula: It provides information regarding the formulation order
and manufacturing instructions, which in turn gives idea of process order,
environmental conditions required, and manufacturing instructions for
dosage form development.
4) Specifications and Standard Test Procedure (STPs): These provide
information regarding the API and excipients profile, in -process parameters
and specifications, product release specification, and finished product details.
The RU should be capable of accommodating the desired production ability. It
should be established at the beginning whether the purpose is to perform single-
batch manufacture, continuous production, or campaigns. The level and depth of
detail to be transferred should be considered for assisting production and
additional process development and optimisatio n at the RU as anticipated in the
transfer project plan.
* *
The technical expertise, site technology , and site abilities for the RU should be
considered. It should be recognised by the SU of any process robustness issues so
that proper plans could be made at the RU. The SU and RU together should make
a protocol for transfer of important information associated to the process under
consideration from SU to the RU, including the development of a similar process
at the RU.
2.2.6.1. Process
The SU should give information to the RU on safety, health and environmental
issues related to the manufacturing processes to be transferred, and the
suggestions, e.g., requirement of gowning or protective clothing.
The SU should give information to the RU on present processing and tes ting,
including:
1) An explanation of facility requirements and equipment,
2) Data on starting materials, applicable MSDS , and storage needs for raw
materials and finished products,
3) An explanation of manufacturing steps (description and process maps or flow
charts, and or master batch records), qualification of in processing hold times
and situations, order and procedure of raw material addition and bulk
transfers within processing phases,
4) An explanation of analytical methods,
5) Recognition and verification of con trol strategy [e.g., recognition of
important performance aspects for particular dosage forms, recognition of
process control points, product quality aspects and qualification of important
processing parameter ranges, Statistical Process Control (SPC) charts],
6) Design space, in circumstances where it has been described,
7) Validation data, e.g., validation plans and reports,
8) Annual product quality reviews,
9) Stability information,
10) An approved group of protocols and operation guidelines for manufacturing,
and
11) Environmental conditions or any particular obligation required for the facility
or equipment based on the nature of the product to be transferred.
During transfer process , the RU should recognise any variations in facilities,
systems and abilities , and communicate with the SU about these variations to
know the potential influence on the capability to run the process to achieve good
product quality. Variations should be known and addressed to ensure equal
product quality. Depending on the information obtained from the SU, the RU
consider its own ability to manufacture and pack the product to the desired
standards and create important plant operating methods and documentation
before initiating production. Process development at the RU should address the
following tasks:
1) Comparisonand assessing suitability and qualific ation of facility and equipment,
2) Explanation (description or process maps or flow charts) of manufacturing
procedure and flow of personnel and materials at the RU,
* *
3) Determining the important phases in manufacture, such as hold times,

endpoints, sampling points, and sampling techniques,
4) Writing and authorising SOPs for all production operations ( e.g., dispensing,
granulation or blending or solution preparation, tablet compression, tablet
coating, encapsulation, liquid filling, primary and secondary packaging , and
in-process quality control), cleaning, packaging, testing, and storage,
5) Estimation of stability information, and obtaining site -specific stability
information, and
6) Abiding by the regulatory requirements to make any change s in terms of
batch size.
2.2.6.2. Packaging
Data on packaging to be transferred from the SU to the RU contains
specifications for an appropriate container or closure system, and also any
important supplementary data on packaging, de sign, processing or labelling
requirements and tamper -proof and anti -counterfeiting measures required for
qualification of packaging components at the RU. For QC testing of packaging
components, specifications should be given for drawings, artwork , and material
(e.g., card, glass, or fibre board).
Depending on the data given, the RU should carry out a suitability study for
initial qu alification of packaging constituents . Packaging is thought to be
appropriate if it offers sufficient protection ( preventing drug degradation from
environmental conditions), safety (absence of unwanted substances released into
the product), compatibility (absence of interaction that may affect drug quality),
and performance (functionality concerning drug delivery).
2.2.6.3. Cleaning
During the manufacturing procedure, the APIs and pharmaceutical products can
get adulterated by other pharmaceutical products or APIs if the plant is
processing multiple products. To reduce the risk of contamination, cross-
contamination, operator exposure, and environmental effects, practicing cleaning
processes is important. Cleaning processes and their verification are site-specific.
For RU to state its cleaning approach, the SU should give data on cleaning at the
SU to reduce cross -contamination because of residues from the earlier
manufacturing stages, operator exposure, and environmental impact, such as:
1) Information on solubility of active ingredients, excipients, and vehicles,
2) Minimum therapeutic doses of active ingredients,
3) Therapeutic category and toxicological assessment, and
4) Current cleaning procedures.
The following additional data should be given:
1) Cleaning validation reports (chemical and microbiological),
2) Information on cleaning agents used, including their efficacy, evidence that
they do not int erfere with analytical testing for residues of APIs and remove
residual cleaning agents, and
3) Recovery studies to validate the sampling method.
* *
Prior to the transfer, the SU should give information on re strictions for product
residues and the justification for limit selection.
Depending on the data given by the SU, cleaning processes should be made at the
RU, considering the important features of starting materials ( e.g., potency,
toxicity, solubility, corrosiveness , and temperature sensitivity), manufac turing
equipment design and configuration, and residues of cleaning agents and product.
2.2.7. Granularity of Technology Transfer (TT) Process

Granularity of API, excipients, finished products, and packaging material s of
technology transfer procedure are discussed below.
2.2.7.1. Active Pharmaceutical Ingredient (API)

The SU should offer the RU with the open (applicant’s) part of the API Master
File (APIMF) or Drug Master File (DMF) or Acti ve Substance Master File
(ASMF), and any important supplement data on a n API suitable for
manufacturing pharmaceutical product. Given below are t he examples of the
data which may be provided; but the data required in every particular case should
be evaluated using the QRM principles:
1) Manufacturer and related supply chain,
2) Stage of the API to be transferred,
3) Flow chart of synthesis pathway, summarising the process, including entry
points for raw materials, important steps, process controls and intermediates,
4) Definitive physical form of the API (including photomicrographs and other
important information) and any polymorphic and solvate forms,
5) Solubility profile,
6) If important, pH in solution,
7) Partition coefficient and its determination procedure,
8) Intrinsic dissolution rate and its determination procedure,
9) Particle size and distribution and its determination procedure,
10) Bulk physical characteristics, along with information on bulk and tap density,
surface area and porosity,
11) Water content and determination of hygroscopicity, along with water activity
information and special handling requirements,
12) Microbiological considerations, such as sterility, bacterial endotoxins , and
bioburden levels where the API assists microbiological growth,
13) In agreement with regional, national or internatio nal Pharmacopoeial
requirements, and
14) Specifications and validation for release and end-of-life limits.
2.2.7.2. Excipients
The excipients to be used influence the final product. Their specifications and
important functional featuresshould be made available by the SU for transfer to the
RU. Given below are the examples of the data which may be provided; but the data
required in every particular case should be evaluated using the QRM principles:
1) Manufacturer and related supply chain,
* *
2) Explanation of functionality, with vali dation for addition of any anti oxidant,
preservative or any excipient,
3) Definitive form, specifically for solid and inhaled dosage forms,
4) Solubility profile, especially for inhaled and transdermal dosage forms,
5) Partition coefficient and its determination procedure (for transdermal dosage
forms),
6) Intrinsic dis solution rate and its determination procedure (for transdermal
dosage forms),
7) Particle size and distribution and its determination procedure (for solid,
inhaled and transdermal dosage forms),
8) Bulk physical characteristics, along with information on bulk and tap density,
surface area and porosity (for solid and inhaled dosage forms),
9) Compaction properties (for solid dosage forms),
10) Melting point range (for semi-solid or topical dosage forms),
11) The pH range (for parenteral, semi -solid or topical, liqui d and tra nsdermal
dosage forms),
12) Ionic strength (for parenteral dosage forms),
13) Specific density or gravity (for parenteral, semi -solid or topical, liqui d and
transdermal dosage forms),
14) Viscosity and /or viscoelasticity (for parenteral, semi -solid or topical, liqui d
and transdermal dosage forms),
15) Osmolarity (for parenteral dosage forms), and
16) Water content and determination of hygroscopicity, along with water activity
information and special handling requirements (for solid and inhaled dosage
forms).
2.2.7.3. Finished Products

The SU should give a thorough description of the product, its qualitative and
quantitative composition, physical description, manufacturing method, in-process
controls, control procedure and specifications, packaging constituents and
configurations, and safety and handling requirements.
The SU should offer data on the history of process development that may be
needed to allow the RU to make any additional development or process
enhancement after transfer. Such data may include the following:
1) Data on cli nical development, e.g., data on the rationale for the synthesis,
route and form selection, selection of technology, equipment, clinical tests,
and product composition.
2) Data on scale -up procedures, such as process optimisation, statistical
enhancement of i mportant process parameters, important quality
characteristics, pilot report, and or data on pilot -scale development activities
showing the number and disposition of batches manufactured.
3) Data or report on full-scale development activities, specifying the number
and disposition of batches manufactured , and deviation and change control
reports that directed to the present manufacturing procedure.
* *
4) The change history and causes, e.g., a change control record, signifying any
changes to the process or primary p ackaging or analytical methods as a part
of process enhancement or improvement.
5) Data on examination of problems and their results.
2.2.7.4. Packaging Materials

The transfer of packaging operations should comply with the same procedural
patterns as those of the pro duction transfer. Data on packaging to be transferred
from the SU to the RU include s specifications for an appropriate container or
closure system, and also any important supplementary data on design, packing,
processing or labelling requirements, tamper -proof and anti-counterfeit measures
required by the packaging components to qualify at RU.
Specifications should be given for drawings, artwork and material ( e.g., glass,
card or fibre board) for QC testing of packaging components.
Depending on the data given, the RU should conduct a suitability study for initial
qualification of the packaging components. Packaging is thought to be
appropriate if it offers sufficient protection (inhibiting drug degradation because
of environmental impacts), safety (absenc e of unwanted substances released into
the product), compatibility (absence of interaction probably influencing drug
quality), and performance (functionality concerning drug delivery).
2.2.8. Documentation
Technology transfer documentation contains information r egarding technology
transfer for transferring and transferred parties. Each and every step performed
from R&D to production, task assignments and responsibilities should be
documented carefully. The quality assurance department is responsible for
examining and approving the documents related to technology transfer processes.
The reports involved are:
1) Development Report: To have documented evidence is one of the crucial
goals for successful technology transfer. The R&D department is in -charge
of the docum entation of R&D report (a type of technical development file).
This file describes the basis for the quality design of drug substances, drug
specifications, and test methods. The development report needs to be
examined properly for its approval. This repor t also provides a raw data for
post-marketing technology transfer.
Information included in the development report is listed below:
i) Data involved in pharmaceutical development of new drug substances.
ii) Drugs produced at different stages from early development phase to final
application of approval.
iii) Information regarding raw materials and components used in drug
development process.
iv) Reason behind different dosage forms, formula designs, and design of
different manufacturing methods.
v) New changes employed in al ready existing processes and control
*
parameters. *
vi) Information regarding stability profile.

vii) Specifications and test methods for drug substances, intermediates, drug
products, raw materials, and components, along with valid requirement
range of important tests like contents impurities and dissolution.
viii) Reason behind the selection of test methods, reagents, and columns.
ix) Traceability of raw data.
2) Technology Transfer Plan: It is useful in defining items and contents of
technology to be transferred, and comple te procedures of individual transfer
and transfer schedules. It also establishes judgement criteria for transfer
completion. The transferring party is responsible for organising plan before
the execution of transfer process. The transferring party should f inalise an
agreement on its contents with the transferred party.
3) Report: After the co mpletion of technology transfer, a report is made by
selecting data as per the technology plan and ensuring whether or not the
predetermined judgement criterion is fulfilled. The technology transfer report
can be documented by both transferring and transferred parties who should
reach an agreement regarding its contents.
2.2.9. Premises
The SU should give data to the RU on t he layout, construction and qua lity of
buildings and se rvices [Heating, Ventilation and Air-Conditioning (HVAC),
relative humidity, power, water, temperature, an d compressed air] , which
influence the product, process, or procedure to be transferred.
The SU should give data on important health, safety and environmental issues:
1) Characteristic risks of the manufacturing methods ( e.g., reactive chemical
hazards, exposure limits, fire and explosion risks),
2) Health and safety necessities for reducing operator exposure ( e.g.,
atmospheric restraint of pharmaceutical dust),
3) Emergency planning concerns (e.g., in events of spillage, gas or dust release,
fire and firewater run-off), and
4) Recognition of waste streams and requirem ents for re -use, recycling and/ or
disposal.
2.2.10. Equipment
The SU should give a list of equipment, b rands and models used in the filling,
manufacture, packing and or control of the product, procedure to be transferred,
along with the prevailing qualification and confirmation documentation.
Important documentation may include:
1) Drawings,
2) Manuals,
3) Maintenance logs,
4) Calibration logs, and
5) Procedures ( e.g., regarding equipment set -up, operation, cleaning,
maintenance, calibration, and storage).
* *
The RU should assess the data given by the SU along with its own inventory list
with the qualification status (IQ, OQ , and PQ) of every equipment and system,
and simultaneously compare the equipment at the two sites in relation to their
functionality, models, and qualification status.
The RU should perform a gap analysis for identifying the necessities for
modification of prevailing equipment, procurement of new equipment, or an
alteration in the process, to allow the RU to replicate the process being
transferred. GMP requirements should be followed and intended production
volumes and batch sizes ( e.g., same, scale -up, or campaign) should be
contemplated. Factors to be compared are as follows:
1) Minimum and maximum capacity,
2) Construction material,
3) Critical operating parameters,
4) Critical equipment components ( e.g., filters, screens, and temperature/
pressure sensors),
5) Critical quality attribute, and
6) Range of intended use.
2.2.11. Qualification and Validation

The degree of qualification and or validation to be done should be estimated
based on the risk management principles. The two major principles of QRM are:
1) Estimation of the risk to quality should be done on the basis of scientific
knowledge and related to the protection of the patient, and
2) The amount of work, formality and documentation of the QRM process
should be proportionate with the level of risk.
Apart from these, the principles given below alsoform a part of the QRM approach:
1) The processes employing QRM procedures should be dynamic, iterative and
receptive to alterations, and
2) The abil ity for continuous enhancement should be embedded in the QRM
procedure.
Qualification and validation should be recorded.
2.2.12. Quality Control

The term quality control denotes the sum of all methods commenced for
ensuring the identity and quality of a specific pharmaceutical product. The se
methods may vary from the performance of simple che mical experiments that
estimate the identity and separation for the availability of a specific
pharmaceutical substance (thin layer chromatography, infrared spectroscopy,
etc.), to much complex necessities of pharmac opoeial monographs. Activities
spread to the site of quality control laboratories (good laborator y management
practices and models) for certificate of analysis and lists of laboratory equipment,
and an external estimation arrangement.
2.2.13. Analytical Method Transfer

Transfer of analytical methods should cover all the analytical tests needed for
showing compliance of the product to be transferred with the registered description.
* *
Analytical methods used for testing pharmaceutical products, packaging

components, cleaning (residue) samples, and starting materials, should be applied
at the testing laboratory , prior to the testing of samples for process validation
studies is done by the RU. Process validation samples may be tested at the SU,
RU, or a third laboratory.
A protocol describing the phases should b e prepared for tran sfer of analytical
methods. This analytical methods transfer protocolshould contain details of the aim,
scope and duties of the SU and the RU; a description of materials and methods; the
experimental design and acceptance conditions; do cumentation (with data to be
supplied with the results, and report forms to be employed, if any); method for the
handling of deviations; references; signed approval; and information about reference
samples (initial materials, intermediates and finished pro
ducts).
The duties of SU for the transfer of analytical methods are to:

1) Offer procedure -specific training for analysts and other quality control
personnel,
2) Help in analysing QC testing results,
3) Describe all procedures to be transferred for testing a part icular product,
starting material, or cleaning sample,
4) Outline the experimental design, sampling procedures , and acceptance
conditions,
5) Deliver any validation reports for procedures under transfer and validate their
robustness,
6) Offer specification s of the equipment used and any standard reference
samples,
7) Offer approved methods used in testing, and
8) Assess and approve transfer reports.
The duties of RU’s are to:

1) Review the analytical methods offered by the SU, and accept the acceptance
conditions before performing transfer protocol.
2) Make sure that the essential equipment for QC is present and qualified at the
RU site. The equipment used by the RU during the analytical transfer should
fulfil the descriptions to confirm that the necessities of the procedure o r
description are fulfilled.
3) Make sure that the analytical tests are performed by sufficiently trained and
experienced personnel.
4) Offer a documentation system to record receipt and testing of samples as per
the needed specification s by approved test method s, and to report, record,
and collect data and title of status (approved, rejected, and quarantine).
5) Perform the transfer protocol.
6) Achieve the suitable level of validation to assist the execution of procedures.
7) Make and attain approval of transfer reports.
Sufficient training should be given and all training procedures and results should
be recorded.
* *
Reference to compendial monographs ( e.g., British Pharmacopoeia, International Pharmacopoeia, European Pharmacopoeia, and United
States Pharmacopoeia), if available, is anticipated.
Potential experimental designs and acceptance criteria for the major analytical testing methods are given in table 2.1. This table presents
high-level guidance to use the general principle that method transfers should account for the variability and sensitivity of the method and
the quality specifications. Different methods and acceptance criteria can be used depending on science and the specifications of the
analytical method and the analyte.
Table 2.1: Possible Experimental Designs and Acceptance Criteria for Analytical Testing
Acceptance Criteria
Tests Considerations for Transfer Replication of Tests Set-Up
Direct Statistically Derived
Identity Transfer should focus on sample One determination is
preparation, data interpretation, usually sufficient to
and instrum ents; acceptable to demonstrate equivalence.
include in assay transfer.
Assay for Non-specific assay should not At e ach site: 2 analysts × Different sets of instruments Comparison of mean and Two one -sided t -tests
potency be used for stability testing; 3 lots, in triplicate (= 18 and columns; independent variability. with inter -site differences
bracketing may be appropriate per site). solution preparation.  2% and 95% confidence.
for multiple strengths.
Content If method is equivalent to assay At each site: 2 analysts, × Different sets of instruments Mean at RU within  3% of Two one -sided t -tests
uniformity method, separate transfer is not 1 lot (= 2 per site). and columns; independent mean at SU; c omparison of with inter -site differences
required. solution preparation. relative standard deviation.  3% and 95% confidence.
 5% of Compare profile (e.g., F ),
2
Dissolution Bracketing may be appropriate 6 units (12 if not routine Mean at RU within
for multiple strengths. at RU, and for extended mean at SU. or compare data at Q time
release products). points as for assay.
Cleaning verification (recovery Confirm that same Use spiked samples, with levels All samples spiked above
of residues from surfaces). swabbing material is used within 3 × validated standard specification should fail;
at Sending Unit (SU) and deviation or within  10% of 90% of samples spiked
Receiving Unit (RU). specification (whichever is the below specification
greater). should pass.
* *
Microbiological testing Execute common on -site Validation in triplicate Use different lots for each Qualitative: Demonstrate
(qualitative and quantitative validation protocol; validation exercise recovery of micro -
limit tests). rationale; method identity; organisms; quantitative:
validation parameters; recovery levels within
data summary; acceptance acceptance limits
criteria; methods of specified in protocol.
compiling and analysing
data; handling of out -of-
specification results; and
follow-up requirements.
Impurity Confirm response factors for At each site: Different days, different sets (For low levels) values at RU (For moderately high
degradation calculation relative to drug peak; 2 analysts × 3 lots, in of instruments and columns; within  25% of values at SU, or levels) two one -sided t -
and confirm limit of quantitation at duplicate (in triplicate if use samples of similar age, Mean at RU within  0.05% of tests, differences  10%
residual RU; compare chromatograms; done together with assay) homogeneity, packaging, mean at SU (5%). and 95% confidence.
solvents compare accuracy and precision storage; use spiked samples
for spiking experiments. if necessary.
The SU and RU should together perform the transfer protocol and make a transfer report.
2.2.14. Exhibit
The exhibit batches are manufactured after the completion of scale up batches. This case involves greater number of batch sizes ,
equipments, and processes involved. Different regulatory agencies require them for filing purposes.
2.2.15. Approved Regulatory Bodies and Agencies

Out of numerous regulatory bodies for drug approval, some are given below:
1) Central Drug Standard Control Organisation (CDSCO): It is the Central Drug Authority for carrying out the functions of th e
Central Government as per the Drugs and Cosmetics Act. Under the control of CDSCO, there are 6 zonal offices, 4 sub -zonal
offices, 13 port offices, and 7 laboratories.
2) Ministry of Health & Family Welfare (MHFW): Earlier, MHWF had two departments, i.e., D epartment of Health and Family,
and Welfare Department of Health Research. Each department was supervised by the Secretary to the Government of India.
* *
3) Indian Council of Medical Research (ICMR), New Delhi: It is one of the

oldest medical research bodies in the world, and is the top body in India for
the preparation, coordination, and advancement of biomedical research.
4) Indian Pharmaceutical Association (IPA): It was established in 1939 and
is the oldest leading association of pharmaceutical professionals i n India,
with a member base of approximately 13,000, spanning throughout the
nation. IPA works in India through 20 state branches and more than 46 local
branches. The members characterise several aspects of the pharmaceutical
profession, such as regulatory , industry, community and hospital pharmacy
practices and education.
5) Drug Technical Advisory Board (DTAB) : It is the major legislative body
that makes decision on technical matters associated to drugs in India. DTAB
was made as per the requirements of th e Drug and Cosmetics Act, 1940. It is
a part of the CDSCO under the Ministry of Health and Family Welfare.
6) Central Drug Testing Laboratory (CDTL), Mumbai : It is one of the
National Statutory Laboratories of the Government of India that works under
the administrative control of the Drugs Controller General (India), CDSCO,
Directorate General of Health Services, and MHFW, New Delhi.
7) Indian Pharmacopoeia Commission (IPC) : It is an autonomous institution
under the MHFW, Government of India. IPC was formed to st andardise
drugs in the country. Its basic purpose is to frequently update the standards of
drugs generally needed for treating the diseases prevailing in this region. It
publishes formal documents to improve quality of medicines by adding new
and updating the existing monographs in the form of Indian Pharmacopoeia
(IP).
8) National Pharmaceutical Pricing Authority (NPPA) : It was made as per
Government of India Resolution dated 29 th August, 1997 as a joint office of
the Department of Pharmaceuticals (DoP), Mini stry of Chemicals and
Fertilisers as an autonomous regulator for the prices of drugs and to confirm
guarantee availability and accessibility of medicines at reasonable prices.
9) Drug Controller General of India (DCGI) : Under the control of CDSCO,
the DCGI is accountable for approval of licenses of particular classes of
drugs, like blood and blood products, IV fluids, vaccines and sera in India.
The DCGI of India falls under the Ministry of Health and Family Welfare.
10) Review Committee on Genetic Manipulation (R CGM): It was established
under the Department of Biotechnology, ministry of Science and technology.
It observes the concerns associated to safety , regarding current research
projects and activities (with small scale field trials) and make manuals and
plans specifying methods for regulatory process , regarding the activities
employing genetically engineered organisms in research, uses and
applications in industry for safeguarding environmental safety.
11) Genetic Engineering Approval Committee (GEAC): It was e stablished
under The Ministry of Environment, Forest and Climate Change (MoEFCC).
*
It is the top body to accord notified under Rules 1989 for authorisation of *
activities comprising large scale use of hazardous microorganisms and

recombinants in research and industrial production from the environment
perspective. GEAC is also accountable for authorisation of proposals related
to release of genetically engineered organisms and products into the
environment with experimental field trials.
2.2.16. Commercialisation
Technology commercialisation is the act of taking an idea to market and
generating financial value by patenting an invention, making a new product or
service, or building a new business ( which is sometimes called as mind-to-
market). Products or services gener ated via commercialisation may be new to
the world or new to the region or country.
Technology commercialisation does not essentially mean moving a particular

finished technology to the market; instead, it signifies a much initial stage
development. This is a significant difference. Many times, efforts will be made to
commercialise (market) a finished technology that does not fulfil any market
need, does not create a new market, or has rival products with established market
presence. Also, a customer company may not buy the finished technology as it
does not fit in their product development cycles, but may be interested in the
know-how, intellectual property, or knowledge related to the technology.
Innovation or a new and better way of doing something creating a positive

change may raise incremental or fundamental changes in thinking, decision
making, or the manner of doing business and products created in an organisation,
and is the major part of technology commercialisation.
Technology adaptation is the act of br inging in a finished technology, making it

appropriate as per a users’ environment, and adapting it for a new use. Research,
as usually performed at a university or research institute, may create ideas which
can later be commercialised. Resear ch and development (R&D) as usually
performed in a company may create ideas for new products and services.
2.2.17. Practical Aspects and Problems (Case Studies)

Technology Transfer Problems Faced by Small and Medium Enterprises (SMEs)
Jagoda and Ramanathan in 2007 studied the difficulties encountered by the
SMEs in planning and managing technology transfer, and categorised them into
technology transfer process issues, corporate proficiency issues, and operating
environment and network information system issues. Th e problems are
summarised as follows:
1) Problems during technology validation and selection stage:
i) Selection of wrong technology because of error in making business case
for a technology transfer project.
ii) High charges of buying, installing, running and maintaining the technology.
iii) The selected technology is complicated for easy understanding and
integration of the transferee.
iv) The technology requires large-scale alteration to suit local conditions.
* *
2) Problems during the planning stage:

i) The seller or transferor misjudges the difficulties faced while transferring
the technology to a developing country setting.
ii) The transferor does not completely realise the transferee needs.
iii) The transferee managers do not play any role in the planning that is only
carried out by the transferor.
iv) High consideration is given to the hardware to be purchased and not
much consideration is given to skills and data procurement.
v) Overestimation of the technological abilities of t he transferee by the
transferor, hence causing impractical antic ipations on how well the
transferee can achieve the target dates.
vi) Low market demand estimation by the transferee of the outputs to be
created by employing the transferred technology.
vii) The intentions of the transferor and transferee are incompatible.
viii) Selection of inappropriate mechanisms for implementing the transfer.
3) Problems during negotiations:
i) Variations in negotiation methodologies and strategies.
ii) Absence of trust between the transferor and transferee.
iii) Objective conflicting during negotiations.
iv) Failure to agree on pricing, product, and marketing strategies.
v) Both parties trying to obtain results in an impractically short time period.
4) Problems during implementing technology transfer:
i) Lack of proficient technology transfer managers.
ii) Shortage of trust in transferor manufactured systems by the transferee.
iii) Lack of ability to meet the quality targets.
iv) Delayed procurement of additional materials from the local environment,
required for speedy execution.
v) Costly and bad quality of locally available materials requ ired for
implementing the transferred technology.
vi) Poor tracking of the technology during application.
vii) Increase in cost due to poor application.
Case Study 1: Tablet Reformulation Technology Transfer/Scale Up
Client Product
Global Pharmaceutical Company Tablet
Needs: Actions:
1) Modify tablet formulation and meet 1) Quality risk management including
several reference features. process mapping.
2) Modify manufacturing processes. 2) Design of experiment.
3) Reduce costs.
4) Increase market competitiveness.
1) Situation: A global pharmaceutical company chose to alter the formulation

and some manufacturing process steps for a drug in tablet dosage form in
order to minimise the cost and increase market competitiveness. Some major
* *
goals were to achieve the reference specific ations, like sufficient physical
stability towards humidity and palatability and equivalent bioavailability as
compared to the actual product.
PTM Consulting applied Quality by Design (QbD) and Quality Risk
Management (QRM) principles integrated with Desi gn of Experiments
(DoE) statistical tool during the expansion and scale up steps for transferring
the process from the laboratory scale, to the pilot scale (made for producing
clinical batches), and then to the industrial scale.
The project goals under consideration are:
i) Expand the quality of t he information during the scale up steps and
reduce failure risks associated to the project,
ii) Follow regulatory principles, and
iii) Reduce costs, time, and resources employed.
The method was made by using the principles given below:
i) Risks associated to the target recognised earlier have been reduced and
maintained through QRM application.
ii) Process capability ( e.g., cost of product quality and defect reduction)
have been enhanced through various statistical tools, like DoE tool.
2) Actions: The limitations of the analysis, dangers and risk tolerability
conditions were described. Process mapping approach was used for building
process activities, inputs, outputs, controls , and mechanisms. The data
obtained from this step is given below:
i) 21 out of 58 total parameters were thought to be potentially critical and
could affect process outputs.
ii) Data traceability associated with every step and activity which would be
essential for the following risk analysis implementation.
iii) Requirements recognition for machines and equipment according to the
perception of the industrial scale up.
iv) Review of the control systems employed for the recognised considerations.
A model was made for increasing the quantity of determinable data from
process mapping . Then an organised and efficient risk analysis was made,
beginning from process mapping.
The Failure Mode and Effect Analysis ( FMEA) method employed for
performing risk analysis is permitted to:
i) Recognise 30 hazards associated to project targets (bu siness, safety, and
regulatory),
ii) Recognise the origin of risks that involved unacceptable risks, and
iii) Make counteractive actions for converting unacceptable risks to
acceptable risks.
Before initiating the optimisation activities, the process was restrain ed.
Proprietary software permitted to maintain traceability in the process mapping
as well as in risk analysis. This methodology handled every variation , like
process, product or controls because it is compliant andeasy to maintain.
* *
3) Design of Experiments App lication: Extrapolated data during risk analysis

to justify the number of those critical parameters that were necessary to test.
There was a need to procure the desi red quality product and reduce
development times, amount of resources used and the associat ed costs. DoE
assisted in quantifying the effects of the variables on outputs (like dissolution
profile, resilience, etc.). All the project targets and goals were accomplished
by employing the design space procured and identified for every
development process scale.
4) Results: Using the laboratory scale, an affordable and scalable formulation
was made and the customer received the expertise in the process. Concerning
the pilot scale, the equipment lab outcomes were verified and the tablet with
specifications relatable to the reference was procured, therefore clinical
studies were performed successfully.
At the industrial scale, the expertise gained during the development process
allowed the customer to enhance the process with a high extent of
reproducibility. All the targets were accomplished by the customer using this
approach:
i) Product qualifications were constantly fulfilled while transferring from
the old to the new process structure,
ii) Regulatory effects were handled using specific risk analysis,
iii) Business effects were reduced by using fewer amounts of batches in
comparison to the amount used in a traditional methodology,
iv) The number of resources employed was not increased, and
v) Costs associated to product development were less than that expected by
the customer.
Case Study 2: Blend Uniformity Issue During Process Validation
1) Situation
i) This was believed to be a widely known unit operation.
ii) It was not found to be a problem of consideration during risk analysis.
iii) Drug load was not very low.
iv) During validation, a b lend uniformity problem was encountered after
material transfer.
v) It caused delay and revalidation after recognition of source of the cause.
2) Solution
i) Risk analysis assessing every potential source of material separation was
executed during blending, materia l transfer , and more downstream
storage and transfer.
ii) Optimisations were recognised and applied.
iii) Revalidation was effectively finished.
3) Conclusion
i) During scale up/technology transfer, there is a necessity to recognise all
probable problems that may occur.
ii) Material handling and equipment, and the formulation/process factors
*
should be taken into consideration during risk analysis. *
iii) Ideal blend capacity should be maintained for operation.

iv) The n ecessity to recognise drop heights of material from blender to
drum/tote should be considered.
v) The downstream effect on material separation should be considered.
vi) A NIR blend control approach can assist in hind sight.
Other Case Studies

The technology transfer process is dynamically being pursued in India in various
government laboratories, academic institutions, and commercial entities.
1) The Bhabha Atomic Research Centre (BARC): It has established and
transferred around 90 technologies in environment and health , electronics;
electrical and mechanical; chemical and metall urgy; and radioisotope and
applications.
2) The National Chemical Laboratory (NCL) , Pune: It has multiple
relationships with universities and pharmaceutical industries for confirming
effective scale up and application of technology.
3) Department of Biotech nology (DBT): It has transferred certain techniques
of forest trees through tissue culture.
4) Eli Lily: It has made a technology transfer agreement with Shasun
Chemicals and Drugs for manufacturing cycloserine (anti-tuberculosis drug)
produced by Shasun to fulfil the global demands of Eli Lily.
5) Cipla: It is a pharmaceutical company that has made technology transfer
agreement with companies in Uganda, Nigeria, Egypt, and Algeria.
6) Themis Laboratory: It has entered into an agreement for technology
transfer with Aventis Pharma Ltd , for developing fixed dose combinations
of glibenclamide and glimepiride with metformin by using technology
patented by Themis.
7) Local divisions of foreign R&D -based pharmaceutical companies , like
Abbott, Pfizer, Bayer, GlaxoSmithKline Beecha m, AstraZeneca, Merck,
Boehringer Ingelheim, Aventis, Bristol -Myers Squibb Novartis, Schering
Plough, Sharp and Dohme, and Wyeth bought local factories to start their
working even though it looks like certain factories have been bought back by
local companies.
8) Laboratorio Elea (ELEA) : It also holds licenses for commercialising
products made by Chiron Corporation (vaccines) and Novo Nordisk
(hormone Therapy) and an agreement of promotion with Novartis for its
transdermal patches in hormone therapy.
9) In 1999, the supplier of Velcade Millennium Pharmaceuticals, teamed up
with Dana -Farber cancer institute for studying Velcade in patients of
multiple myeloma after the University of North Carolina accomplished full
response with the compound in the first patient of multiple myeloma.
10) Indian pharmaceutical companies , such as Torrent Pharmaceutical Ltd .,
Wockhardt Ltd ., Dr Reddy’s Laboratories Ltd ., Cipla Ltd ., and USV Ltd .
have already entered into in-licensing agreements with foreign drug makers.
* *
2.3. TECHNOLOGY TRANSFER AGENCIES

IN INDIA
2.3.1. Introduction
Some technology transfer agencies in India are:
1) APCTT (Asian and Pacific Centre for Transfer of Technology),
2) NRDC (National Research Development Corporation),
3) TIFAC (Technology Information, Forecasting and Assessment Council),
4) BCIL (Biotech Consortium India Limited),
5) TBSE (Technology Bureau for Small Enterprises), and
6) SIDBI (Small Industries Development Bank of India).
2.3.2. APCTT (Asian and Pacific Centre for Transfer of

Technology)
APCTT is a United Nations local organisation that comes under the Economic
and Social Commission for Asia and the Pacific (ESCAP). The Centre was
established in 1977 in Bangalore, and was moved to New Delhi, in 1993. APCTT
endorses technology transfer to and from Small- and Medium-Scale Enterprises
(SMEs) in Asia and the Pacific.
APCTT employs development projects that are financed by international donors

focussed at strengthening the environment for transfer of technology between
SMEs in Asia and the Pacific. Regarding this, the centre makes efforts for
inspiring women to participate in the field of technology. APCTT handles
consultancy assignments in several areas concerning technology transfer (human
resource development, business partnership development, institution building,
and studies).
The goal of APCTT is to strengthen the technology transfer abilities in the area
and to assist import/expor t of environmentally sound technologies to/from the
member countries. All member states and related members of UNESCAP are
effective members of APCTT.
APCTT proposes technology transfer assistance facilities to technology providers

and seekers, mainly by joining hands with its major focal points in the country
and technology transfer intermediary networks. Various major technology
transfer assistance facilities of APCTT are as follows:
1) Providing data on technology transfer, joint venture, business/research
partnerships and opportunities.
2) Conducting meetings among businesses, technology exhibitions , technology
transfer related conferences and technology distribution workshops by
partnering with APCTT focal points in the member countries.
3) Providing support facilities to assist techno -entrepreneurs to cooperate with
technology transfer mediators, source technology internationally, and also
discover venture capital funding.
* *
2.3.3. NRDC (National Research Development Corporation)

NRDC was formed in 1953 by the Government of India, with the goal to sponsor,
make, and commercialise the technologies, knowledge, discoveries, patents, and
procedures originating from multiple national R&D organisations or universities.
It is currently working under the administration of the Department of Scientific
and Industrial Research, Ministry of Science and Technology.
In the past 60 years of its existence and in acquirement of its corporate

objectives, NRDC has made strong contacts with the scientific and industrial
community in India and overseas, and made a huge network of research
organisations, universities and industries.
It has also made official engagements with them for commercialisi ng the
expertise developed in their laboratories and is now established as a large source
of extensive range of technologies spread in m ost of the areas of industries like
agriculture and agro -processing, chemicals such as pesticides, drugs and
pharmaceuticals, biotechnology, electronics and instrumentation, mechanical,
metallurgy, electrical and electronics, building materials , etc. NRDC has granted
license of native technologies to more than 4800 entrepreneurs and assisted to
create several small and medium scale industries.
Apart from being the leader in the technology transfer field, NRDC also conducts
various activities under its organised promotional programme for inspiration and
improvement of research, promotion of discoveries and innovations like
meritorious inventions awards, techno -commercial assistance, technical and
financial support for IPR protection, value addition facilities , and assistance for
further advancement of the technologies.
NRDC has also effectively transferred technologies and facilities to both

developed and developing countries. It is established, especially in the
developing countries, as the origin of reliable technology, machines and facilities
that are appropriate for these countries.
2.3.4. TIFAC (Technology Information, Forecasting and

Assessment Council)
TIFAC is an independent organisation founded in 1988 under the Department of
Science and Technology to plan ah ead in technology domain, evaluate the
technology trajectories, and assist innovation through coordinated actions in
specific areas of national importance. It continuously endeavours for technology
development in the country by leveraging technology invent ions through continued
and determined programmes inproximity with industry and universities.
TIFAC undertook the duty of developing a technology vision for the country in
several evolving technology areas. Under the management of Dr. APJ Abdul
Kalam, the chairman of TIFAC at that time, use of technology vision 2020 led to
set of 17 documents, comprising 16 technology fields and one on services.
TIFAC has given many technology evaluation and prudence reports to the
country in its more than 25 years of service.
* *
The objective of TIFAC is to strengthen the weak areas of technol ogy

development and commercialis ation in specific sector by promoting te chnology
development in the industry with little, average, and extensive risk prospects. The
technological urgencies for India are:
1) Increasing capital efficiency by updating and lowering costs by continuous
technological contributions to the huge base of primary infrastructure such as
transport, energy, housing, communication, etc. But, some may have to depend
on large scale imports of capital goods and expertise in the shorter term.
2) Technology assistance in fields that are presently exporting to increase value-
addition for enhancing the quality, quantity and value of exports.
3) Technology assistance in specific small scale divisions whose future is based
on high technology innovation.
4) Act on specific area of market -oriented technologies at global scale where
India can influence and achieve an internationally competitive edge.
TIFAC actively plays role in each of the a bove categories for positive effects
which can add growth to economy and society in a sustainable way.
2.3.5. BCIL (Biotech Consortium India Limited)

BCIL was founded in 1990 by Shri. Chandra Shekhar (Prime Minister of India at
that time ), in the presence of Shri. Yashwant Sinha (Finance Minister) and Dr.
Manju Sharma (Secretary in Department of Biotechnology , DBT). It is a public
limited company that is promoted by DBT, Mini stry of Science and Technology,
Government of India, and All India Financial Institutions for giving the important
connections between stakeholders and business assistance to enable speedy
commercialisation of biotechnology.
BCIL was established under the Indian Companies Act , 1956. Its board of
directors comprises of senior representatives of Council of Scientific and
Industrial Research (CSIR), DBT, Indian Council of Agricultural Research
(ICAR), top financial institutions, and the biotechnology industry.
In the last decade and a half, BCIL has actively involved in transfer of
technology, project consultancy, fund syndication, data distribution, and
manpower training and placement associated to biotechnology. It has helped
several clients comprising tech nologies, scientists, universities, first
entrepreneurs, research organisations, corporate sector, banks and financial
institutions, national and international organisations, central government, and
several state governments.
BCIL provides an interface be tween the technology sources and technology
seekers, both inside and outside the country. It helps in technology sourcing,
marketing tie-ups and recognition of joint venture partners by using the network
of gl obal linkages provided by BCIL. To enable the t ransfer of native
technologies, BCIL uses a systematic stepwise methodology involving:
1) Screening for leads,
2) Evaluation,
3) Validation,
4) Scale up,
* *
5) Packaging,
6) Technology pricing,
7) Entrepreneur selection,
8) Technology transfer, and
9) Monitoring, support, and consultancy.
In the beginning, commercial leads are separated for selection of technology after
which official technology transfer agreement is implemented with the institute
that has developed the technology. The technology is assessed for measuring its
commercial potential. After the technology looks more or less workable , it is
bundled into a package to assist the entrepreneurs and financial institutes for
assessing the commercial possibilities of the technology.
Recognition of an appropriate entrepreneur is a major step and based on the
necessity of the technology plans are accepted to ensure their direction to suitable
potential sectors. License agreement is implemented after choosing an
appropriate entrepreneur. Pricing of the technology depends on multiple factors
such as growth potential, market demand, innovativeness of the technology , etc.
BCIL spreads all assistances to the licensee in the form of constant monitoring
and consultancy facilities to convert the technology into a commercial venture.
2.3.6. TBSE (Technology Bureau for Small Enterprises)

TBSE offers a stage on which small enterprises can grab chances at the
international level for procuring technology or establishing business partnerships.
It was formed by the joint initiative of the United Nations’ Asian and Pacific
Centre for Transfer of Technology (APCTT) and Small Industries Development
Bank of India (SIDBI); and signifies collaboration of technology and finance.
TBSE is also partially financed by the office of DC (SSI), Government of India.
The significant characteristics of TBSE facilities are:
1) It provides a skilfully handled system for technology and partnership search.
2) It assists in developing confidence among potential partners.
3) It helps in the difficult task of negotiations and matching of opinions.
4) It offers access to international technology market through networking.
5) It is an exceptional mechanism for establishing technology and finance.
6) It handles project evaluation and development of business plan.
Range of Services
1) Technology Information : TBSE has a huge computerised data base on
technology options present in various countries. It provides the user with
latest information on sources of technology and procedure of gaining access
to them. Data on technology -seeking enterprises is also provided to the
interested technology suppliers and partners.
2) Match Making : TBSE recognises the business associates eager to partner
up, arranges their communi cation and offers assistance to tie up financial
support and other necessities for technology transfer and joint ventures.
Moreover, the collaborating partners are also helped for drafting agreements,
procuring several approvals and making business plans.
* *
3) Finance Syndication : Based on the cost of the project, nature and

importance of help needed, the TBSE commences financial syndication by
SIDBI covering term loans, venture capital, equity assistance, foreign
currency, lines of credit, and on specific basi s no interest loans to achieve
early expenditure in the pre-technology absorption stage.
4) Business Collaboration: The TBSE provides assistance to small enterprises
for exporting the technologies and products made by them through business
tie-ups as a compon ent of the package. To increase global cooperation
between SMEs, the bureau conducts overseas visits of business delegations.
5) Support Services : The TBSE organises consultancy services, visits of
foreign experts for in -plant counselling, buyer -seller meetin gs for certain
product process technologies , and signifies the business orientation of small
enterprises in international events.
2.3.7. SIDBI (Small Industries Development Bank of India)

SIDBI was founded on 2nd April, 1990 according to an Act of Indian parliament.
It acts as the major financial organisation for the promotion, financing, and
development of the Micro, Small and Medium Enterprise (MSME) section and
also for managing the functions of organisations involved in related activities.
The actions of SIDBI have continuously remained associated to the national
interests of poverty removal, employment creation, entrepreneurship, and
promoting competitiveness in MSME sector.
2.4. SUMMARY
1) The technology transfer in pharmaceutical industry refers to the processes
required for successful progress from drug discovery to product
development, to clinical trials to full scale commercialisation.
2) The WHO defined transfer of technology as “a procedure that controls the
transfer of any process together with its documentation and professional
expertise between development and manufacture or between manufacture sites ”.
3) Any substance or mixture of substances that is used for manufacturing a
pharmaceutical dosage form, or that which when used acts as an active
ingredient of that pharmaceutical dosage form is known as Active
Pharmaceutical Ingredient (API).
4) Bracketing is an experimental design for testing the limits of dosage
strength. The design presumes that the limits will represent all the samples
within the limits.
5) The originating lab receives the results on a data report form and adds it to
the transfer protocol or sends their Laboratory Information Management
System (LIMS) or results report and all required data.
6) Quality risk management is defined as “a systematic process for the
identification, assessment and control of risks to the quality of
pharmaceutical products across the product lifecycle”.
* *
7) It is necessary to detect risks in the initial phases of product development

which may challenge the accomplishments of the Quality Target Product
Profile (QTPP).
8) QRM principles used as a procedure assists science -based a nd practical
decisions when used in commercial manufacturing.
9) Design of Procedure and Selection of Excipients by R&D is based on the
features of the innovator product, R&D designs procedures and selects
excipients.
10) Master Formula Card (MFC) provides information on the product name,
generic name, strength, MFC number, page number, effective date, shelf-life,
and market.
11) Master Packaging Card provides information regarding the type of
packaging, material used for packaging, stability profile of packaging, and
packaging shelf-life.
12) Master Formula provides information regarding the formulation order and
manufacturing instructions, which in turn gives idea of process order,
environmental conditions required, and manufacturing instructions for
dosage form development.
13) Specifications and Standard Test Procedure (STPs) provide information
regarding the API and excipients profile, in -process parameters and
specifications, product release specification, and finished product details.
14) To reduce the risk of contamination, cross-contamination, operator exposure,
and environmental effects, practicing cleaning processes is important.
15) Information on cleaning agents used, including their efficacy, evidence that
they do not interfere with analytical testing for residues of APIs and remove
residual cleaning agents.
16) The SU should offer the RU with the open (applicant’s) part of the API
Master File (APIMF) or Drug Master File (DMF) or Active Substance
Master File (ASMF), and any important supplement data on an API suitable
for manufacturing pharmaceutical product.
17) The SU should offer data on the history of process development that may be
needed to allow the RU to make any additional development or process
enhancement after transfer.
18) Technology transfer documentation contains informat ion regarding
technology transfer for transferring and transferred parties.
19) Technology transfer plan is useful in defining items and contents of
technology to be transferred, and complete procedures of individual transfer
and transfer schedules.
20) The SU should give data to the RU on the layout, construction and quality of
buildings and services [Heating, Ventilation and Air -Conditioning
(HVAC), relative humidity, power, water, temperature, and compressed air],
which influence the product, process, or procedure to be transferred.
21) The RU should perform a gap analysis for identifying the necessities for
modification of prevailing equipment, procurement of new equipment, or an
alteration in the process, to allow the RU to replicate the process being
transferred.
* *
22) Estimation of the risk to quality should be done on the basis of scientific
knowledge and related to the protection of the patient.
23) The amount of work, formality and documentation of the QRM process
should be proportionate with the level of risk.
24) The te rm quality control denotes the sum of all methods commenced for
ensuring the identity and quality of a specific pharmaceutical product.
25) The exhibit batches are manufactured after the completion of scale up
batches.
26) Indian Pharmaceutical Association (IPA) was established in 1939.
27) DTAB was made as per the requirements of the Drug and Cosmetics Act, 1940.
28) Jagoda and Ramanathan in 2007 studied the difficulties encountered by the
SMEs in planning and managing technology transfer.
29) APCTT is a United Nations local organisation that comes under the
Economic and Social Commission for Asia and the Pacific (ESCAP) and its
Centre was established in 1977 in Bangalore, India, and was moved to New
Delhi, India in 1993.
30) TIFAC is an independent organisation founded in 1988 under the
Department of Science and Technology to plan ahead in technology domain.
31) BCIL was founded in 1990 by Shri Chandra Shekhar (Prime Minister of
India at that time), in the presence of Shri Yashwant Sinha (Finance
Minister) and Dr. Manju Sharma (Secretary in Department of Biotechnology,
DBT).
32) SIDBI was founded on 2nd April, 1990 according to an Act of Indian
parliament.
2.5. EXERCISE

1) Define API and Bracketing.
2) Define technology transfer process.
3) What do you mean by FPP and DMF?
4) Define the terms IQ and OQ.
5) What is VMP?
6) Name some of the regulatory bodies for drug approval.

1) Write a short note on technology transfer process.
2) Write a note on technology transfer protocol.
3) Write about technology transfer documentation.
4) Give a note on APCTT and NRDC.

1) Briefly explain Quality Risk Management (QRM).
2) Give a detailed note on transfer from R&D to production.
3) Write an illustrative note on granularity of technology transfer process.
* *
Technology Transfer Related Documentation (Chapter 3) 71
CHAPTER Technology Transfer

3 Related Documentation
3.1. TECHNOLOGY TRANSFER RELATED

DOCUMENTATION
3.1.1. Introduction
The documents needed for the transfer project are broadly ranging. The
documented proof that the transfer of technology has been effective should be
described and specified in a technology tra nsfer summary report. This report
should outline the scope of the transfer , the important parameters as found in the
SU and RU (in a table form) , and the conclusions of the transfer. Probable
inconsistencies should be listed and required actions should be taken to remove
them.
Every stage of research and development including the production should be

documented, task obligations and duties should be explained and acceptance
criteria for finishing the technology transfer related to a specific technology to be
transferred. It is the responsibility of quality assurance department to verify and
approve the documentation for every process of technology transfer.
Some documents associated to transfer technology are as follows:

1) Development Report: The research a nd development report is a document
of technical development, and research and development department holds
the responsibility of its documentation. This report is an essential document
to justify the quality design of drug materials and its specifications and test
methods. The development report is not essential for the authorisation of
application. It can be used at the pre -authorisation of an inspection as a valid
document for quality design of a new drug.
The development report comprises of:

i) Information on pharmaceutical development of new drug materials and
drug pro ducts at stages from early development to final application for
approval.
ii) Data on raw materials and components.
iii) Design of manufacturing methods.
iv) Variations in histories of essential processes and control parameters.
v) Specifications and test methods for drug materials.
vi) Effectiveness of specification range of important tests , like content
impurities and dissolution.
vii) Verifications of results.
* *
2) Technology Transfer Plan: It defines the items and contents of technology

to be transferred and detailed methods of individual transfer and transfer
schedule, create s judgement conditions for the completion of transfer. The
transferring party should form the plan prior to the execution of transfer and
should make an agreement on its contents with the transferred party.
3) Technology Transfer Report: It should be made once information is taken
as per the technology plan and are estimated to ensure that the predetermined
judgement criteria are followed. Both tra nsferring and transferred parties
should make the technology transfer report.
4) Exhibit Batches: These batches are manufactured after taking scale up
batches of the product. In exhibit instances, batch sizes are increased along
with equipment and their proce dures, for the purposes of filing in regulatory
organisations. The objective of running three successive batches is to
demonstrate process reliability and reproducibility, and to show that the
manufacturing process is within control across all the phases.
3.1.2. Confidentiality Agreement

Confidential data is not present in the public domain . As an example, it may
include a compound, a target, a small molecule, a protein, a genetic structure, a
gene sequence, or any other type of creation or innovation. Confidential data is
not essentially restricted t o data that concerns technology, but can also be
business and financial and marketing data and strategies.
A confidentiality agreement is a lawful binding agreement between the provider

of confidential informa tion and the receiver of confidential information, and
states the conditions under which the confidential information is made public.
Confidentiality agreements may be referred by other names like confidentiality
deeds, non-disclosure agreements , secrecy agreement , mutual disclosure
agreement, etc.
A confidentiality agreement generally identifies the allowed use or objective to

which the recipient can put the confidential information. For example , the
confidentiality agreement may specify that the receiver may use it for the purpose
of evaluation or testing. The allowed purpose or use will be the only use to which
the receiver can apply the confidential information, and the confidentiality
agreement will restrict the receiver on applying the confidential information to
any other use or objective.
3.1.2.1. Ending of Obligations of Confidentiality

Generally, a confidentiality agreement will state that the obligations of
confidentiality should end in either of the following events:
1) The confidential information is made available to the public.
2) The receiver gets the confidential information from another person who is
allowed to disclose it, without any obligation of confidentiality.
3) The receiver can prove it was individually developed by the receiver, along
with employees with no access to the confidential information.
* *
3.1.2.2. Duration of Obligations of Confidentiality

In some industries, it is not uncommon for confidentiality agreements to specify that
the obligations present in the agreement stay forever, until one of the events given
above occurs. This is specifically necessary when the confidential information is a
trade secret that is purposefully kept a trade secret, and deliberately not patented.
But in the biotechnology sector, the obligations of the confidentiality agreement
usually end it automatically after a specified period(generally 5-7 years).
The reason given for this random period of ending the obligations of a
confidentiality agreement is that the rate of change of the science is fa st, and at
such a speed if the discloser has not pursued patent protection within a specified
period, the receiver should be relieved from the problem of continuing be aware
of the confidentiality agreements entered into in excess 5 years previously.
The useful outcome of this convention of obligations of confidentiality lasting

only for 5 years is that disclosures in the biotechnology sector should only be
confined to a patentable subject matter, and should not cover trade secrets for
which no patent is ever planned.
3.1.2.3. One Way and Two Way Agreements

A confidentiality agreement may be a one way or two way agreement. In one
way agreement , one party discloses the confidential information a nd the other
party receives it; while i n two way agreement , each party discloses the
confidential information and each party receives the information disclosed by the
other party.
3.1.2.4. Confidential Disclosure Agreement

This Agreement is entered into this ____ day of ________, 20____ by an d
between _______________ with offices a t __________________ (hereinafter
"Recipient") and ____________________, with offices at __________________
(hereinafter "Discloser").
WHEREAS Discloser possesses certain ideas and information relating to

__________________ that is confidential and propri etary to Discloser
(hereinafter "Confidential Information"); and
WHEREAS the Recipient is willing to receive disclosure of the Confidential

Information pursuant to the terms of this Agreement for the purpose of
_______________________;
NOW THEREFORE, in consideration for the mutual undertakings of the

Discloser and the Recipient under this Agreement, the parties agree as follows:
1) Discloser agrees to disclose, and Receiver agrees to receive the Confidential
Information.
2) Confidentiality.
i) No Use: The recipient accepts not to use the Confidential Information in
any way, or to manufacture or test any product representing Confidential
Information, excluding the purpose given above.
* *
ii) No Disclosure : The recipient accepts to use its best efforts for
prevention and protection of Confidential Information, or any part
thereof, from disclosure to any person excluding the Recipient’s
employees who require disclosure in association to the Recipient’s
authorised use of the Confidential Information.
iii) Protection of Secrecy : The recipient accepts to take all steps rationally
essential for protecting the secrecy of the Confidential Information, and
for preventing the Confidential Information from entering the public
domain or the hands of unauthorised persons.
3) Limits on Confiden tial Information : Confidential Information should not
be considered proprietary and the Recipient should have no obligation
concerning such information where the information:
i) Was known to the Recipient before receiving the Confidential
Information from the Discloser;
ii) Has entered the public domain but not due to any wrongful act of the
Recipient;
iii) Was received by the Recipient without breaching this Agreement from a
third party without restriction on using and disclosing the information;
iv) Was independently developed by the Recipient without using any
Confidential Information; or
v) Was ordered to be released into the publ ic domain by the necessity of a
government institution.
4) Ownership of Confidential Information : The r ecipient accepts that all
confidential infor mation should stay as the property of Discloser, and that
Discloser may use that Confidential Information for any purpose without any
obligation to Recipient. Nothing enclosed here should be interpreted as
granting or implying any transfer of rights to Rec ipient in the Confidential
Information, or any patents or other intellectual property protecting or
associating to Confidential Information.
5) Term and Termination : The obligations of this agreement should continue
till the Confidential Information provided to the Recipient is no longer
confidential.
6) Survival of Rights and Obligations : This Agreement should be binding
upon, inure to the benefit of, and be enforceable by:
i) Discloser, its successors, and assigns, and
ii) Recipient, its successors and assigns.
IN WITNESS WHEREOF, the parties have executed this agreement effective as

of the date first written above.
DISCLOSER (______________) RECIPIENT (________________)
Signed______________________ Signed: _______________________

Name: ______________________ Name: _______________________
Title: _______________________ Title: ________________________
* *
3.1.3. Licensing
It may be eminent that multiple contractual agreements can be accepted for
supplying technology and the performance of other obligations under such
agreements. The t ransfer of technology may take place through the grant of
licenses concerning industrial property, through supply of confidential
knowledge, or through the information of a joint project between the parties.
The first type of arrangement, called licensing, is related to the applicable rules of
the concerned legal system. A usual type of industrial property consists of patents.
According to the legal system of several countries, a person who creates a method
or product can apply for a patent in a government institution for safeguarding the
invention in the country. After obtaining the patent for a particular period, the
invention that is the subject matter of the patent cannot be misused by a person
other than the owner of the patent without his/her permission. License is an
important legal expression of that agreement. In addition to patents, other types of
industrial and commercial property are also acknowledged by almost every legal
system, such as trademarks, designs, and utility models.
3.1.4. Memorandum of Understanding (MoUs)

A memorandum of understanding (MoU) is a non -binding agreement between
two or more parties depicting the terms and specifics of an understandi ng, such
as each party’s necessities and duties. MoU is usually the first phase in the
formation of a formal contract. A memorandum of understanding is not lawfully
binding but is considered as an important document by the law. In the United
States, a MoU is similar to the letter of intent, which is a non-binding agreement
declaring that a binding agreement will occur soon. MoUs are generally used as a
part of multinational international associations, because with respect to treaties,
they are fast and can be kept secret. But, MoUs can also be used natively and as
an instrument for modifying the existing treaties.
MoUs have different length and complications; however, every understanding

signifies jointly acknowledged expectations among people, organisation s, or
government. Other major resemblances between all the MoUs are that they are
not legally obligatory and do not include the exchange of money.
Basic Process for Drafting a MoU

Every party begins with a planning phase in which it chooses the preferred
outcome, what it can give, how much can be negotiated, and how much is non-
negotiable. An initial draft is then formed, after which the leaders from each
party meet f or discussing the details. The MoUs often contain communication
prospects for assisting the mediation process.
During this period, agreements concerning the time period for which the MoU
takes effect are discussed. Agreements depicting how or when a party can end the
understanding are also decided. This is when a party adds disclaimers, limitations
or privacy declarations, as desired. Followed by the discussions, a final MoU is
formulated and signed.
* *
3.1.5. Legal Issues

A transaction including the transfer of technology has t echnical, commercial,
financial and even political aspects. But one aspect of utmost significance is
mutual to every agreement for the transfer of technology, i.e., the legal one.
The legal aspect of technology transfer has a dual character. Generally, such an
agreement is a contract ruled by the law of contracts. In its special aspect, it is a
contract for a particular purpose, containing a n unusual type of property and
involving some special obligations not found in other contracts.
It is si mple that the principles of law and contracts also apply on agreements for
the transfe r of technology. These comprise of contractual capacity, agreement
centred on free consent, lawful consideration, and requirement form wherever
essential. The special aspects of an agreement for technology transfer originate
from the fact that whatever is being transferred is not an observable property or
commodity, but something immaterial. It is a notion, an attainment of the mind,
and a part of intellectual expertise, that is being divided by one person for
supporting another. Such a property is now know n as intellectual property
because it is being intellect and also needs intellect for utilisation. But the legal
principles involving intellectual property related to the technology are themselves
in an emerging and evolving state. Several people in the bu siness and law field
do not have a n accurate idea of the type of property being transferred and the
precise consequences of the transfer.
3.2. SUMMARY
1) Exhibit Batches are manufactured after takin g scale up batches of the
product.
2) A confidentiality agreement is a lawful binding agreement between the
provider of confidential information and the receiver of confidential
information, and states the conditions under which the confidential
information is made public.
3) Confidentiality agreements may be referred by other names like
confidentiality deeds , non-disclosure agreements , secrecy agreement ,
mutual disclosure agreement.
4) The receiver can prove it was individually developed by the receiver, along
with employees with no access to the confidential information.
5) The recipient accepts not to use the Confidential Information in any way, or
to manufacture or test any product representing Confidential Information,
excluding the purpose given above.
6) The recipient accepts to use its best efforts for prevention and protection of
Confidential Information, or any part.
7) The first type of arrangement, called licensing, is related to the applicable
rules of the concerned legal system.
* *
8) A memorandum of understanding (M oU) is a non -binding agreement

between two or more parties depicting the terms and specifics of an
understanding, such as each party’s necessities and duties.
9) A transaction including the transfer of technology has many aspects such as
technical, commercial, financial, and even political.
10) It is simple that the principles of law and contracts also apply on agreements
for the transfer of technology.
3.3. EXERCISE

1) Define one way and two way agreements.
2) What do you mean by exhibit batches?
3) Define confidentiality agreement.
4) What is technology transfer plan?

1) Enumerate the documents related to transfer technology.
2) Explain memorandum of understanding and legal issues.
3) Discuss licensing of technology transfer related documentation.
3.3.3. Long Answer Type Question

1) Write a detailed note on confidentiality agreement.
* *
CHAPTER
4 Regulatory Affairs
4.1. REGULATORY AFFAIRS (RA)
4.1.1. Introduction
Regulatory affairs (or government affairs) is an occupation in regulated industries,
like pharmaceuticals, energy, medical devices, and banking. Reg
ulatory affairshold a
precise meaning in healthcare industries, like medical devices, biologics,
pharmaceuticals, and functional foods. Almost every company, be it major
multinational pharmaceutical companies or small, advanced biotechnology
companies, havespecial departments forthe professionalsof regulatory affairs.
Regulatory affairs are an exclusive mi xture of science and management, and it
aims to attain a commercial ly essential objective in drug-development
organisations. Regulatory affairs supervise development plan, writing/reviewing,
collecting and submission management. They provide tactical and practical
advices at t he top level in their companies. During the initiation of product
development, they provide commercial and scientific support; and, they also play
a major role in the success of a development programme and the company.
Quality assurance
Unapproved products
Communications
Management Investigational exemptions

Initial
Licensees Amendments
Meetings
Reviews
Development Annual reports

Lot release(s)
Regulatory authority
Regulatory Affairs
Suppliers Process changes

Adverse events
Clinical
Approval applications
Manufacturing
Communications
Inspections
Approval products
Licensors
Changes
Meetings
Reviews
Customers Annual reports

Adverse events
Marketing License updates
Quality control Promotional materials Inspections
Legal Compliance action
Figure 4.1: Spectrum of RA
4.1.2. Objectives
Regulatory affairs have the following objectives:
1) They acquire approval quickly and completely.
2) They make submissions according to the project timelines, and maintain the
portfolio as per the regulations all over the world.
* *
Regulatory Affairs (Chapter 4) 79
3) They maintain good communication with the health authorities for ensuring
efficient and suitable drug development in various areas of the world.
4) They make CMC submissions with least enquiries, maintain regular supply
of medicines to the market, introduce new medicines in the market, and obey
regulatory compliance guidelines established by the health authorities.
5) They determine whether or not a product with t he provided trial designs
could be endorsed, and also ensure that all marketing and sales materials for
external distribution are compliant.
4.1.3. Need of Regulatory Affairs

The medical device research and development and pharmaceutical biotechnology
industries are one of the most regulated industries in India. As the pharmaceutical
sector of India is developing very rapidly , professionals of regulatory affairs are
needed to fulfil the current requirements of industries for global competition. The
professionals of regulatory affairs create links between pharmaceutical industries
and global regulatory agencies. They should have a good knowledge of laws,
regulations, guidelines and guidance of the regulatory agencies. There is a ri sing
requirement for including the current needs of pharmaceutical industries in the
standard syllabus of pharmacy colleges. This will prepare the students with the
modern advances required to assist the industries.
As the pharmaceutical industries acros s the world are developing and becoming
more competitive, they understand that they can survive by performing the tasks
by knowing the guidelines associated with several activities performed to give a
reassurance that the process is being regulated. Being one of the highly regulated
industries, the pharmaceutical industries are proficient enough to handle the
issues associated with regulatory affairs.
4.1.4. Historical Overview of Regulatory Affairs

Till the 20th century, the Indian drug industry was at a very initial stage. Majority
of the drugs were imported from other countries. The requirement of drugs
immensely increased a fter the First World War , and this resulted in the entry of
affordable and sub -standard dr ugs in the market . The milestones of regulatory
affairs are given below:
1) 1900-1960: Government passed thePoisons Act, 1919 for controlling the cheap
drugs in market. This Act controls the possession or sale of poisonous
substances. It also postulates the safe custody , labelling and packaging,
maximum quantity to be sold , and inspection and examination of poisons sold by
vendors during these years. The Dangerous Drugs Act, 1930 was passed after
the Poisons Act, 1919 to controlthe cultivation of opium plant,manufacture and
possession of opium, its trade(import and export), tranship andsale.
The Narcotics and Psychotropic Substances Act was passed in 1985, and it
annulled the Dangerous Drugs Act, 1930 and Opium Act, 1878. The acts and
rules given below were passed during this time period:
i) Drugs and Cosmetics Act, 1940: This act was passed to control the
import, production, distribution and sale of Allopathic, Unani,
Homeopathic, and Siddha drugs.
* *
ii) Drugs and Cosmetics Rules, 1945: The rules under Drugs and
Cosmetics Act control the production of Ayurvedic drugs for sale, and
not for consumption, use or possession.
iii) Pharmacy Act, 1948: This act was last amended in 1986 and it controls
the pharmacy profession in India.
iv) Drugs and Magic Remedies (Objectionable Ad vertisements) Rules,
1955: This act regulates the advertisement of drugs in India.
v) Drugs Prices Control Order, 1955 (DPCO) (under the essential
commodities Act): In 1995, DPCO was amended again. According to
this rule, the government may assess and fix max imum selling price for
bulk drugs and formulation.
2) 1960-1970: The market share was ruled by multinational companies and only
a few Indian manufacturers were available during these years. The Indian
pharmaceutical industry was in its early development sta ge. Not much
emphasis was put on pure research and development due to absence of patent
production. Because of high dependency on import of drugs, the ir prices
were very high but their availability in market was comparatively low.
3) 1970-1980: Government took medicine control under its hand and passed the
following rules and acts:
i) Indian Patent Act , 1970: This act lays the foundation for patent
protection in India. According to this act, only the manufacture method
and procedure of drug materials was perm itted to get the patent.
Patenting of products was not permitted under this act. Indian Patent Act,
1970 t ook effect from April 20, 1972, and it s ubstituted the Indian
Patents and Designs Act, 1911.
ii) Drug Prices Capped: Drug Prices Control Order (DPCO) was made for
regulating the high price against consumers.
iii) Local Companies Begin to Make an Impact: As the product patent
was allowed by Indian Patent Act , 1970, the indigenous companies
started producing products/ drugs using various manufacturing
procedures by reverse engineering. As a result, new drugs were available
at affordable rates and many substitute drugs were available in the
market in place of the expensive imported new drugs. This increased
exports to Russia, A frica, China, and South America, and als o increased
export of bulk drugs after patent expiry.
4) 1980-1990: The pharmaceutical industry started investing in API process
development and made infrastructure for production. Government also
supplied export incentives. The Narcotic Drugs and Psychotropi c Substances
Act, 1985 was passedto control the processes of narcotic drugs and substances.
5) 1990-2000: The pharmaceutical industry underwent a fast development of
domestic market , and globalisation also occurred at the same time period.
The companies star ted research activity. India became a member of Paris
Cooperation Treaty (PCT) in 1999 and implemented product patent effective
*
from Jan 1, 2005. *
6) 2000-2010: This period is the era of Innovation and Research as du ring this
time period, advanced research ac tivity, patenting of drugs formula and
method, and merger of companies was initiated.
i) Patent Amendment Act, 2005: Under this act, provisions for Black Box
Application were established. According to this, if the application for
patent is applied before Jan uary 1, 2005, the manufacturer can advertise
the product after 2005 according to the transit provision of Trade Related
aspects of Intellectual Property Rights (TRIPS), without trespassing the
product patent, if he has invested substantial ly in the manufacturing of
product produced and advertised on or after January 1, 2005.
ii) Compulsory Licenses: These licenses can be granted for manufacturing
and exporting the drug products to any country having shortage or no
manufacturing capacity at all , for a particular product, for addressing
public health problems.
Herbal preparations with medicinal values can be patented under new amended
laws. Major regulatory change s were made as per the marketing authoris ation
process and guidelines. Some of them are:
1) Drugs and Cos metics (First Amendment) Rules, 2011: It obligates
registration of Clinical Research Organisation (CRO) for carrying out
Clinical Trials (CT). Schedule Y1 recommends the requirements and
guidelines for registration of CROs.
2) Clinical Trial Registry India (C TRI): The ICMR’s (Indian Council of
Medical Research) National Institute of Medical Statistics (NIMS) has
established the CTRI. India has made an online registry system and obligated
CRO registration prior to the admission of first patient for clinical tri als.
CRO is required to reveal the obligatory items as given under the dataset of
WHO International Clinical Trials Registry Platform (ICTRP).
3) Pharmacovigilance Programme of India (PvPI): The Central Drugs
Standard Control Organis ation (CDSCO) started a p harmacovigilance
programme for ensuring drugs safety to Indian patients. This assist s in
monitoring the adverse drug reactions and also the benefit-risk ratio in Indian
patients.
4) Guidance Documents: CDSCO passed direction for i ndustry of Fixed Dose
Combinations (FDCs) registration and guidance for preparing common
technical document for import or manufacture and marketing approval of
new drugs for human use ( i.e., New Drug Application - NDA). CDSCO
employed a system for preliminary inspection at the time of receiving
application for marketing approval of FDCs.
4.1.5. Regulatory Authorities

With the development and increasing competitiveness ofpharmaceutical industries
across the world, regulatory authorities are being established in different countries
all over the world. Regulatory authorities and organisations are accountable for
efficient drug regulation needed for ensuring the safety, efficiency and quality of
drugs, and the precision and correctness of the drug information avail able to the
* *
public. Regulatory bodies give tactical, planned and operative direction and
assistance for working under regulations to accelerate the growth and transfer of
safe and efficient healthcare products to people across the world.
Pan American Heal th Organis ation (PAHO), Inte rnational Conference on

Harmonisation (ICH), World Health Organisation (WHO), World Trade
Organisation (WTO), and World Intellectual Property Organis ation (WIPO) are
various international regulatory authorities and organisations that are important
for all facets of pharmaceutical regulations associated to drug product
registration, manufacturing, supply, price control, marketing, research and
development, and intellectual property protection.
Each country has a regulatory agen cy that is accountable for imposing rules and
regulations and passing guidelines for drug development, registration, licensing,
manufacturing, marketing and labelling of pharmaceutical products.
Table 4.1: Some Countries and their Regulatory Authorities
Countries Name of Regulatory Authorities
USA Food and Drug Administration (FDA)
UK Medicines and Healthcare Products Regulatory Agency (MHRA)
Australia Therapeutic Goods Administration (TGA)
India Central Drug Standard Control Organisation (CDSCO)
Canada Health Canada
Europe European Medicines Agency (EMEA)
Denmark Danish Medicines Agency
Costa Rica Ministry of Health
New Zealand Medsafe  Medicines and Medical Devices Safety Authority
Sweden Medical Products Agency (MPA)
Netherlands Medical Evaluation Board
Ireland Irish Medicines Board
Italy Italian Pharmaceutical Agency
Nigeria National Agency for Food and Drug Admi nistration and Control
(NAFDAC)
Ukraine Ministry of Health
Singapore Centre for Pharmaceutical Administration Health Sciences Authority
Hong Kong Department of Health  Pharmaceutical Services
Paraguay Ministry of Health
Sweden Medical Products Agency (MPA)
Thailand Ministry of Public Health
China State Food and Drug Administration
Germany Federal Institute for Drugs and Medical Devices
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Pakistan Drugs Control Organisation, Ministry of Health
South Africa Medicines Control Council
Sri Lanka SPC, Ministry of Health
Switzerland Swissmedic, Swiss Agency for Therapeutic Products
Uganda Uganda National Council for Science and Technology (UNCST)
Brazil Agencia Nacional de Vigilonica Sanitaria (ANVISA)
Japan Ministry of Health, Labour and Welfare (MHLW)
* *
4.1.5.1. Scope
Regulatory agencies oper ate as a protector that confirms the safety, efficiency
and quality of drugs accessible by the public, that identifies the strength s and
weaknesses of drug regulation , and that suggests approaches for improving drug
regulation. They are also important for ensuring and increasing regulatory
implementation in non -regulated regions of the world for protection of people
living there. The international regulatory authorities perform a vital role in all
facets of pharmaceutical regulations associated to drug prod uct registration,
manufacturing, supply, price control, marketing, research and development, and
intellectual property protection.
4.1.5.2. Challenges
The main challenges of these regulatory agencies are:
1) To support public health and provide protection to the public from harmful
and suspicious drugs.
2) To create suitable legalisation for e very product with a medicinal claim and
all significant pharmaceutical activities , whether performed by the public or
by the private sector.
3) To increase the regulatory growth across the world for ensuring the public
safety.
4.1.6. Role of Regulatory Affairs Department

The regulatory affairs division of a pharmaceutical company is accountable for
procuring the approval for new pharmaceutical pro ducts and guaranteeing that
the approval is retained till the time the company wants to market the product. It
acts as an interface between the regulatory agency and the project team. It is the
medium of communication with the regulatory agency as the proj ect continues,
with the objective to confirm that the project plan properly precedes what the
regulatory agencies will need for product approval.
It is the duty of regulatory affairs departmentto be up-to-date with latest legislation,

guidelines and other regulatory intellect. Such rules and guidelinesfrequently allow
flexibility, and the regulatory authorities anticipate companies to take accountability
for determining how they should be understood. The regulatory affairs department
has an essential rol e in advising the project team on how to understand the rules
properly. At the time of development, good working relationsshould be maintained
with the authorities, e.g., for discussing issues like divergence from guidelines,
formulation development, andclinical study programme.
Majority of the companies analyse and give priority to new products on the basis
of an intended Target Product Profile (TPP). The regulatory affairs specialists
give advices on what will be the accurate prescribing information (l abel) for the
anticipated product. Being a member of the project team , professionals of
regulatory affairs also help in designing the development programme. The
regulatory affairs department analyses every documentation from a regulatory
perception, and certifies that it is clear, reliable, complete, and its conclusions are
clear. The department also prepares the core prescribing information that serves
* *
as a base for global approval, and will later offer the marketing platform. The
documentation comprises of clinical trial applications and regulatory submissions
for new products and f or changes to approved products; this is the main duty of
the regulatory affairs department and it accounts for almost half of the work.
An essential hands-on duty of the regulatory affairs department is to supply input

when legislative modifications are discussed and recommended. In the ICH
surroundings, there is a greater chance to exercise influence at an initial stage.
4.1.7. Responsibility of Regulatory Affairs Professionals

The professionals of regulatory affairs stay up-to-date with the dynamic
legislation in every region where the company wants to market its products. They
also give advises on the legal and scientific l imitations and necessities, and
collect, organise, and analyse the scientific data generated by their research and
development associates. They are accountable for presenting the registration
documents to regulatory authorities, and perform all the negotia tions required for
maintaining marketing authorisation for the concerned products. They provide
tactical and practical advices at the top level in their companies. During the
initiation of product development, they provide commercial and scientific
support; and, they also play a major role in the success of a development
programme and the company.
It may require up to 15 years for producing and launching a new pharmaceutical

product. Several problems may arise during the process of scientific development
and because of a varying regulatory environment. The professionals of regulatory
affairs aid the company in avoiding complications caused by poorly kept records,
incorrect scientific thinking , or poor data presentation. In several product areas
where regula tory requirements are obligatory, limitations are enforced on the
claims that can be made for the product on labelling or in marketing.
Regulatory a ffairs advisor shows important portfolio in Health Authorities as

well as pharmaceutical industries:
1) Role of Regulatory Affairs Professionals in Health Authorities (HA)
i) Evaluation of MAA (Marketing Authorisation Application) : This
involves:
a) Evaluation of new drugs application , new biologics a pplication,
medical device and cosmetics application , generic applicat ion,
clinical trial application, v ariation application, drug master files for
API, excipients and packaging materials, and site master fi le for
GMP inspection.
b) Issue of evaluation comments/exigencies to manufacturers.
c) Management of various application s, po st-approval changes , and
maintenance of annual update record.
d) Approval of post-marketing management.
e) Issue of MAA, GMP, and GCP approval certificate.
f) Management of MAA on-line and up-gradation to common technical
document format.
* *
ii) Input for Guidelines and Guidance Documents: This involves:

a) Issue of guidelines and guidance documents for quality, safety,
efficacy, pricing control, and CTD for implementation.
b) Collaboration with global and regional harmonisation units to
exchange technical information , to develop guidelines, and to
allocate mutual recognition status for technical documents, GMP
status, and product approval.
c) Facilitating smooth management of p harmaceutical business in
countries as a part of foreign trade delegation and reducing barrier by
decreasing duplicate generation of technical data and timeline to
evaluate and approve by respecting each others regulatory framework.
iii) Inspection: It involves audit of GMP at drug manufacturing site, audit of
GCP at clinical study site and bio-equivalence centre , and issuance of
certificate to confirm the approval status.
iv) Support to Pharmaceutical Manufacturers: This involves:
a) Providing support to the pharmaceutical manufacturers to define
drug development pathway during p re-NDA meeting and to provide
comments/confirming development pathway.
b) Conducting timely meetings with the pharmaceutical manufacturers
association to discuss on -going challenges , technical issues,
guidelines/guidance documents discussion and future development.
v) Monitoring of Drug Safety and Efficacy: This involves:
a) Collection of pharmacovigilance and timely reviewing drugs in markets
by studying the labels and taking necessary actions if required.
b) Monitoring clinical t rials and also approv ing the results of study to
perform the next phase of study.
c) Performing fast track designation for drugs which are critical for
patient population.
2) Role of Regulatory Affairs Advisor in Pharmaceutical Industries
i) Define Regulatory Strategy for Drug Development: The regulatory
strategist actively plays the followi ng roles d epending on the intended
market:
a) Selection of drug products for specific market.
b) Acts as an essential part of business development, marketing and
project team meeting.
c) Explains the type of application by consulting with the specified
Health Authority, i.e., New Drug or Generic Application.
d) Defines clinical regulatory pathway by interacting with the Health
Authorities.
e) Prepares Global Regulatory Plan (GRP) defining Chemistry,
Manufacturing and Control (CMC), Clinical and Non -Clinical
Requirements.
f) Give advises to the Research and Development (R&D) team for
developing product at a laboratory scale matching regulatory criteria.
For a generic drug , the regulatory strategist advise s on which
* *
Reference Listed Drug (RLD) should be used, test criteria and

specifications for API and drug product of different dosage forms,
stability data requirement of specific climatic zone (Zone I -IV) for
drug substance and product, analytical validation requirement, and in
vitro equivalence data.
g) Provide support for the ex ecution of validation batches at
manufacturing location, for defining batch size, number of batch
sizes, criteria and ju stification for specification and evaluation of
technical data.
h) Defines procedure for Bio -Equivalence (BE) or Bio -Availability
(BA) and allows agreements from the respective Health Authority.
i) Describes labelling requirement s for generic submission, replica of
innovator labelling information. A new drug is labelled on the basis
of actual clinical and non-clinical study.
j) Applies for site ins pection for good practices confirmation, for
manufacturing site for GMP certification, and for BE and clinical site
for GCP certification.
ii) Marketing Authoris ation Application: The regulatory advisor
performs the following functions in pharmaceutical indust ry, under the
Marketing Authorisation Application:
a) Provides information about the submission type , i.e., New Drug
Application (NDA), New Biologic Application (NBA), Clinical Trial
Application (CTA), generic application, branded generic application,
post-approval changes, variation application, etc.
b) Helps in compiling the Type I -IV Drug Master Files (DMF), i.e.,
Active Substance DMF, Site Master File (SMF), packaging material
master file, and excipient master files. These files are submitted prior
to marketing.
c) Prepares dossier in an acceptable national format or Common
Technical Dossier (CTD) format for global submission.
d) Explains dossier application with recommendation and precedence of
other regulatory agencies and global and regional requirements.
e) Gives formal application for MAA to the respective Health
Authority.
f) Provides technical evaluation and support to manufacturing location
and clinical sites at the time of inspection.
g) Helps in drafting query/exigency’s response to the respective Health
Authority prior to discussion.
h) Helps in drug submission, preparation of approval calendar ,
prediction of timeline required for approval of drug product, and
supporting marketing department for launch schedule.
i) Manages life cycle of drug product r egistration by timely submitting
post-approval changes, annual update, and renewal submission.
j) Submits pharmacovigilance data to the respective Health Authority
for drugs already in the market.
k) Withdraws or cancels the application for drug, if required.
* *
iii) Health Authority Relationship: This involves:

a) Participates in meeting of Health Authorities and gives advises
regarding the guidelines as per the industrial requirements.
b) Gives suggestions and recommendation s for drafting guidelines and
circular.
c) Helps in maintaining good working relationship with the evaluators
of Health Authority.
d) Stays updated about latest regulatory guidelines and forthcoming
changes in order to act proactively for aligning the manufacturers as
per the regulations.
iv) Regulatory Systems and Processes: This involves:
a) Maintains records for drug product submission and approval
database.
b) Drafts Standard Operating Procedure (SOP) for smooth management
of drug regulatory affairs department.
c) Provides internal training to staff to keep them updated about
regulatory environment.
d) Exchanges regulatory knowledge by participating in regulator y
forums/conferences/webinars/seminars.
e) Keeps records of documents through Information Technology (IT).
f) Maintains software for on -line submission in Common Technical
Dossier (CTD) format.
4.2. SUMMARY
1) Regulatory affairs (or government affairs ) is an occupation in regulated
industries, like pharmaceuticals, energy, medical devices, and banking.
2) Regulatory affairs hold a precis e meaning in healthcare industries, like
medical devices, biologics, pharmaceuticals, and functional foods.
3) Regulatory affairs are an exclusive mixture of science and management, and
it aims to attain a commercially essential objective in drug -development
organisations.
4) They make submissions according to the project timelines, and maintain the
portfolio as per the regulations all over the world.
5) They maintain good communication with the health authorities for ensuring
efficient and suitable drug development in various areas of the world.
6) They make CMC submissions with least enquiries, maintain regular supply
of medicines to the market, introduce new medicines in the market, and obey
regulatory compliance guidelines established by the health authorities.
7) They determine whether or not a product with the provided trial designs
could be endorsed, and also ensure that all marketing and sales materials for
external distribution are compliant.
8) The professionals of regulatory affairs create links between pharmaceuti cal
industries and global regulatory agencies.
9) Government passed the Poisons Act, 1919 for controlling the cheap drugs in
*
market. *
10) The Dangerous Drugs Act, 1930 was passed after the Poisons Act, 1919 to
control the cultivation of opium plant, manufacture a nd possession of opium,
its trade (import and export), tranship and sale.
11) The Narcotics and Psychotropic Substances Act was passed in 1985, and it
annulled the Dangerous Drugs Act, 1930 and Opium Act, 1878.
12) Drugs and Cosmetics Act, 1940 was passed to cont rol the import,
production, distribution and sale of Allopathic, Unani, Homeopathic, and
Siddha drugs.
13) Drugs and Cosmetics Rules, 1945 control the production of Ayurvedic
drugs for sale, and not for consumption, use or possession.
14) Pharmacy Act, 1948 was last amended in 1986 and it controls the pharmacy
profession in India.
15) Drugs and Magic Remedies (Objectionable Advertisements) Rules, 1955
regulates the advertisement of drugs in India.
16) Drugs Prices Control Order, 1955 (DPCO) was amended again. According
to this rule, the government may assess and fix maximum selling price for
bulk drugs and formulation.
17) Drugs and Cosmetics (First Amendment) Rules, 2011 obligates
registration of Clinical Research Organisation (CRO) for carrying out
Clinical Trials (CT).
18) The ICMR’s (Indian Council of Medical Research) National Institute of
Medical Statistics (NIMS) has established the CTRI.
4.3. EXERCISE

1) Define regulatory affairs.
2) Mention the objectives of regulatory affairs.

1) What are scope and challenges of regulatory affair authorities?
2) Explain the role of regulatory affairs department.

1) Briefly discuss the historical overview of regulatory affairs.
2) Discuss the responsibilities of regulatory affairs professionals.
* *
Regulatory Requirements for Drug Approval-I (Chapter 5) 89
CHAPTER Regulatory Requirements

5 for Drug Approval-I
5.1. REGULATORY REQUIREMENTS FOR

DRUG APPROVAL
5.1.1. Introduction
Drug approval process is a regulatory procedure, through which a
person/sponsor/innovator/organisation gets approval to promote a drug in
the market . Generally, a drug approva l process involv es many stages, like
application for conducting clinical trials, conducting clinical trials, approval
application for marketing of drug, and post -marketing studies. All countries have
their own regulatory agencies that impl ement the rules and regulations a nd pass
guidelines for controlling the marketing of drugs.
Every country has to follow diverse regulatory requirements for approval of a

new drug. A single regulatory method is applicable for Marketing Authorisation
Application (MAA) in different countrie s, and this is a very difficult task. Thus ,
it is important to know about regulatory requirements for MAA of each country.
The regulatory requirements of every country should be fulfilled for getting
approval for a new drug in that country.
It is challeng ing to follow the same regulatory procedure for approval of a new
drug in different countries. Henceforth, gain ing knowledge about regulatory
requirements of different countries is a necessity . It is known that the United
States of America (USA) and the Eu ropean Union (EU) are the most budding
markets for drug products across the world; majority of the companies , therefore,
emphasise on their pharmaceutical legislations.
Drug Drug Development Clinical Trials in Marketing

Discovery Application
and Manufacturing Human
Compliance with Regulatory Requirement is Necessary
Figure 5.1: Regulation of Drug Approval Process
When a lead molecule is recognised for a target disease, it should be optimised.

Following the discovery of a drug, pre -clinical trials should be performed on
animals to guarantee safety and efficiency. An application to get approval for
performing clinical trials should be submitted to the concerned authority of the
related country. Clinical trials are carried out in four phases to guarantee safety
* *
and efficiency, and then the drug dose in humans is optimised. Thereafter, a
Marketing Authorisation Application (MAA) is submitted to the concerned
authority. The application is approved if the drug fulfils the criteria for safety and
efficiency, and proves that its benefits are more than its risks.
5.1.2. Drug Approval Process in India

The Drug and Cosmetic ’s Act 1940 and Rules 1945 was announced by the
Indian Parliament to control the import, manufacture, supply, and sale of drugs
and cosmetics. The Central Drugs Standard Control Organisation (CDSCO),
and the office of its head, the Drugs Controller General of India (DCGI) was
established.
Indian government included Schedule Y to the Drug and Cosmetics Rules 1945
in 1988 . Schedule Y offers the guidelines and requirements for clinical trials,
which were revised in 2005 to make it equivalent to the procedure recognised
across the world.
An Indian company if wishes to manufacture/import a new drug should apply for

approval from the licensing authority (DCGI) by filling in Form 44 and also
submitting data as provided in Schedule Y of Drugs and Cosmetics Act 1940 and
Rules 1945. To validate the efficiency an d safety of the new drug in Indian
population, clinical trials should be conduc ted as per the requirements and
guidelines specified by Schedule Y . These guidelines for clinical trials were
revised in 2005 to make it equivalent to theprocedure recognised across the world.
According to the Rule-122A of the Drugs and Cosmetics Act, it is not necessary
to conduct clinical trials for new drugs that are approved and being used for
many years in other countries. Section 2.4 (a) of Schedule Y of Drugs and
Cosmetics Act 1940 and Rules 1945 states that drugs discovered in India should
undergo all phases of clinical trials. Section 2.4(b) of Schedule Y of Drugs and
Cosmetics Act 1940 and Rules 1945 states that for drugs discov ered outside
India, the applicant should submit the data presented by other countries and the
licensing authority may replicate all the studies or allow the applicant to start
from Phase III clinical trials.
The modifications in Drugs and Cosmetics Act comprises of launching

definitions for Phase I-IV trials and duties of investigators and sponsors. In 2006,
the clinical trials were divided into two classes. In one class, clinical trials can be
performed in other countries having competent and reputable regulatory systems,
while the other ones fall in the other class.
An appli cation for performing clinical trials in India and the data of
manufacturing, chemistry, control and animal studies should be submitted to
DCGI. The data concerning the trial protocol, investigator’s brochures, and
approval documents should also be submitted. One copy of the application
should also be submitted to the ethical committee and the clinical trials are
performed only after getting approval from the DCGI and ethical committee.
* *
Phase I clinical trials are performed f or controlling the adverse reactions and
maximum tolerated dose in healthy human volunteers. Phase II clinical trials
are performed for determining the therapeutic uses and effective dose ranges in
10-12 patients at each dose level. The confirmatory or Phase III trials are
performed for generating data related to the efficacy and safety of the drug in
about 100 patients from 3 -4 centres and confirming the efficiency and safety
claims. If the new drug is not marketed in any country, Phase III trials should be
performed on at least 500 patients from 10-15 centres.
After getting NDA approval, the o rganisation can supply and sell the product,
and it is thought to be in Phase IV trials, in which new applications or new
populations, lasting effects, etc. are discovered.
Applicant
IND application filing to

CDSCO headquarters
Application to ethical
committee Examination by new drug
division
Detailed review by IND

Report of ethical committee
committee
Recommendation to DCGI
Within 12 weeks IND application approved

If positive
Clinical trials started
Application for new drug

registration to CDSCO
If not complete
Review by DCGI
Refused grant license
If complete
License is granted
Figure 5.2: Drug Approval Process in India
5.1.3. Drug Development Teams

New drug development can be performed by various types of drug development
organisations that may be private companies, not -for-profit organisations , or
private foundations. Some examples of private not-for-profit organisations
include the Drugs for Negl ected Diseases initiative (DNDi ), European
Organisation for the Research and Treatment of Cancer (EORTC), One World
Health, and the Global Alliance for Tuberculosis (TB) Drug Development.
New drugs are developed by drug development teams that are assisted by efficient
departments, like clinical operations, pharmaceutical development, or toxicology.
Drug development teams are regularly extended with academic and industrial
advisors and important opinion leaders who assist in the decision-making process.
* *
The teams may request contract research organisations or academic research

entities to perform some parts of the drug development activities. For example, a
team may choose to outsource the manufacturing of the new drug to a third party.
But, it should be kept in mind that the financial, legal and regulatory responsibility
and accountability stays with the drug development organisation, called as the
sponsor of the development of a new drug.
The sponsor provides infrastructural requirements (laboratories, offices,

manufacturing, and pilot plants) and other required resources (financial and
human) to the drug development teams and work as a partner with whom the
regulatory agencies communicate. Association between the drug development
organisation and its contributing partners and service providers facilitate the
development of a new drug. Health agencies are also essential for directing drug
development organisations in the course of their development efforts.
Due to the versatile nature of a drug development project , it is not possible for a
particular person to gain knowledge about all the scientific fields (varying from
chemical engineering to clinical practice) that contributein drug development. This
problem is resolved by a close association between the members of an international
drug development team. A team like this is led by global drug development team
leader who is a proficient manager and reports to the higher management.
Such a team comprises of experts who are accountable for a particular drug
development area. They represent every function required for the drug
development, and this representation may alter during the development of drug.
For example , during initial development , the emphasi s is on using the drug
candidate in humans for the first time and on demonstrating that the drug is
therapeutically active; while, in the later stages of development , emphasis is put
on the commercial facets of the drug.
Generally, the main functions in the team are represented by experts in:
1) Chemical and pharmaceutical development,
2) Non-clinical development,
3) Clinical development,
4) Regulatory affairs,
5) Finance,
6) Marketing, and
7) Project management.
These experts are the leader s of a functional team that is resp onsible for
implementing the decisions taken at the level of the drug development team.
Each efficient team ( e.g., chemical and pharmaceutical development) c omprises
of scientists who help in particular parts, ( e.g., pharmaceutical development,
chemical pr oduction, analytical development, chemical pilot -plant production,
stability investigations, sup ply-chain management, and packaging and materials
science). For example, development of a suitable dosage form (tablet) is directed
by a proficient plant manage r or pharmaceutical drug delivery expert having
interpersonal and technical skills that are necessary for the task.
* *
Figure 5.3 presents the structure of drug development team and its association
with the functional teams.
Drug Development Team Leader
Drug Chem-pharm Non-clinical Clinical Regulatory Project Finance

Development leader leader leader affairs leader manager manager
Team
Chem-pharm
leader
Analytical Pharmaceutical Process Project
Functional development development Production chemistry Finance
manager manager manager
Team leader leader leader
Analytical development
leader
Analytical Analytical Quality Quality Stability Specification
Functional development development
control API control drug testing and
development
Department API drug product product shelf-life
Figure 5.3: Drug Development Team and Functional Teams
The compositio n of drug development team may vary during development.

Figure 5.4 depicts a modification in functional representation in the team when a
drug candidate is transferred from the early phases of development to the later
phases. The size of the squares repres ent their contribution in the team. For
example, the role of clinical development increases considerably when a drug
candidate is transferred from initial development phase to late development phase
during the major clinical trials.
Early Development Late Development
Function input Team Team
Chemical/Pharmaceutical
Non-clinical
Clinical
Regulatory affairs
Project management
Finance
Pharmacoeconomics
Marketing and Sales
Figure 5.4: Functional Input in Early and Late Development Teams
5.1.4. Non-Clinical Drug Development

Non-clinical drug development (or pre-clinical drug development) is a risk-based
process involving evaluation of safety and efficiency of drugs in animal drugs that
extrapolate to probable human outcome. The pre -clinical pharmacological and
toxicological drug responses in comparison to dose schedule and route of
administration allows initiating and continuing research in humans. Generally, pre-
* *
clinical studies are conducted to forecast the safetyand efficiency data from animal
models that assist in conducting research in human s. Before using a new active
substance as a medicinal product,its safety and efficiencyis tested in animals before
using it in humans; this is known as a pre-clinical study. The pre-clinical studies
also require approval from the regulatory authorities that should assure that the
clinical trials are being performed ethically and safely and should give approval
only for safe and effective drugs. ICH has put down some basic guidelines, which
summarise technical necessities of satisfactory pre-clinical drug development.
The goals of non-clinical development in the development of a drug are:
1) Selecting drug molecules in late discovery (lead optimisation phase) for
transferring the drug candidate to initial development.
2) Evaluating the s afety and bioavailability of drug candidates for the first -in-
man study.
3) Evaluating the safety and bioavailability of drug candidates for l ong-term
treatment, involving women of child -bearing age a nd children in clinical
trials, combining with other drugs, introducing new pharmaceutical
formulations and administration routes.
4) Evaluating the carcinogenicity potential of drugs under development.
5) Elucidating the mechanisms of toxic action and estimating their significance
in man.
6) Studying the toxicology and genotoxicology conditions of drug impurities.
7) Evaluating the safety of intermediates in drug manufacturing for
occupational health and safety.
8) Evaluating the safety of excipients used in formulations.
9) Elucidating the mechanisms of toxic action in translational drug research.
Each new drug molecule should cross the hurdle of pre -clinical phase to enter
clinical trial phases. A drug which successfully finishes this phase has only 20%
probability to reach the market. Pre-clinical studies restrict the risks to patients to
minimum. It is essential to harmonise all the drug characteristics as per the
ethical principles of medicine and animal protection.
New active
molecule
Pre-clinical
In vitro tests (safety and
studies
efficacy)
In vitro tests in animals (safety

and efficacy)
Clinical studies
Phase I - Phase II -
Phase III - Phase IV
Figure 5.5: Non-Clinical Drug Development
The objective of non -clinical developmen t is to fulfil all the necessities that
require to be fulfilled before a new compound is considered ready to be tested for
the first time in humans. The pre -clinical drug development process can be
conducted disciplines of General Pharmacology and Toxicology.
* *
5.1.4.1. Pharmacology
Pharmacology deals with the pharmacokinetic and pharmacodynamic aspects of
a drug. It is essential to examine the unwanted pharmacological activity in
suitable animal models and observing them in toxicological studies.
Pharmacokinetic stu dies are essential ly useful in discovering the safety and
efficacy parameters in terms of Absorption, Distribution, Metabolism and
Excretion (ADME). Pharmacokinetic or ADME studies are used to determine
the drug pathway in body. These studies provide infor mation on absorption rate
for various administration routes that assist in dosage form selection,
mechanism of distribution, and metabolism and excretion rates, which further
help in estimating the drug half-life (t1/2). Half-life of a drug tells about the
safety profile of that drug that is essential for a drug for getting approved by the
regulatory authorities.
Preliminary pharmacology assessments in in-vitro or animal models have

suggested that a molecule and a biological process undergo interaction indicative
of a human therapeutic benefit. Depending on the design and amount of these
initial studies, more pharmacology studies may be required for further
characterisation of the dose or physiological fluid concentration, response curve
using the suggested clinical route and administration frequency.
These pharmacology studies should possibly be performed on a minimum of two

species to demonstrate that the biological response is independent of species. The
ED50 dose should be estimated and divided into no -observable-toxic-effect dose
in same animal species, specified in the toxicology section. This value gives the
therapeutic ratio or index. If the ratio is 1 or less, a molecule will produce
adverse effects along with the therapeutic response. As long as th e molecule is
for treating a fatal disease (like AIDS, some cancers, or some CNS condtions), a
low therapeutic ratio is a warning sign that the molecule may not have the
required properties to continue its development. If the ratio is 5 or 10 or more, a
molecule will produce a pharmacological effect before pr oducing dose -limiting
toxic effects.
These developability pharmacology studies should be performed with dosing to

steady state, unless the dosing rate to be used in clinical trials is as a single dose
therapeutic. The frequency of doses needed to achieve steady state is dependent
on the molecule’s pharmacokinetic profile in the same animal model. These
multiple-dose studies give data on the frequency of dosing required to increase
the biological response. This is especially necessary for compounds inhibit ing an
enzymatic system or is operative only in some specific phases of cell cycle.
These pharmacology assessments help in choosing the dose levels and route and
frequency of administration for preliminary and final toxicology studies, and also
for initial phase one safety and tolerance human trials. In case the effective
pharmacological dose is not known, underdosing and attaining no -therapeutic-
response or overdosing and not able to define a no-observable-toxic effect dose
are unwanted pro babilities. In such conditions, development of a potentially
useful therapeutic agent should be inappropriately stopped.
* *
Preliminary Animal Pharmacokinetics

The first animal pharm acokinetic study showed that the bioa nalytical chemistry
procedure help s in chara cterising the absorption and desorption profiles of the
lead molecule. The animal species employed for this study is same as that
employed in pharmacological evaluations, i.e., a rodent.
A study design for a mol ecule exhibiting pharmacological activity on oral

administration to rats may comprise of dosing a minimum of two rats with
intravenous bolus injections at a dose level between 25% and 50% of th e
pharmacologically active dose. This also involves dosing a mi nimum of two rats
orally at the pharmacologically active dose. Serial blood samples of each rat are
processed to acquire the required physiological fluid, and are evaluated by
bioanalytical chemistry method.
The plasma concentration versus time profiles after dosing intravenously give the
preliminary data on distribution and disposition kinetics of the molecule. These
intravenous outcomes assure that the assay method is used for measuring the lead
molecule in samples collected from animals, forecasting the concentration range
that can be anticipated in animal samples, and determining the sampling times in
more conclusive animal pharmacokinetic experiments.
Toxicology studies should be essentially performed in two or more species f or

majority of drug develo pment programs . In this condition, preliminary animal
pharmacokinetic studies should be carried out in every species proposed to be
used in animal safety studies.
If variations in delivery or disposition occurs between species and this

consequently increases or decreases the toxicology profiles, the pharmacokinetics
may explain the different toxicology profiles. Physiological fluid samples should
be acquired from animals in the preliminary toxicology studies for determining
the amo unt and regularity of exp osure; and this study is referred to as
toxicokinetics.
Generally, three to four samples from every animal are collected for toxicokinetic
evaluations; however, that much amount of sampling may not be achievable for
all studies. A single sample at a certain collection time can be acquired from one
to two animals in a dose group . The other animals in that dose group can be
sampled later. Evaluation of these samples gives information only on the amount
of exposure in a dose group (and not on the uniformity of exposure).
Samples for conducting multiple-dose studies are obtained after the first dose and
after the last, or next to the last dose. The outcomes give information on possible
variations in exposure and on the accumulation capability of the lead molecule or
drug candidate. The results can be employed for designing multiple -dose animal
pharmacokinetic and tissue distribution studies.
If the disposition or accumulation undergo significant modifications, the dosing

regimen should essentially be changed f or obtaining the required concentration
profile after dosing to a steady state.
* *
5.1.4.2. Drug Metabolism

Estimation of d rug metabolism or ADME gives information about the fate of a
compound in the body, i.e., its absorption (how a compound enters the body),
distribution (where the compound goes in the body ), disposition (how long the
compound stays in the body) , metabolism ( whether the compound is changed in
the body and to what) , and elimination (how the compound is removed from the
body).
Drug metabolism studies in animal species already used or to be used in

toxicology studies are performed using a labeled compound, generally a
radioactive isotope , like carbon -14. Sometimes, drug metabolism studies are
performed with a less than re quired radiolabel, like I 125 on a protein or H 3 at a
potentially exchangeable site on an NCE. But, the study outcomes can be
confusing, reflecting the distribution and disposition of the label ed compound
and not the lead molecule or its metabolites.
To get more dependable results, the radiolabeled compounds should be

radiochemically pure, stable, and have a specific activity that is sufficiently high
to be measurable after dosing. The label should be at a position where it does not
affect the physical, chemical or pharmacological properties of the drug candidate,
and is not lost during phase 1 (oxidation, reduction, and cleavage) or ph ase 2
(conjugation) metabolism.
Before dosing the animals, the radiochemical purity should be determined and
the stability in physiological matrices should be studied. If the radiolabel is non-
metabolically removed from the compound, the outcomes of drug metabolism
studies or other studies employing the labeled compound will have a little
significance or practicality in the evaluation of the metabolic fate of the lead
molecule.
If the lead molecule has a slow disposition phase (signifying distribution into
some extravascular tissues ) or if the preliminary toxicology experiments
recognise probable organs of toxicity, an initial mass balanc e along with tissue
distribution study can be designed. This study evaluates the radioactivity level
versus time profile in tissues, like liver, kidney, fat (for a lipophilic drug), skin,
muscle, heart, and brain and finds the primary route(s) and rate(s) of elimination.
The outcomes of this preliminary metabolism study can also be effectively used
for designing (i.e., selection of time points and matrices for evaluation) the
perfect mass balance and tissue distribution studies to support regulatory
authority submissions.
The amount of total metabolites present is estimated by subtracting the parent

compound concentration (determined by bioanalytical chemistry method) in a
sample of plasma, serum, urine, bile from total radioactivity. The extent of
metabolism is low if the d ifference is minimum and does not vary with time. A
small difference for plasma or serum samples suggests that metabolites are not
available in systemic circulation. A high radioactivity level for bile or urine
samples indicate a primary route of elimination for the parent and metabolites.
* *
A preliminary metabolite profile of a lead molecule (cleared by metabolism ) in

urine and bile can estimate the amount of each potential metabolite. When the
metabolite in a matrix is present in high levels, i.e., > 5% of the parent
compound, efforts should be made for isolating and identifying the metabolite ,
and the outcomes should be compared with in vitro drug metabolism studies (if
conducted). When appropriate quantities of metabolites are present, their
pharmacological and toxicological activity potential can be determined, and this
provides more information on the pharmacological and toxicological mechanism
for the lead molecule.
One of the first metabolism studies performed should be protein binding in

physiological fluid of animals and human s. The pharmacological and
toxicological activity of a lead molecule is generally associated to the free or
unbound fraction in systemic circulation (and not to the total drug content
comprising of free as well as bound drug). The unbound drug passes through the
cell walls of blood vessels and spread s to different organs, like pharmacological
and toxicol ogical action sites. The free and bound parts of a drug are in
equilibrium in a way that the free drug is removed from systemic circulation, the
bound drug separates to sustain the free-to-bound ratio.
A lead molecule highly and tightly bound to blood proteins, i.e., > 95%, may not
have enough distribution to achieve the required concentration at the action site
to produce a pharm acological action. In cases like this, a bioanalytical chemistry
method may be required to quantify the unbound drug so that the
pharmacokinetic profile of the free fraction can be estimated.
In a lead molecule bound to blood proteins in < 95% extent, the quantity of free
drug and the equilibrium process correlates the total drug concentration in
systemic circulation with the pharmacological or toxicological responses.
Mass balance and tissue distribution are the two most usual drug metabolism
studies. Mass balance studies are performed in rodent and non -rodent species for
toxicology estimations; while, tissue distribution studies are conducted only in
rodents. In mass balance studies, a radiolabeled compound is administered to the
test species , and sample s from urine, faeces, and expired air are collected at
particular intervals (0-4, 4-8, 8-12, 12-24, and then daily up to 168 hours or till
more than 95% of the administered dose has been eliminated) and quantified for
total radioactivity. However, the phar macokinetic profile of the drug candidate
determines the collection intervals so that a better view of the excretion profile
can be obtained.
In tissue distribution studies, a radiolabeled compound is administered to the test

species, which are sacrifice d after predefined time intervals (2, 4, 8, 24, and 48
hours), and tissues are collected, treated, and quantified for total radioactivity.
The estimated tissues are similar to those collected in toxicology studies during
necropsy ( table 5.1) plus the carcass. A technique which is in use by some
pharmaceutical companies for substituting tissue distribution studies is the
Quantitative Whole Body Autoradiography (QWBA).
* *
With the latest developments, this technique can measure low levels of
radioactivity in tissues. Some researchers believe that QWBA should completely
replace the classic tissue distribution study to profile the exposed organs and
systems and may accumulate the lead molecule and its metabolites.
Table 5.1: Tissues Collected at Necropsy and Prepared for Histopathological
Evaluation
1) Adrenal glands 22) Pancreas
2) Aorta 23) Pituitary gland
3) Bone marrow (sternum) 24) Prostate gland (males)
4) Brain (at least three levels) 25) Rectum
5) Cervix/vagina 26) Salivary gland (mandibular)
6) Epididymis (males) 27) Sciatic nerve
7) Oesophagus 28) Skeletal muscle
8) Eyes with optic nerve 29) Skin from the abdomen
9) Femur with articular surface 30) Spinal cord (at least three levels)
10) Gall bladder 31) Spleen
11) Heart 32) Thymus
12) Large intestine (including cecum and 33) Thyroid and parathyroid (when in
colon) same section)
13) Testes 34) Tongue
14) Small intestine (including duodenum, 35) Stomach (including cardia, fundus,
jejunum, and ileum) and pylorus)
15) Kidneys 36) Trachea
16) Liver 37) Uterus
17) Lungs with bronchi 38) Urinary bladder
18) Lymph nodes 39) Gross lesions
19) Lacrimal gland 40) Seminal vessels (males)
20) Mammary glands (females) 41) Vertebra
21) Ovaries 42) Injection site (if appropriate)
These preclinical drug metabolism studies also involve metabolite profiling in

plasma, specific tissues, urine, and bile to evaluate the distribution and
disposition of potential metabolites, like those having 5% or greater amount than
the parent compound. Metabolite profiling requires a technique for separating the
parent compound from metabolites and other endogenous compounds. HPLC is
the preferred method for small organic molecules; while, gel or capillary
electrophoresis techniques with appropriate resolution ability to separate the
compounds are suitably used for macromolecules.
Mass spectrometry and nuclear magnetic spectroscopy are the techniques used
for identifying metabolites having more than 5% of the parent compound. The
metabolites that may produce a pharmacological or toxicological response after
identification are synthesised and te sted in suitable animal models. Many novel
drugs have been invented during metab olite characterisation of the lead
molecules. These new drugs may exhibit better amount of delivery, longer or
shorter disposition kinetics, less possibility for accumulation, or better clearance
properties, thus making them better than the parent compounds.
* *
5.1.4.3. Toxicology
Before initiating clinical trials on humans , some toxicology studies should be
completed and documented in the IND submission. Along with the studies given
above for toxicology developability evaluation, the preclinical toxicology
experiments also involve local tolerance, genotoxicity, safety pharmacology, and
sub-chronic tests.
A problematic characteristic in the understanding of toxicology results is defining

whether these data are predictive of safety in humans. Animal toxicology and
human safety may not correlate as the observed adverse effects are species
specific.
For example, HMG-CoA reductase inhibitors cause cataracts, a drug -candidate-

killing effect, in beagle dogs but not in rats and monkeys. Clinical use of these
therapeutic agents in humans has also not shown this adverse effect, indicating
that only the beagle dogs (and not the other species) are vulnerable to this
problem. Species specificity is sometimes discovered in the initial phases of drug
development, and can be employ ed for designing the early human trials for
determining if humans also demonstrate the observed toxicity.
Local Tolerance
An ICH guideline suggests thatassessments of local tolerance should be performed
in animals employing the administration route suggested for human clinical testing
and these assessmentsshould be conducted before human exposure. The evaluation
of local exposure may bea part of other toxicity studies.
Genotoxicity
For getting registration to market p harmaceutical products, the drug ca ndidate’s
genotoxic potential should be evaluated . Two ICH guidelines for genotoxic
testing have been passed, comprising of in vitro and in vivo studies designed for
determining if a compound induces direct or indirect genetic damage and through
any mechanism. Positive genotoxic compounds are capable of being human
carcinogens or mutagens, thus indicating these drug candidates can cause cancer
or heritable defects.
The following three tests are suggested for evaluating the genotoxicity
potential of a drug candidate:
1) A test for gene mutation in bacteria (the Ames test),
2) An in vitro cytogenetic assessment of chromosomal damage by using
mammalian cells , like human lymphoblastoid TK6, CHO, V79, and AS52
cells or an in vitro mouse lymphoma L5178Y cell line TK assay, and
3) An in vivo study for chromosomal damage in rodent hematopoietic cells.
Drug candidates giving negative results of these tests are considered to have no
genotoxic activity. Depending on the suggested therapeutic use, the drug
candidates giving positive results should be tested more broadly.
* *
Safety Pharmacology
In s afety pharmacology , the effects of a drug candidate are evaluated for
pharmacological activity on the functions of different organ systems other than the
target system. Central nervous, cardiovascular and respiratory systems are generally
evaluated.
Based on the physical and chemical characteristics of the drug candidate and their
administration route, the r enal/urinary, autonomic nervous and gastrointestinal
systems should also be evaluated. Safety pharmacology studies, along with other
toxicology studies,should be performed before human exposure.
Sub-Chronic Toxicology
The FDA and other regulatory organisations need sub-chronic toxicity studies to
be performed in two species (on e of which is a non -rodent), before initiating
human clinical trials . The duration of sub -chronic toxicity studies and the
duration of planned clinical trials are co-related.
An ICH guideline recommends the minimum duration for toxicity studies (table
5.2) required to support phase 1, 2, and 3 clinical trials, in which humans are
exposed to the drug candidate for changing durations.
Table 5.2: Duration of Multiple Dose Toxicology Studies Needed to Support
Phase 1, 2, and 3 Clinical Trials
Minimum duration of toxicity study
Duration of clinical trial Rodents Nonrodents
Single dose 2-4 wka 2 wk
a
Up to 2 wk 2-4 wk 2 wk
Up to 1 mo 1 mo 1 mo
Greater than 6 mo 6 mo Chronic
Rats and dogs are the two most commo n species employed in sub -chronic
toxicology studies. Charles River CD rat (Spraque-Dawley derived and an
outbred strain) is the most commonly used strain in pharmaceutical and
biotechnology industries.
In some companies, Fisher 244 albino rat (an inbred strain) is used as this strain
does not grow as big as the Charles River CD rat. Mouse and hamsters are the
other species of rodents that may be used for sub-chronic toxicity studies.
Among the non -rodent species, b eagle dogs (purebred and particularly br ed for
research) are most common ly used in toxicology evaluations. Biotechnology
industries developing macromolecule therapeutics and also the pharmaceutical
industries assessing NCEs employ c ynomolgus and rhesus monkeys (non-rodent
species) in sub -chronic toxicity studies . Rabbits (species used in reproduction
toxicology assessments ) have also been used as non -rodent species for sub -
chronic testing.
* *
In last few years , noticeable developments have been made for efficient dosing
regimens of animals in toxic ology studies. Oral administration route (tablets or
capsules) is the most common for human treatment. However, intravenous,
dermal, pulmonary, subcutaneou s, intramuscular, nasal, buccal and rectal routes
may also be considered . Whatever administration route is suggested for humans,
in the preclinical animal toxicology studies the same route of delivery should be
used. In rodents, oral dosing of tablets or capsules is impossible; however, daily
or more regular oral gavage is a standard procedure.
In larger species, the tablets or capsules are placed in soft gelatin capsules and
dosed. Present-day technology allows constant infusion of rodent and non -rodent
species for assessment of drug candidates to be administered as intravenous
infusions. For other admin istration routes, special techniques are used for
ensuring that the test species is properly exposed to the test article.
If possible, the suggested clinical formulation should be used in pre clinical

toxicology assessments as the formulation excipients ca n be essential in the
extent and duration of delivery and in local tolerance. For oral dosing in rodents,
the solid clinical formulation is powdered and dissolved or suspended in water in
suitable amount before gavaging. The most usual dosin g volume for r odents is
10ml/kg. The administered volume should be same for all dose groups and the
vehicle control group.
For conducting sub -chronic studies in rodents, 10 to 25 animals/sex/group are

used. The short-term (2 -4 week) studies employ smaller groups, and t he long-
term (more than 13 weeks) studies employ larger groups. If a temporary sacrifice
or a reversibility phase (a drug -free recovery phase ) is included in the study
design, 10 more animals/sex are usually added to every dose group, including the
vehicle control group. For conducting sub -chronic studies in non -rodents, 3 to 6
animals/sex/group are used , based on the study duration and the projected
toxicology profile. Dose selection for sub-chronic and chronic toxicology studies
should depend on the resul ts from acute toxicity studies and pharmacokinetic
evaluations. The three typical dose levels are:
1) A no-toxic-effect level that should be at least equal to and a multiple of the
proposed human dose,
2) A dose level that causes a toxic effect in clinical obse rvations, clinical
pathology, or histopathological changes, and
3) A dose level between these two.
Formulation Analyses
Formulations for a drug candidate content are analysed to confirm that doses
administered to animals in toxicology, pharmacokinetic, and drug metabolism
studies have the appropriate qu antity of drug candidate. Prior to conducting the
analyses, a stability -indicating analytical method to quantify the drug candidate
in the formu lation should be defined and validated for sensitivity, linearit y,
precision, accuracy, and robustness. If the dosing formulation is modified
between the studies, the analytical method should be revalidated for application
to the new formulation.
* *
Formulations for each dose level and the vehicle control should be analy sed
before and after drug administration in acute toxicity, single -dose
pharmacokinetic, and single-dose drug metabolism studies. If there are no visible
changes in the drug molecule, an appropriate dose of the drug should be given to
the animals. Formulations for each dose level should be analysed before the first
dose, at predefined times during the study, and after the last dose in sub-chronic
and chronic studies, carcinogenicity studies, and multiple -dose pharmacokinetic
and drug metabolism studies.
In case, the formulations need to be prepared periodically during the study,

content analysis for newly designed formulations should be performed so that the
preparation method provides uniform drug content. In case, the formulation drug
content either drops or crosses the predefined acceptance limit ( 95-105%), the
formulation should not be given to animals.
Toxicokinetics
The toxicokinetic studies are performed by administering dose levels of a drug
molecule to the test species in various dose groups to correlate the observed toxic
effects with the drug candidate and to show that the therapeutic effects increase
by increasing the dose. It is assumed that the administered dose levels can predict
and are proportional to the amount of drug candidate present in the body. But, the
administered dose can not predict toxicity for the drug candidates not absorbed
properly, having variable absorption, or undergoing saturable absorption when
the dose level increases.
The exposure of test species to drug candidates increases as the increase in dose
levels has become a critical standard in toxicology studies. Another important
fact is that even after multiple -dose administration, the extent and duration of
exposure remains the same . On the generation of toxicokinetic data , an ICH
guideline has been issued in support of the development of a drug candidate.
Following are the objectives of toxicokinetics:

1) It is used to explain the systemic exposure of each test spe cies used in
toxicology studies.
2) It also explains how exposure relates to dose level and the duration of study.
3) It correlates the toxicological findings with the extent of exposure , and also
helps in the evaluation of these findings to clinical safety.
4) It helps in the selection of test species and designing of treatment regimen for
non-clinical toxicology studies.
5) It also provides information on suitable design for subsequent non -clinical
toxicity studies and human clinical trials, along with toxicity results.
Toxicokinetic data is an essential part of a non

-clinical regime, and is obtained from
the test species in a toxicology study or in specifically designed supportive studies.
The toxicokinetic data does not characterise the basic pharmacokinetic parameters of
the drug candidate being studied, rather it focuses on the interpretation of toxicity
results. I t is not necessary that all toxicology studies include a toxicokinetic
* *
component. Additional toxicokinetic evaluations are notrequired if the extent and

duration of exposure of a drug candidate in a particular formulation for a given test
species has been generated for the dose rangeto be used in toxicological study.The
toxicology studies supported bytoxicokineticdata include the following:
1) Single-dose studies in which results obtained from preliminary
pharmacokinetic studies are used.
2) Multiple-dose studies in which toxicokinetic data predict s whether or not
multiple-dose pharmacokinetic studies are necessary.
3) Reproductive studies in which those test species are employed whose
absorption and disposition profiles have changed due to pregnancy.
4) Carcinogenicity studies in which the test speciesare dosed differently compared
to other toxicology studies and changes in exposure occur due to age.
Haematology, Clinical Chemistry, and Histopathology

The following three important factors are considered to detect and understand the
adverse effects observed in a toxicology study:
1) Haematology,
2) Clinical chemistry assays and,
3) Histopathology evaluation of tissues collected at necropsy.
Table 5.3 enlists the commonly evalu ated haematology parameters . In

toxicology studies, these parameters are periodically determined, with the
number of evaluations depending on the length of study.
Table 5.3: Haematology Parameters Evaluated During Toxicology Studies
Parameters Abbreviations
White blood cell count WBC
Red blood cell count RBC
Haemoglobin concentration HGB
Haematocrit HCT
Mean corpuscular volume MCV
Mean corpuscular haemoglobin MCH
Mean corpuscular haemoglobin concentration MCHC
Platelet count PLT
Prothrombin time PT
Activated partial thromboplastin time aPTT
The clinical properties that should be determined routinely are listed in table 5.4.
Table 5.4: Clinical Chemistry Parameters Evaluated During Toxicology Studies
Parameters Abbreviations
Total protein TP
Triglycerides TRI
Albumin Alb
Globulin Glob
Albumin/globulin ratio A/G
Glucose GLU
Cholesterol CHOL
Total bilirubin TBILI
Urea nitrogen BUN
Creatinine CREAT
Creatine phosphokinase CPK
* *
Alanine aminotransferase ALT

Aspartate aminotransferase AST
Alanine phosphatase ALK
Gamma-glutamyltransferase GGT
Lactate dehydrogenase LDH
Calcium Ca
Phosphorus Phos
Sodium Na
Potassium K
Chloride Cl
Sometimes, urinalysis may also be performed, but only in non-rodents, and should
include microscopical examination of sediment. Pre-treatment clinical chemistry
analyses and the number of determinations per group should be the same as for
haematology. Along with haematology and clinical chemistry evaluations, other
biological marker analyses can also be included depending on the pharmacology
and toxicology profile of a drug candidate. The results of these analyses provide
information on changes in physiological parameters in animal models caused by
the drug candidate. The t est results are also used for evaluating the
pharmacological and toxicological effectsin human clinical studies.
Table 5.4 enlists the tissues collected at necropsy and prepared for
histopathological evaluation. In sub-chronic and chronic studies, the ro dent and
non-rodent animal tissues should be routinely sectioned and examined.
Generally, the requirements for special histopathology examination depend on
case-by-case basis and on adverse effects indicated by in -life clinical pathology
changes. Morphological changes occurring in the cellular structures are examined
by Electron Microscopy (EM). The use of EM for all tissues is impractical and
needless, therefore only some specific specimens are examined under EM.
Immunogenicity
Various large molecules, including proteins, polypeptides, and oligonucleotides
are immunogenic in animal models used in pharmacology and toxicology studies.
An ICH guideline suggests that in sub-chronic toxicology studies , the potential
for antibody formation should be determined to interpret the results obtained
from these and later studies . The formed antibodies are characterised as to titer,
neutralising or non -neutralising reactions, number of animals responding,
alterations in pharmacological or toxicological response, activa tion of
complement, and formation and deposition of immune complex. If the
pharmacological or toxicological effects of the drug candidate is neutralised by
the observed immune response, the study design should be allowed to change.
The induction of antibody formation in animal models differs from the responses
in humans, therefore animal antibody formation does not play any special
significant role unless the interpretation of results from pharmacology or safety
studies is compromised. In case , formation of antibodies takes place during
animal studies, the potential for antibody formation in humans should be
evaluated in the initial phase of clinical development. This evaluation ensures
that antibodies do not increase the potential toxicity of the drug can didate and
also do not adversely affect its pharmacological profile in humans.
* *
Chronic Studies
As per the regulatory agencies, chronic toxicity studies for drug candidates to be
administered to humans for more than 3 months should be perf ormed in a rodent
and non-rodent species. These studies are performed to produce a toxic effect and
to define a safety factor.
A dose -response relationship can be obtained by these studies that result from
prolonged exposure to the drug candidate. These studies provide a dose-response
relationship to effects arising on prolonged exposure to the drug candidate and
should reveal adverse effects that require a long exposure to be expressed or that
are cumulative.
Chronic studies can be conducted in animal species having metabolism similar to

that in humans. This is because before initiating chronic studies, early human
evaluations have been completed. The most common rodent species used in
chronic studies are rats, while the common ly used non -rodent species are b eagle
dogs and non-human primates.
The metabolism of compounds in dogs ( carnivores) is different than that in

humans, therefore the compounds should be used cautiously. The non -clinical
drug development metabolic systems in non-human primates are not similar to
that in humans. For analysis of macromolecules, monkeys are the preferred
species as their anatomy and physiology are somewhat similar to that of humans.
The time duration for chronic toxicology studies is decided based on the
anticipated duration of administration to humans. According to the FDA, for drug
candidates to be used for long-term in human s, a 6-month carcinogenicity study
is sufficient for rodent s (in rats or other appropriate species) and a 9-month
carcinogenicity study is sufficient for non-rodents for evaluating the potential for
tumor production.
Reproductive and Developmental Toxicology

Studies on reproductive a nd developmental toxicology aim to discover the effect
of a drug or its metabolite on mammalian reproduction , and to determine the
potential risks to humans. These studies involve the evaluation of male and
female fertility, embryo and foetal death, parturition and the new -born, the
lactation process, care of the young, and teratogenicity caused by the drug. In
history, these reproductiv e parameters were evaluated in three types of studies,
i.e., segment I, segment II, and segment III.
In segment I studies, fertility and general reproductive performance was

evaluated in rats; in segment II studies, embryo toxicity or teratogeni c effects of
the drug was evalua ted in rats and rabbits; and in segment III studies, perinatal
and postnatal study was conducted in rats to evaluate the effects of drug on late
foetal development, labour and delivery, lactation, neonatal viability, and growth
of the new-born. Reproductive toxicity of the drug was also evaluated in other
rodents and non -rodent species, such as mice, guinea pigs, mini pigs, ferrets,
hamsters, dogs, and non-human primates.
* *
As per an ICH guideline, the selected combination of studies needs to expose the
mature adults and all development stages , starting fro m conception to sexual
maturity, to conception in the next generation. This sequence is sub -divided into
various stages, designated as (A) premating to conception, (B) conception to
implantation, (C) implantation to closure of the hard palate, (D) closure of the
hard palate to the end of pregnancy, (E) birth to weaning, and (F) weaning to
sexual maturity. With the help of these designations, stages A and B of the
reproductive process ar e evaluated by the segment I, stages C and D are studied
by segment II, and adverse effects in stages E to F are detected by segment III.
Commonly, segments I and III are combined into a single study and segment II
studies are conducted separately in rats and rabbits.
Segment I studies evaluate the fertility and reproductive process in stages A and
B in sexually mature male and female rats. Male fertility is determined by
premating dosing of at least 4 weeks and continuing dosing during the mating
period. The drug effects on spermatogenesis can be determined by
histopathology of the testes and sperm analysis. Female fertility is determined by
premating dosing of at least 2 weeks and continuing dosing during the mating
period. A mating ratio of 1:1 is recomm ended, and documentation should allow
identification of both the parents of a litter.
Copulation is assessed everyday by taking vaginal smears or by observing the

copulatory plug. The day when proof of copulation is found is considered day 0
of gestation. Half female rats are sacrificed after mid -pregnancy (usually on day
13 of gestation) and the number and distribution of embryos in each uterine horn,
embryos undergoing resorption, and presence of empty implantation sites are
examined. The male rats are sacrificed after mating and assuring successful
induction of pregnancy. The remaining female rats give birth normally and the
litter size, number of alive or dead new -borns, and any abnormal observations
during gross examination are recorded.
Segment II (or teratology) studies determine if a drug can cause embryotoxicity or

teratogenic effects (stages C and D)in a rodent and non-rodent species. The drug is
administered during organogenesis (usually 6 to 15 gestation day for mice and rats
and 6 to 18 gestation day for rabbits). The foetuses are delivered by caesarean section
one or two days before the expected normal delivery. Half foetuses of rats are
examined for visceral alterations and the remaining are examined for skeletal
abnormalities. All the foetuses of rabbits are examined for soft tissue and skeletal
abnormalities by microdissection techniques for soft tissue alterations.
Segment III studies determine the effects on perinatal and postnatal development
of pups and on maternal function (stages C to F) in rats. The drug is administered
from implantation to the end of lactation (stages C to E). At the time of weaning,
one male and one female offspring per litter are selected for nurturing to adulthood
and mating to evaluate their reproductive capabil ity. The physical development,
sensory functions, reflexes, and behaviour of these offspring are also evaluated by
using behavioural and other functional tests. The remaining parents and litter are
sacrificed at the time of weaning for histopathological ev
aluation.
* *
In most of the toxicology studies, three dose levels and a vehicle control group
are recommended for reproductive studies. A dose-range-finding study, involving
toxicokinetic evaluation, is performed in pregnant animals that are more prone to
toxic effects. This study defines the dose levels, one of which should produce
signs of toxicity and another one should not produce any toxic effects.
Sometimes, d rug metabolism studies are conducted to validate that the parents
and their litter have been exposed to the drug and its metabolites.
Carcinogenicity
Carcinogenicity studies involve the life span of most of the test species, measure
tumor induction in animals, and evaluate the relevant risk in humans. These
studies are conducted simultaneously with phase 3 human clinical trials and are
required by regulatory agencies when a human has been exposed to a drug for
more than 6 months. Carcinogenicity studies should be performed for drugs
developed to treat some of the life-threatening diseases, after marketing approval
but during human clinical testing. These studies should be started earlier during
the drug development process when:
1) The drug or its metabolite is structurally similar to a known carcinogen.
2) A special aspect of the drug’s biological action (e.g., members of the
therapeutic class have shown a positive carcinogenic response) causes concern.
3) The drug in early studies produces toxic effects , indicating preneoplastic
changes.
4) The drug or its metabolite accumulates in organ systems.
5) The drug is proved to be a potential carcinogen through mutagenicity tests.
Carcinogenicity studies are performed on mice and rats having life spans of 18
and 24 months, respectively, because of the economy of these species, their
susceptibility to tumor induction, and the availability of large database on their
physiology and pathology. If other non -clinical or clinical results show that
rodents are not fit for conducting studies, the carcinogenicity studies are
conducted on other species, such as dogs for the developm ent of birth control
drugs. As per an ICH guideline, one rodent (usually the rat) carcinogenicity study
along with a sub -chronic or chronic in vivo rodent study can determine a drug’s
carcinogenicity potential.
If possible, the exposure route and the clin ical route of administration should be
the same in test species . An alternative route can be used if the exposure route
shows similar metabolism and systemic exposure (mainly to organs, such as the
lungs for inhalation agents) as the clinical route. Suppor tive data on drug
metabolism and toxicokinetic studies are required while selecting a suitable
alternative administration route.
As per an ICH guideline, the selected doses should have the following features:
1) They should provide a test species that on exp osure to the drug allows an
adequate safety margin over the human therapeutic exposure.
2) They should be tolerated without chronic impairment of physiological
function and should be compatible with good survival.
* *
3) They should be guided by a comprehensive set of animal and human data

focusing on the drug properties and the suitability of the test species.
4) They should permit data interpretation in the context of proposed clinical use.
In all the cases, dose-ranging studies should be conducted for 90 days.
Systemic exposure of the drug in the test species that represent a large multiple of
human exposure, based on the plasma concentration versus time curve (AUC) at
maximum proposed human daily dose , may be used for carcinogenicity study
dose selection. The valu e of AUC is the most significant pharmacokinetic end
point, because it inc ludes the plasma concentration of drug as well as its in vivo
residence time. For using saturation of absorption for dose selection, information
that the absorption process has been saturated using the proposed administration
route is necessary. These data can be obtained during pharmacokinetic studies,
evaluating linearity of absorption and proportionality of dose using the route and
frequency of dosing during the human clinical studies.
Using pharmacodynamic end points for high -dose selection is highly compound -
specific and is suitable for individual study designs. High drug dose should
produce a pharmacodynamic response in the test species that prevents further
increase in dose, but does not disturbs the physiology or homeostasis that would
otherwise compromise the validity of carcinogenicity study. Examples of such
pharmacodynamic end points include hypotension and blood clotting inhibition.
Using maximum feasible dose for dose selection is applicable to studies in which
the drug is administer ed with diet; however when routes other than dietary
administration are used, the high dose is limited because of practicality and local
tolerance.
If pharmacokinetic end points are used for d ose selection, the necessity to select
high dose for carcinogenicity studies is reduced based on feasibility criteria.
The mid and low doses for a carcinogenicity study provide information for
evaluating the significance of study findings to humans. The l ow dose should be
either equal to or a multiple of the maximum dose suggested for human testing.
The low and mid dose should be selected based on pharmacokinetic linearity,
saturation of metabolic pathways, human exposure to therapeutic dose,
pharmacodynamic response in the test species, alteration in the normal physiology
of test species, mechanistic information, the potential for threshold effects, and the
unpredictability of toxicity progression in other toxicology studies.
5.1.5. Data Presentation for FDA Submission

Data st andards help the FDA to update and rationalise the review process , and
also allow a more consistent use of analysis tools for better observation of drug
data and for highlighting the areas of concern. Data standards of a study involve
a stan dard way of sharing the clinical and non -clinical research data between
computer systems. These standards also provide a consistent general framework
to organis e study data, including templates for datasets, standard names for
variables, and standard calculation methods using common variables.
* *
FDA is establishing new requirements for data standards for most of the study
data submitted to FDA’s Centre for Drug Evaluation and Research (CDER) and
Centre for Biologics Evaluation and Research (CBER). The FDA ma y refuse to
file for New Drug Applications (NDAs) and Biologics License Applications
(BLAs) or refuse to receive for Abbreviated NDAs (ANDAs) any electronic
submission whose study data do not abide by the required standards specified in
the FDA Data Standards Catalogue.
An analysis of study data conformance has been conducted by the FDA on

submissions received during a specified time period and a presentation was
developed on the overall conformance results. FDA established the Technical
Rejection Criteri a Self -Check Worksheet (PDF) and Worksheet Instructions
(PDF) to help the sponsors at the time of submitting study data.
In the early stages of product development life cycle, CDER and CBER inspire
Investigational New Drug (IND) sponsors and N DA applicants for implementing
and using the study data standards. This allows the use of data standards in the
design, conduct, and analysis of studies. The sponsors who started their studies
after 17 th December, 2016, should submit data in formats supported by the FDA
and listed in the FDA data standards catalogue . This applies to NDAs, BLAs,
ANDAs, and subsequent submissions to these types of applications. In case of
INDs, the requirement applies for studies started after 17th December, 2017.
The s tudy data should be submitted in a format as prescribed by the FDA and
FDA data standards catalogue , on the start date of study. The data standards
catalogue includes the data standards supported by the FDA, as well as all the
goals. These study data standards were develop ed as part of an association
between the FDA, the non -profit Clinical Data Interchange Standards
Consortium (CDISC), and other stakeholders.
The currently supported study data standards are:

1) CDISC Standard for Exchange of Non -clinical Data (SEND) for non -
clinical data,
2) CDISC Study Data Tabulation Model (SDTM) for clinical data,
3) CDISC Analysis Data Model (ADaM) for analysis of clinical data, and
4) CDISC Case Report Tabulation Data Definition Specification (Define -
XML) for the metadata that accompaniesSEND, SDTM, and ADaM datasets.
Following is the procedure for updating standards as per the FDA:

1) FDA publishes its intent periodically to support the new standards and new
versions of the current standards.
2) FDA will give at least a year’s notice before a new ver sion of a standard is
required.
3) FDA will give two years notice for completely new standards.
4) FDA supports the efforts required to develop clinical terminology standards
for particular therapeutic areas of the SDTM. The new and revised standards
for specific therapeutic areas are updated periodically in the SDTM.
* *
5.2. SUMMARY
1) Drug approval process is a regulatory procedure, through which a
person/sponsor/innovator/organisation gets approval to promote a drug in the
market.
2) A single regulatory method is applicable for Marketing Authorisation
Application (MAA) in different countries, and this is a very difficult task.
3) The Drug and Cosmetic Act 1940 and Rules 1945 was announced by the
Indian parliament to control the import, manufacture, supply, and sale of
drugs and cosmetics.
4) The Central Drugs Standard Control Organisation (CDSCO) , and the
office of its head, the Drugs Controller General of India (DCGI) was
established.
5) Indian government included Schedule Y to the Drug and Cosmetics Rules
1945 in 1988.
6) Schedule Y offers the guidelines and requirements for clinical trials, which
were revised in 2005 to make it equivalent to the procedure recognised
across the world.
7) Section 2.4(a) of Schedule Y of Drugs and Cosmetics Act 1940 and Rules
1945 states that drugs discovered in India should undergo all phases of
clinical trials.
8) Section 2.4(b) of Schedule Y of Drugs and Cosmetics Act 1940 and Rules
1945 states that for drugs discovered outside India, the appl icant should submit
the data presented by other countries and the licensing authority may replicate
all the studies or allow the applicant to start from Phase III clinical trials.
9) Phase I clinical trials are performed for controlling the adverse reactions
and maximum tolerated dose in healthy human volunteers.
10) Phase II clinical trials are performed for determining the therapeutic uses
and effective dose ranges in 10 -12 patients at each dose level. The
confirmatory.
11) Non-clinical drug development (or pre-clinical drug development ) is a
risk-based process involving evaluation of safety and efficiency of drugs in
animal drugs that extrapolate to probable human outcome.
12) Before using a new active substance as a medicinal product, its safety and
efficiency is teste d in animals before using it in humans; this is known as a
pre-clinical study.
13) Pharmacology deals with the pharmacokinetic and pharmacodynamic
aspects of a drug.
14) Pharmacokinetic studies are studies of Absorption, Distribution,
Metabolism and Excretion (ADME) of the drug.
15) Physiological fluid samples should be acquired from animals in the
preliminary toxicology studies for determining the amount and regularity of
exposure; and this study is referred to as toxicokinetics.
* *
16) Mass balance and tissue distribution are the two most usual drug
metabolism studies.
17) A technique which is in use by some pharmaceutical companies for
substituting tissue distribution studies is the Quantitative Whole Body
Autoradiography (QWBA).
18) Charles River CD rat (Spraque-Dawley derived and an outbred strain) is
the most commonly used strain in pharmaceutical and biotechnology
industries.
19) Fisher 244 albino rat (an inbred strain) is used as this strain does not grow
as big as the Charles River CD rat.
20) Studies on reproductive and developmental toxicology aim to discover the
effect of a drug or its metabolite on mammalian reproduction, and to
determine the potential risks to humans.
21) In segment I studies, fertility and general reproductive performance was
evaluated in rats.
22) In segment II studies, embryo toxicity or teratogenic effects of the drug was
evaluated in rats and rabbits.
23) In segment III studies, perinatal and postnatal study was conducted in rats to
evaluate the effects of drug on late foetal development, labour and delivery,
lactation, neonatal viability, and growth of the new-born.
24) This sequence is sub-divided into various stages, designated as (A) premating
to conception, (B) conception to implantation, (C) implantation to closure of
the hard palate, (D) closure of the hard palate t o the end of pregnancy, (E)
birth to weaning, and (F) weaning to sexual maturity.
25) The sponsors who started their studies after 17 th December, 2016, should
submit data in formats supported by the FDA and listed in the FDA data
standards catalogue.
5.3. EXERCISE
1) Define drug approval processes.
2) Write the full form of CDSCO and DCIG.
3) What do you mean by pharmokinetics?
4) What is genotoxicity?
5) Define carcinogenicity.

1) Write a note on drug aprroval process in india.
2) Write a note on data presentation for FDA submission.
3) What is non-clinical drug development? Also mention its goals .
4) Write a note on toxicokinetics.

1) Beifly discuss about drug development teams.
2) Explain pharamcology in detail.
* *
Regulatory Requirements for Drug Approval - II (Chapter 6) 113
CHAPTER Regulatory Requirements

6 for Drug Approval - II
6.1. GENERAL CONSIDERATIONS OF

INVESTIGATIONAL NEW DRUG (IND)
APPLICATION
6.1.1. Introduction
Investigational New Drug (IND) is a pharmaceutical form of an active substance
or placebo being tested or used as a reference in a clinical trial. It also includes
the products already with a marketing authorisation but used or assembled
(formulated or packaged) in a way different from the authorised form, or when
used for an unauthorised indication, or when used to gain informat ion about the
authorised form. The terms investigational drug, investigational new drug, and
investigational medicinal product can be used synonymously.
As per the current Federal law, a drug should be the subject of an approved
marketing application prio r to its transportation or distribution across the state
lines. If a sponsor (usually the manufacturer or potential marketer) wishes to ship
the investigational drug to the clinical investigators in many states, it should
obtain from the FDA an exemption from the above mentioned legal requirement
through IND application.
The sponsor, during the early preclinical development of a new drug, determines
whether or not the product is safe for initial use in humans and is
pharmacologically active, before developing it commercially. Once the product is
considered sustainable for further development, the sponsor collects information
through early stage clinical studies to prove that the product will not pose any
irrational risks to humans if used limitedly.
When t he sponsor (the manufacturer or potential marketer) after screening the

pharmacological activity of new molecule and its acute toxicity potential in
animals, wants to test its diagnostic or therapeutic potential in humans, the FDA
steps in. At this point, the legal status of the molecule changes under the Federal
Food, Drug and Cosmetic Act , and it becomes a new drug that should meet the
specific requirements of the drug regulatory system.
After the submission of IND, the sponsor need s to wait for 30 day s before
starting the clinical trials. During these 30 days, the FDA reviews the IND for
safety to ensure that the research subjects will not be exposed to any irrational
risks.
* *
6.1.2. Types
IND application is of the following three types:
1) Investigator IND Application: It is submitted by a physician who initiates
and conducts an investigation, and under whose direction the investigational
drug is administered or dispensed. The physician should submit a research
IND application for studying an unapproved drug or an approved product for
a new indication or in a new patient population.
2) Emergency Use IND Application: It allows the FDA to approve the use of
an experimental drug in an emergency situation that does not all ow time for
submission of an IND application. It is also used for patients who do not
meet the criteria of an existing study protocol, or if an approved study
protocol does not exist.
3) Treatment IND Application: It is submitted for experimental drugs
showing promise in clinical testing for serious or immediately life -
threatening conditions while the final clinical work is conducted and the
FDA review takes place.
The process of IND application is used for commercial and research or non-
commercial experimen tal drug use . Both these categories are used to seek
authorisation for a pharmaceutical manufacturing company to ship an
experimental drug to clinical investigators across the state lines, before the
approval of the marketing application for the drug. The FDA officials review the
IND application to ensure that the research subjects will not be subjected to any
unreasonable risks after receiving the drug. Once the FDA clears the IND, the
drug is ready to undergo Phase I clinical trial study.
6.1.3. Content and Format of an IND Application

A sponsor who wishes to conduct a clinical investigation should submit an IND
application in the following order:
1) Cover sheet and table of contents,
2) Introductory statement and general investigational plan,
3) Investigator‟s Brochure (IB),
4) Protocols,
5) Chemistry, Manufacturing and Control (CMC) information,
6) Pharmacology and toxicology information,
7) Previous human experience with the investigational drug,
8) Additional information, and
9) Relevant information.
6.1.3.1. Cover Sheet and Table of Contents

A cover sheet for the IND application should bear the following information:
1) The sponsor‟s name and contact details (e.g., address and telephone number),
the date of the application, and the name of the investigational new drug.
2) Identification of the phase(s) of clinical investigation to be conducted.
3) A commitment that clinical investigations will not be conducted till the FDA
approves the IND application.
* *
4) A commitment that an Institutional R eview Board (IRB) will review and

approve each study in the proposed clinical investigation and the investigator
will report to the IRB on proposed changes in the research.
5) A commitment that the investigation will be conducted following all the
other regulatory requirements.
6) The name and title of the person who monitors the conduct and progress of
the clinical investigations.
7) The name(s) and title(s) of the person(s) who reviews and evaluates the
information regarding the drug safety.
8) If the sponsor has transferred any ob ligations for the conduct of a clinical
trial to a Contract Research Organisation (CRO), a statement bearing the
name and address of the CRO, identification of the clinical study, and a
listing of the obligations transferred should be sub mitted. If all the
obligations have been transferred, a statement of this transfer along with the
list of specific obligations transferred should be submitted.
9) The sponsor‟s signature or the sponsor‟s authorised representative.
All sections under the table of contents should be paginated.
6.1.3.2. Introductory Statement and General Investigational Plan

This includes the following:
1) A brief introductory statement bearing the drug name, its active ingredients,
pharmacological class, structural formula (if known), formulation of the
dosage form(s) to be used, administration route, and the objectives and
planned duration of the proposed clinical investigation(s).
2) A brief summary of past human experience with the drug, with reference to
other IND‟s and to investigational or marketing experiences in other
countries if relevant to the safety of the proposed clinical investigation(s).
3) If the drug has been withdrawn from investigation or marketing in any
country(ies) due to any reason related to safety or effectiveness, entification
id of
the country(ies) and thereasons for withdrawal of drugshould be submitted.
4) A brief description of the plan for investigating the drug product should be
submitted, that includes:
i) The rationale for the drug or research study,
ii) The indication(s) to be studied,
iii) The approach to be followed for drug evaluation,
iv) The types of clinical trials to be conducted in the first year after the
submission (if plans are not developed for the entire year, the sponsor
should so indicate).
v) The estimated number of patients who will be administered the drug
during the studies.
vi) Any risks of particular severity predicted based on the toxicological data
in animals or earlier studies in humans with the drug or related drugs.
6.1.3.3. Investigator’s Brochure (IB)

A copy of the IB, bearing the following information should be submitted:
1) A brief description of the drug substance, the formulation, and the structural
*
formula (if known). *
2) A summary of the pharmacological and toxicological effects of the drug in

animals and in humans (if known).
3) A summary of the pharmacokinetics and biological disposition of the drug in
animals and in humans (if known).
4) A summary of information related to safety and effectiveness in humans
obtained from prior clinical studies (reprints of publis hed articles on such
studies can be submitted).
5) A description of potential risks and side effects based on the past experience
with the drug or related drugs under investigation.
6) A description of precautions or special monitoring to be done as part of the
investigational use of the drug.
6.1.3.4. Protocols
The following should be submitted:
1) A protocol should be submitted for each planned study or for studies not
initially submitted in the IND. Phase 1 protocols should provide an outline of
the investigation, i.e., the number of patients to be involved, a description of
safety exclusions, and a description of the dosing plan including duration,
dose, or method to be used in determining dose. Phase 1 protocols should
also provide details on those study elements that are critical to safety, such as
monitoring of vital signs and blood chemistries.
2) If the sponsor believes that some deviation from the study design is
necessary for the investigation, alternatives or possibilities for such deviation
should be given in the protocols for Phase 2 or 3 investigation.
3) A protocol should contain the following:
i) A statement of the study objectives should be submitted.
ii) A statement of the name, address, and qualifications (curriculum vitae or
other statement of qualifications) of each investigator; name of each sub-
investigator ( e.g., research fellow or resident working under the
investigator); name and address of the research facilities to be used; and
the name and address of each reviewing Institutional Review Board
(IRB) should be submitted.
iii) The criteria for patient selection and exclusion, and an approximate
number of patients to be studied should be submitted.
iv) A description of the study design, the kind of control group to be used,
and the methods to be used to minimise bias o n the part of subjects,
investigators, and analysts should be submitted.
v) A description of the method for determining the dose(s) to be
administered, the planned maximum dosage, and the duration of
individual patient exposure to the drug should be submitted.
vi) A description of the observations and measurements to be made to fulfil
the study objectives should be submitted.
vii) A description of clinical procedures, laboratory tests, or other measures
to be taken for monitoring the drug effects in human subjects and to
minimise risks should be submitted.
* *
6.1.3.5. Chemistry, Manufacturing and Control (CMC) Information

IND should be produced as per the principles and guidelines of cGMP:
1) As appropriate for the particular investigations covered by the IND, a section
for composition, manufacture, and control of the drug substance and the drug
product should be contained. SFDA recognises that variations in the
preparation method of new drug substance and dosage form are included
under the investigation progresses. Therefore in the initial Phase 1
submission, the focus should be to identify and control raw materials and
new drug substance. Final specifications for the drug substance and drug
product are not expected till the investigational process ends.
2) It should be emphasised that the information to be submitted depends on the
scope of the clinical investigation to be carried out.
3) With the progression of drug development, the scale or production changes
from the pilot scale production (for limited initial clinical investigatio ns) to
larger scale production (for expanded clinical trials). Therefore, the sponsor
should submit information amendments to complement the initial
information submitted on CMC processes , along with information
appropriate to the investigation scope.
4) IND submission should contain the following:
i) Drug Substance: SFDA expects the sponsors to reference one of the
most current Pharmacopoeias. Information on the drug substance should
be submitted in a report encompassing the following:
a) An account of the drug substance, including its physical, chemical,
or biological features.
b) Address of the manufacturer of the investigational drug substance.
c) A description of the manufacturing process, including a detailed flow
diagram and the list of used reagents, solvents and catalysts.
d) A description of the test methods, proposed acceptable limits of the
clinical trials, a copy of the analysis certificate, and the validation data
and established specifications at the initial stage of drug development.
e) A description of the stability study and the test methods used for
monitoring the drug stability.
ii) Drug Product: SFDA expects the sponsors to reference one of the most
current Pharmacopoeias. Information on the drug product should be
submitted in a report encompassing the following:
a) A list of all components and the alternatives for inactive compounds
used for manufacturing the investigational drug product, including
the components intended to appear in the drug product and those
which may not appear, but are used in the manufacturing.
b) Quantitative composition of the investigational new drug product,
including any modifications that may be expected during the
investigational stage.
c) The address(es) of the manufacturer(s) of the investigation al drug
product.
d) A flow diagram and a description of the manufacturing process,
*
including the sterilisation process for sterile products. *
e) The acceptable limits and analytical methods used for checking the
identity, strength, quality, and purity of the drug product.
f) A description of the sta bility study and the test methods used for
monitoring the stability of the drug product packaged in the
container/closure system, along with the storage conditions.
6.1.3.6. Pharmacology and Toxicology Information

Information on the pharmacological and toxicologic al studies of drug (involving
laboratory animals or in vitro ), based on which the sponsor has come to the
conclusion that the proposed clinical investigations can be conducted safely ,
should be submitted as follows:
1) Pharmacology and Drug Disposition: This section should contain the
following data:
i) A description of the pharmacological effects and action mechanism of
the drug in animals.
ii) Information on drug pharmacokinetics (ADME).
2) Toxicology: This section should summarise the toxicological effects of the
drug in animals and in vitro. The studies required depend on the drug nature
and the human investigation phase. If the species specificity,
immunogenicity, or other considerations make a number of or all the
toxicological models inappropriate, the sponsors should indicate so.
The toxicological findings should be summarised in a report bearing the
following information:
i) A description of the trials‟ design and any deviations from the design
during the conduct of trials.
ii) An organised presentation of the findings from the animal toxicology and
toxicokinetic studies. The findings that are considered as possible signals
of human risk should be emphasised.
iii) Identification and qualifications of the individual(s) who evaluated
animal safety data and made the concl usion that the proposed human
study is safe to begin; this individual should sign the summary and
attest that it reflects the animal toxicology data from the completed
studies.
iv) A statement of the location where animal studies were conducted and
where the study records are available for inspection.
Full Data Tabulation

The sponsor should submit a full data tabulation, consisting of line listings of
the individual data points and laboratory data points for each animal used in
the trials, and the summary tabulations of these data points.
For the interpretation of line listings, either of the following should be
submitted along with the line listings:
i) A technical report or abstract of a few pages giving the description of the
study, or
*
ii) A copy of the study protocol and amendments. *
3) Compliance with the Good Laboratory Practice (GLP) Regulations: For

each non -clinical laboratory study, a declaration stating that the study was
conducted as per the GLP regulations should be submitted. If the study was
not conducted in accordance to these regulations, a statement mentioning the
reason for non -compliance and the sponsor‟s opinion on how the non-
compliance will affect the interpretations of the findings should be submitted.
6.1.3.7. Previous Human Experience With the Investigational Drug

If the applicant knows about any earlier human experience with the investigational
drug, a summary containing the following information should be submitted:
1) If the investigational drug has been investigated or marketed before in Saudi
Arabia or other countries, detailed information about the experience that is
appropriate for the safety of the proposed investigation.
2) If the drug is a combination of drugs investigated or ma rketed before, the
information mentioned in point (1) should be p rovided for each active drug
component.
3) If the drug has been investigated or marketed outside Saudi Arabia, a list of
all the counties where the drug has been marketed and where the drug has
been withdrawn from the market.
6.1.3.8. Additional Information

In some applications, the information on following special topics should be included:
1) Drug Dependence and Abuse Potential: If the drug is a psychotropic or
abusive substance, relevant clinical studies and experience and studies in test
animals should be described in the related section.
2) Radioactive Drugs: Data obtained from animal or human studies should be
submitted to allow estimation of radiation -absorbed dose to the whole body and
critical organs in a human subject. Phase 1 studies of radioactive drugs should
include the studies that will acquire sufficient data for dosimetry calculations.
3) Paediatric Studies: Plans for evaluating paediatric safety and effectiveness
should be submitted.
4) Other Information: A statement of any other information that would support
the evaluation of the proposed clinical investigations should also be submitted.
6.1.3.9. Relevant Information

Any other relevant information required for reviewing the application should be
submitted:
1) Information Previously Submitted: The sponsor need not to resubmit the
information that has been already submitted. However, the sponsor should
add a reference to the previously submitted information by mentioning the
file name, reference number, volume, and page number from where the
information can be retrieved.
2) Material in a Foreign Language: The sponsor should submit English
translation (accurate and complete) of each part of the IND that is not in
English. The sponsor should also submit a copy of each original literature
publication for which the English translation is submitted.
* *
3) Number of Copies: The sponsor should submit two hardcopies and one
softcopy of all IND submissions.
4) Numbering of IND Submissions: The sponsor should serially number each
submission related to an IND by using a single, three-digit serial number. The
initial IND is numbered 000; each subsequent submission ( e.g., amendment,
report, or correspondence) is numbered chronologically in sequence.
6.2. GENERAL CONSIDERATIONS OF

INVESTIGATOR’S BROCHURE (IB)
6.2.1. Introduction
The clinical and non-clinical data on investigational product(s) that are relevant to
the study of the product(s) in human subjects are compiled in the Investigator‟s
Brochure (IB). It provides information to the investigators and others participating
in the trial to help them in understanding the rationale for and their compliance with
many important features of the protocol (such as the dose, dose frequency/interval,
administration methods, and safety monitoring procedures). The IB also suppo rts
the clinical management of the study subjects during the clinical trial.
This guideline outlines the least information that should be included in an IB and
provides suggestions for its layout. Type and extent of the available information
varies with the development stage of the investigational product. There is no
need of an extensive IB, if the investigational product is marketed and its
pharmacology is understood by the medical practitioners. As permitted by the
regulatory authorities, a basic produ ct information brochure, package leaflet, or
labelling including current and detailed information on the investigational
product (important to the investigator) may be an appropriate alternative.
If a marketed product is under study for a new indication,an IB should be prepared
specifically for that new use. The IB should be annually reviewed and revised
(whenever required) in compliance with the written procedures of a sponsor. The
IB should be revised more frequently, depending on the development stageand the
generation of relevant new information. However as per the Good Clinical
Practice, the relevant new information should be communicated to the investigators
and if possible to the Institutional Review Boards (IRBs)/Independent Ethics
Committees (IECs) and/or regulatory authorities before including in a revised IB.
Generally, it is the duty of the sponsor to ensure that an updated IB is provided to
the investigator(s); while it is the duty of the investigators to provide the updated
IB to the responsible IRBs/IECs.
6.2.2. Information to be Included

The following information should be included in the IB:
1) Title Page: It should include the sponsor‟s name, identity of each
investigational product (i.e., research number, chemical or approved generic
name, and tr ade name(s) where legally permitted and preferred by the
sponsor), the release date, an edition number, a reference to the number, and
*
date of the edition it replaces. *
TITLE PAGE OF INVESTIGATOR’S BROCHURE (Example)

Sponsor‟s Name: Product: Research Number: Name(s): Chemical, Generic
(if approved)
Trade Name(s) (if legally permissible and desired by the sponsor) Edition
Number:
Release Date:
Replaces Previous Edition Number:
Date:
2) Confidentiality Statement: The sponsor can include an instruction statement
to the investigator/recipients to treat the IB as a confidential document for the
information and use of the investigator‟s team and the IRB/IEC.
3) Contents of Investigator’s Brochure: It should contain the following
sections, along with literature references (where appropriate):
TABLE OF CONTENTS OF INVESTIGATOR’S BROCHURE (Example)
Confidentiality Statement (Optional) Signature Page (optional)
1) Summary
2) Introduction
3) Physical, Chemical, and Pharmaceutical Properties and Formulation
4) Non-Clinical Studies
i) Non-clinical Pharmacology
ii) Pharmacokinetics and Product Metabolism in Animals
iii) Toxicology
5) Effects in Humans
i) Pharmacokinetics and Product Metabolism in Humans
ii) Safety and Efficacy
iii) Marketing Experience
6) Summary of Data and Guidance for the Investigation NB: References on:
i) Publications ii) Reports
6.2.2.1. Summary
A brief summary of not more than two pages should be given on the significant
physical, chemical, pharmaceutical, pharmacological, toxicological,
pharmacokinetic, metabolic, and clinical information that is re levant to the
clinical development stage of the investigational product.
6.2.2.2. Introduction
A brief introductory statement bearing the chemical name (and approved generic
and trade name) of the investigational product(s), the active ingredients, the
pharmacological class and its position within the class ( e.g., advantages), the
reason for performing research with the investigational product(s), and the
expected prophylactic, therapeutic or diagnostic indication(s) should be provided.
The introductory statement s hould also provide the general approach to be
followed in evaluating the investigational product.
6.2.2.3. Physical, Chemical, & Pharmaceutical Properties & Formulation
A description of the investigational product substance(s) including the chemical
and structural formula(e) and a summary of the appropriate physical, chemical,
and pharmaceutical properties should be provided.
* *
A description of the formulation(s) and excipients to be used should be provided

and justified (if clinically relevant). This permits appropriate safety measures that
need to be taken during the clinical trial. Instructions for the storage and handling
of the dosage form(s) should also be given. If the product is structurally similar
to any other known compounds, it should also be mentioned.
6.2.2.4. Non-Clinical Studies

A summary of the methodology used for all non -clinical pharmacology,
toxicology, pharmacokinetic, and investigational product metabolism studies,
along with the results should be provided.
A description of the relevance of the find ings to the investigated therapeutic and
the possible unfavourable and unintended effects in humans should also be given:
1) Non-Clinical Pharmacology: A summary of the pharmacology of the
investigational product and its significant metabolites studied in ani mals
should be provided. Studies evaluating the potential therapeutic activity (e.g.,
efficacy models, receptor binding, and specificity) and the safety (such as
special studies to determine the pharmacological actions other than the
intended therapeutic effects) should also be added in the summary.
2) Pharmacokinetics and Product Metabolism in Animals: A summary of
the pharmacokinetics and bio transformation and disposition of the
investigational product studies should be provided. The results relevant to the
absorption and local and systemic bioavailability of the investigational
product and its metabolites, and their relationship to the pharmacological and
toxicological findings in animal species should also be described.
3) Toxicology: A summary of the toxicol ogical effects observed in the studies
performed in different animal species should be given under the following
headings: Single dose , Repeated dose Carcinogenicity special studies (such
as irritancy and sensitisation ), Reproductive toxicity , and Genotoxicity
(mutagenicity).
6.2.2.5. Effects in Humans

The known effects of the investigational product(s) in humans should be
summarised, along with the information on pharmacokinetics,
pharmacodynamics, dose response, safety, efficacy, and other pharmacological
activities. A summary of each completed clinical trial should also be provided.
The results obtained from any use of the investigational product(s) other than in
clinical trials, such as from experience during marketing , should also be
provided:
1) Pharmacokinetics and Product Metabolism in Humans: Information on
the pharmacokinetics of the investigational product(s) including the
following should be summarised:
i) Pharmacokinetics (absorption, plasma protein binding, distribution,
metabolism, and elimination) of the investigational product,
ii) Bioavailability (absolute or relative) of the investigational product using
a reference dosage form,
* *
iii) Population sub-groups (sex, age, and impaired organ function),

iv) Interactions (product-product interactions and effects of food), and
v) Other pharmacokinetic data (results of population studies performed
within clinical trials).
2) Safety and Efficacy: Information on the investigational product‟s safety
(including metabolites), pharmacodynamics, efficacy, and dose -response
obtained from pre ceding trials in healthy volunteers or patients should be
summarised. If a number of clinical trials have been conducted, the use of
summaries of safety and efficacy across multiple trials by indications in sub -
groups should be summarised to provide a clea r data presentation. The
adverse drug reactions for all the clinical trials should be presented in tabular
form. Important differences in adverse drug reaction patterns/incidences
across indications or sub-groups should be discussed.
The IB should descri be the possible risks and adverse drug reactions based
on the past experiences with the product being investigated and the related
products. The precautions or special monitoring to be done as part of the
investigational use of the product should also be provided.
3) Marketing Experience: The IB should identify the countries where the
investigational product has been marketed or approved. Information obtained
regarding the drug (such as formulations, dosages, administration routes, and
adverse product reactions) from the marketed use should be summarised. The
countries where investigational product did not receive approval/registration
for marketing or was withdrawn from the market should also be identified by
the IB.
6.2.2.6. Summary of Data and Guidance for the Investigator

A general description of the clinical and non -clinical data, along with the
information obtained from various sources on different aspects of the
investigational product should be provided. This gives the investigator the most
informative interpre tation of the available data, with a valuation of the
consequences of the information for future clinical trials. The published reports
on related products should be discussed to help the investigator to predict the
adverse drug reactions or other problems that might occur during the clinical
trials.
The entire section provides such information that will help the investigator to
understand the potential risks and adverse reactions, and the specific tests,
observations, and precautions required for a clinic al trial. The provided
information should be based on the available physical, chemical, pharmaceutical,
pharmacological, toxicological, and clinical information on the investigational
product.
Guidance to the clinical investigator on the recognition and treatment of possible

overdose and adverse drug reactions , based on past human experience and
pharmacology of the investigational product, should also be provided.
* *
6.3. GENERAL CONSIDERATIONS OF NEW

DRUG APPLICATION (NDA)
6.3.1. Introduction
The New Drug Application (NDA) is the formal final step a drug sponsor takes,
in which he/she applies to the Food and Drug Administration (FDA) to get
approval for marketing a new drug.
An NDA is a document comprising of 15 sections of data and analyses on animal

and human studies, the drug‟s pharmacology, toxicology and dosage, and its
manufacturing process.
The NDA aims to provide information that is sufficient enough for the FDA
reviewer to take the following key decisions:
1) Whether or not the drug is safe and effective in its anticipated use(s), and its
benefits overcome the risks.
2) Whether or not the drug‟s proposed labelling (package insert) is appropriate,
and bearing the required data.
3) Whether or not the manufacturing method of the drug and the controls used
to maintain its quality are sufficient to reserve its identity, strength, quality,
and purity.
The documentation required in an NDA should describe every detail about the
drug, including the phases of clinical tests, the drug ingredi ents, the results of
animal studies, drug behaviour in the body, and the method of manufacturing,
processing and packaging the drug.
6.3.2. General Format of NDA

The index of NDA should bear the volume and page number for the summary,
the technical sections, and any related information. Index is a detailed table of
contents for the entire application. The sponsor should keep extra copies of the
index and present them if the drug regulatory personnel are contacted by a
reviewer. In case microfiche has been used fo r some sections of an application,
the fiche number should be noted.
Every technical review section should keep a copy of the index and a
customised table of contents based on the relevant portions of the application
index. As per the NDA regulations, an archival copy and a review copy should
be submitted.
6.3.3. Archival Copy

Archival copy is a complete copy of an application submission. The FDA
reviewers and other FDA officials use it as a reference source for locating the
information not available in the section of the review copy assigned to them. It is
also used as a source of the copies of tabulations and cl inical trial case report
forms.
* *
The FDA after giving approval keeps the archival copy that serves as the
complete file copy of the approved applicat ion. Some sections of the archival
copy are accepted on microfiche, another suitable microform system, or by
computer. This is because it befits the applicant to check with the FDA division
reviewing the NDA on the acceptability of the format chosen by the applicant.
6.3.4. Review Copy

Review copy of an application is divided into 5 or 6 sections (i.e., pharmacology,
statistics, etc.) bearing the technical and scientific information required by the
FDA reviewers. Each technical section of this copy is separately bound and is
sent to the reviewer in charge of that specific section. Each section of review
copy should contain a copy of Volume 1.1 along with the following:
1) A copy of the FDA cover letter,
2) A copy of the application form,
3) A copy of index to the entire application,
4) A copy of the overall summary, and
5) A copy of a reference or authorisation letter to access NDAs, DMFs, etc.
The applicants should use coloured folders for binding the specific sections of the
review copy; this is because of the procedures used at the FDA to file and
retrieve material from the document rooms where all the applications are kept.
The colours of the folder and form numbers are listed in table 6.1.
Table 6.1: Documents and the Corresponding Folders and Form Number
Documents Folder Colour Form Number
Archival copy Light blue FD 2626
Chemistry, manufacturing, and controls section Red FD 2626a
Non-clinical pharmacology and toxicology section Yellow FD 2626b
Human pharmacokinetics and bioavailability section Orange FD 2626c
Microbiology section White FD 2626d
Clinical data section Light brown FD 2626e
Statistical section Green FD 2626f
Field copy Maroon FD 2626h
The NDA number (if known), applicant‟s name, and the drug‟s name should be
present on the cover of each folder. It should also identify the kind of submissi on
by the headings shown above. These folders should be purchased by the
applicants from the FDA. Requests should be made on company letterhead,
specifying the folder colour, FD form number, quantit ies required, location
where the shipment should be sent, and the name and telephone number of a
contact person if any further information is required about the order.
6.3.5. Paper Size and Binding

The applications should be bound on the left side of the page u sing the standard
size loose -leaf page (8 1/2 × 11 ). Both sides of the page should be used for
presenting the information and data, provided:
1) Information and data on both sides are not hidden in the binding,
2) Legibility is not impaired because of bleeding of the copy through the page, and
3) The order and number of the pages are accurate.
* *
6.3.6. Pagination
Pagination can be done by any suitable method, provided that the paging and
indexing allow rapid access to the entire submission. All the pages in the application
should be numbered and the numbering of the review copy pages should be the
same as the numbering of the corresponding pages in the archival copy.
If the archival copy is submitted on microfiche, the numbers on the microfiche
page image should correspond to the review copy page numbers.
6.3.7. Volume Size and Identification

Thickness of the volumes submitted in hard copy form should not be more than 2
inches. The front cover of each volume should bear the name of applicant and
drug, and NDA number, which can be obtained from the FDA‟s central
document room. This information should be clearly written with waterproof
marking pen or on typed stick -on labels. The volume number should be pre -
printed in the right upper corner.
The statement, “THIS SUBMISSION: VOL., ____ OF ____VOLS.” should be

present in the lower right -hand corner of each jacket cover. The applicant should
fill up the above blanks to identify the specific volume and the total number of
volumes submitted. For example , the first volume of a 50 -volume submission
would be, “VOL. 1 OF 50 VOLS.” A sample of such label is shown below:
Labelling
NDA# Volume__________
Drug Name
Sponsor Name Address
This Submission
Vol. 1 of 100 Vols.
The volumes for the technical sections of the review co py should be numbered
same as the volumes of the archival copy.
“VOLUME _____” should be pre-printed on the upper right-hand corner of each

jacket, and should be filled in for original applications and for chemistry pre -
submissions only. This section sh ould be filled in with t wo numbers; the first
number indicates the order in which the submission has been made and the
second number indicates the specific volume of the total number in that
submission.
If more than one volume of the paper (hard copy) app lication has been submitted
on microfiche and each volume of microfiche is easily distinguishable based on
their physical characteristics, they can be bound together. This can be
accomplished if one or more empty slots are left between the last microfiche
sheet of one volume and the first microfiche sheet of the next volume. The NDA
numbers for applications submitted on microfiche should be pre -assigned. The
FDA has prepared a guideline for submitting the archival copy of the application
in microfiche. This provides more information and details on the use of
microfiche.
* *
6.3.8. Packing Carton

The applications should be shipped to the FDA in boxes of 14 × 12 × 9 1/2 size.
Since ANDAs (Abbreviated New Drug Applications) are handled and stored
separately, smaller bo xes are considered appropriate for them. An exterior label
should be put on bearing the applicant‟s name, drug‟s name, and volume
numbers. An identification guideline should be made for differentiating the
cartons containing the archival copy from the ones containing the review copy.
Full applications should be sent to:

Food and Drug Administration,
Office of Drug Evaluation and Review
Central Document Room
Park Building, Room 214
12420 Parklawn Drive
Rockville, MD 20852
6.4. CLINICAL RESEARCH
6.4.1. Introduction
The preclinical research provides answers to basic questions regarding a drug‟s
safety. Thus, it is not a substitute for the studies that would identify the ways in
which a drug will interact with the human body. Clinical resear ch involves the
studies or trials conducted in human subjects. While designing the clinical study,
the developers will consider what they want to accomplish for each clinical
research phase and begin the Investigational New Drug (IND) process before
initiating the clinical research. The clinical development stream is the most
complex part of the drug development process. It also extensively consumes
financial and human resources.
The objectives of clinical development of a drug candidate are to:

1) Study th e pharmacological and pharmacokinetic features of the drug in
healthy volunteers and patients,
2) Determine the required dose range and dosing regimen of the drug to validate
its therapeutic efficacy and safety in targeted population,
3) Study drug-drug and drug-food interactions,
4) Establish a positive benefit-to-risk ratio in patients,
5) Determine the drug‟s optimal conditions of use in clinical practice, and
6) Explore new indications, formulations and combinations of the drug.
6.4.2. Designing Clinical Trials

Clinical t rials are designed by the researchers to respond to particular research
questions related to a medical product. These trials are conducted by following a
protocol (specific study plan) that is developed by the researcher or
manufacturer. Before starting a clinical trial, the researchers review the available
information about the drug to develop research questions and objectives.
* *
After reviewing, the researchers decide the following:

1) The people who will be qualifying to participate in the study (selection
criteria),
2) The number of people who will be participating in the study,
3) The duration of the study,
4) Whether or not there will be a control group and other ways to limit research
bias,
5) The route and dosage of the drug that will be given to the patients,
6) The a ssessments that will be conducted, when they will be conducted, and
what data will be obtained, and
7) The method of reviewing and analysing the collected data.
Clinical trials are conducted following a series from early, small -scale, phase 1
studies to late-stage, large-scale, phase 3 studies.
The basic activity in clinical drug development is the clinical trial (an experiment
involving human subjects, either healthy volunteers or patients, to examine the
effects of the drug being studied). Guideline E8 „Ge neral Cons iderations for
Clinical Trails‟ that was issued in 1997 by the International Conference on
Harmonisation (ICH), classified the clinical trials with drugs into four categories as
per their objectives, i.e., human pharmacology trials, therapeutic exploratory trials,
therapeutic confirmatory trials, and therapeutic use trials. The different types of
clinical trials organised according to their objectivesare summarised in table 6.2.
Table 6.2: Summary of Types of Clinical Trials According to Objectives
Study Types Study Objectives Study Examples
1) Evaluate tolerance. 1) Dose-tolerance studies.
Human 2) Pharmacokinetic and 2) Singles and multiple dose
Pharmacology pharmacodynamic studies. pharmacokinetic and/or
pharmacodynamic studies.
3) Drug metabolism and drug - 3) Drug-drug interaction studies.
drug interaction studies.
4) Estimate activity. 4) Compare pharmacokinetic
profile of drug formulations.
5) Bioequivalence. 5) Single and multiple dose
pharmacokinetic with other
administration route ( e.g.,
subcutaneous).
6) Explore other administration
routes.
Therapeutic 1) Explore use for the targeted 1) Earliest trials of relatively short
Exploratory indication. duration in well-defined narrow
patient populations, using
surrogate or pharmacological
endpoints or clinical measures.
2) Estimate dosage for 2) Dose-response exploration
subsequent studies. studies.
3) Provide basis for
confirmatory study design,
endpoints, and
*
methodologies. *
Therapeutic 1) Demonstrate efficacy. 1) Adequate and well -controlled

Confirmatory studies to establish efficacy.
2) Establish safety profile. 2) Randomised parallel dose -
response studies.
3) Provide a base for evaluating 3) Clinical safety studies.
the benefit-risk relationship to
support licensing.
4) Establish dose -response 4) Studies of mortality/morbidity
relationship. outcomes.
5) Large simple trials.
6) Comparative studies.
Therapeutic 1) Refine understanding of 1) Comparative effectiveness
Use benefit-risk relationship in studies.
general or special populations
and/or environments.
2) Identify less common adverse 2) Studies of mortality/morbidity
reactions. outcomes.
3) Refine dosing recommendation. 3) Studies of additional end
points.
4) Large simple trials.
5) Pharmacoeconomic studies.
A rational clinical drug development plan begins wi th human pharmacology
trials and shifts to the other three categories of trials (i.e., exploratory,
confirmatory, and therapeutic use) . Human pharmacology and therapeutic
exploratory trials are performed in early phase of clinical drug development;
while therapeutic confirmatory and therapeutic use trials are conducted in the late
phase of clinical drug development. However, this ordered approach does not
impose a fixed order of studies, as this is inappropriate for some drugs. Besides,
the results of an on-going study may change the development strategy or identify
the need for conducting more studies from the previous category. For example,
some human pharmacology trials (a QT interval study) are performed during the
late phase of clinical development.
6.4.3. Clinical Research Phase Studies

After the preclinical research, the tests and treatments undergo a series of clinical
trials to evaluate if the tests or treatments are safe and effective for the human
subjects. Clinical trials are conducted in the following five phases:
1) Phase 0: The trials of this phase are the first clinical trials conducted in
human subjects. Their objective is to learn the processes a drug undergoes
within the body and the effect it produces in the body. In these trials, 10 to 15
human subjects are administered with a very small dose of the drug.
2) Phase I: The trials of this phase are conducted to determine that dose of a new
drug which will produce the least side effects. In these trials, the drug is tested
in 15 to 30 patients. The physicians administer the drug to a few patients in very
low doses, and in other patients the drug is given in high dose s till the time
either severe side effects are produced or the desired effect is observed. Phase I
trials are conducted to test whether or not the drug under study is safe. If it is
*
found to be sufficiently safe, it is processed further for phase II clinical trial. *
3) Phase II: The trials of this phase evaluate the safety and effectiveness of the
drug. The drug is tested in patients having a specif ic type of cancer. These
trials are conducted in a large number of patients using new drug
combinations. Patients are monitored to check the drug effect, and if it is
found to be effective, it is processed further for phase III clinical trial.
4) Phase III: The trials of this phase compare a new drug to the standard -of-
care drug being used. These trials are conducted in around 100 or more
patients to evaluate the side effects of each drug and determine the drug
showing better efficacy. These trials are general ly randomised, i.e., the
patients are randomly put into a treatment group, called trial arms, using a
computer program. Randomisation ensures that the people in all the trial
arms are identical. This also allows the scientists to identify that the clinical
trial results are the outcomes of treatment and not the differences between the
groups.
Phase III trials can involve more than two treatment groups. The control
group gets the standard -of-care treatment, and the other groups get a new
treatment. Neither the patients nor their physician can choose the group. The
patients will even not know their group until the trial ends.
If the new drug produces severe side effects or if one group shows much
better results, the phase III trial is stopped early. Phase II I clinical trials are
conducted before the FDA approves the use of a new drug for the public.
5) Phase IV: The trials of this phase are conducted to test the FDA -approved
new drugs in several hundreds or thousands of patients. This allows for better
research on short -lived and long -lasting side effects and safety. In some
cases, some rare side effects are only found in large groups of people. The
physicians can also learn about the drug efficacy alone and when used with
other treatments.
6.4.4. Investigational New Drug Process

The drug developers or sponsors should submit an Investigational New Drug
(IND) application to the FDA before beginning the clinical research. The
developers should include the following details in the IND application:
1) Animal study data and toxicity data (side effects that cause great harm),
2) Manufacturing information,
3) Clinical protocols (study plans) for the studies to be conducted,
4) Data from any previous human research, and
5) Information about the investigator.
6.4.5. Asking for FDA Assistance

The drug developers can ask for help from the FDA during the following stages
of drug development process:
1) During the pre -IND application to review FDA guidance documents and get
answers to questions that will help in their research,
2) After phase II to obtain guidance on the design of large phase III studies, and
3) Any time during the process to obtain an assessment of the IND application.
* *
The FDA offers a broad technical assistance; still the drug developers are not
required to take FDA‟s suggestions. As long as clinical tr ials are considerately
designed to reflect the knowledge of developers about a product, defend
participants, and meet Federal standards, the FDA allows wide latitude in clinical
trial design.
6.4.6. FDA IND Review Team

The FDA IND review team comprises of a group of specialists in different
scientific fields, each having different responsibilities:
1) Project Manager: He/she coordinates the team‟s activities throughout the
review process, and is the primary contact for the sponsor.
2) Medical Officer: He/she r eviews the clinical study information and data
before, during, and after the trial.
3) Statistician:He/she interprets the clinical trial designs and data, and collaborates
with the medical officer to evaluate protocols and safety and efficacy data.
4) Pharmacologist: He/she reviews the pre-clinical studies.
5) Pharmacokineticist: He/she focuses on the drug‟s ADME processes. He/she
interprets blood -level data at different time intervals from clinical trials to
evaluate drug dosages and administration schedules.
6) Chemist: He/she evaluates and analyses how a drug was made, its chemical
compounds, stability, quality control, continuity, presence of impurities, etc.
7) Microbiologist:He/she reviews the data submitted, and evaluates whether or not
the product is an antimicrobial, and its response in different classes of microbes.
6.4.7. Approval
The FDA review team reviews the original IND submission within a month. This
process protects the volunteers of clinical trials from irrational and significant
risks in clinical trials. The FDA answers to IND applications in either of the
following ways:
1) The FDA gives approval to begin the clinical trials, or
2) The FDA puts a clinical hold to delay or stop the investigation due to the
following reasons:
i) Participants are exposed to unreasonable or significant risk.
ii) Investigators are not qualified enough for conducting the trials.
iii) Materials for the volunteer participants are misleading.
iv) The IND application does not present sufficient information on the
related risks.
The FDA rarely puts a clinical hold; rather, provides comments for improving the
quality of a clinical trial. If the FDA finds that the trial meets the Federal
standards, it allows the applicant to proceed with the proposed study. The
developer should inform the review team about ne w protocols and severe side
effects that occurred during the trial. On receiving this information, the team
closely monitors the trials to detect any signs of problems. After the trial is over,
the researchers submit the study reports.
* *
This entire process continues till the developer decides to stop the clinical trials or
files a marketing application. Before filing a marketing application, the developer
should have collected adequate data from two large, controlled clinical trials.
6.4.8. Clinical Research Protocols

Clinical investigations are started with the development of a clinical protocol ,
which is a document that describes the objectives, design, method s, statistical
considerations and organisation of a clinical trial, and ensures the safety of trial
subjects and reliability of the obtained data.
A research protocol is a document that describes the background, rationale,

objectives, design, method, statistical considerations, and organisation of a
clinical research project. According to the ICH good clinical practice guidelines,
the following topics should be included in a protocol:
1) General Information
i) Protocol title, identifying number, version number, and date.
ii) Name and address of the sponsor.
iii) Name and title of the person authorised to sign the protocol and the
protocol amendments for the sponsor.
iv) Names and titles of the investigators conducting the study.
v) Address and telephone number of the trial sites.
vi) Name, title, address, and telephone number of the sponsor‟s medical
expert.
vii) Name, title, address, and telephone number of the qualified physician
taking all the study-related medical decisions.
viii) Names, addresses, and telephone numbers of all the institutions, clinical
laboratories, and other medical or technical departments involved in the
study.
2) Background Information
i) Description of the problem for which the study is proposed to be
conducted and its public health significance.
ii) Conclusions of clinical or non -clinical studies that may be significant to
the proposed study.
iii) Summary of the potential risks and benefits to human subjects.
iv) Statement that the trial will be conducted in compliance with the
protocol, GCP, and the regulatory requirements.
v) Description of the study population.
vi) References to related literature and data compiled in a separate section in
the protocol.
vii) If an investigational product or therapy has been used in the study:
a) Name and description of the investigational product or therapy.
b) Description of and justification for the administration route, dose,
dosage regimen, and treatment period.
3) Study Objectives and Purposes: A detailed description of the primary
(major) and secondary (minor and exploratory) objectives and the purpose of
*
the trial. *
4) Study Design: It influences the scientific reliability of the study and the
integrity of the data attained. This section of the protocol describes:
i) Primary and secondary end points to be measured and their
measurement.
ii) Study type ( e.g., double-blind), along with a schematic diagram of the
study design, procedures, and stages.
iii) Measures to be taken for avoidi ng or minimising partiality ( e.g.,
randomisation, blinding).
iv) Dose, dosage form, dosage regimen, packaging, and labeling of
investigational products.
v) Expected duration of subject‟s participation, sequence and duration of all
study periods, including follow-up.
vi) Stopping rules or discontinuation criteria for each subject, parts of the
study, and the entire study.
vii) Accountability procedures for the investigational product, including the
placebo and comparator.
viii) Maintenance of study treatment randomisation codes and procedures for
breaking codes.
ix) Identification of any data to be recorded directly on the Case Report
Forms (CRFs) and considered to be source data.
5) Selection and Withdrawal of Participants
i) Criteria for addition and elimination of subjects.
ii) Procedures for removal of subjects that may be subject - or investigator-
initiated:
a) When and how to remove subjects from the study or investigational
product treatment.
b) Type and timing of the data to be collected for subjects who were
withdrawn from the study.
c) Whether and how the subjects are to be replaced.
d) Follow-up for the subjects removed from trial treatment.
6) Treatment of Participants
i) Pharmacological treatment:
a) Names of the products to be administered.
b) Doses and dosing schedules.
c) Administration methods (i.e., oral, intramuscular).
d) Other medications or treatments allowed (including rescue
medication) and not allowed before and/or during the study.
ii) Other interventions (i.e., chiropractic, physical therapy, social therapy,
behavioural therapy, counselling):
a) Name of inte rvention (i.e., motivational interviewing, cognitive
behavioural therapy).
b) Frequency of sessions.
c) Duration of each session.
d) Method of intervention (i.e., individual, group).
e) Treatment adherence.
* *
iii) All interventions:

a) Period(s) of intervention, including foll ow-up periods for subjects in
each group.
b) Procedures for monitoring subject compliance.
c) Identification of who will administer an intervention.
7) Assessment of Efficacy: Description of the methods to be used for
determining the treatment effectiveness, including:
i) Criteria for determining the treatment effectiveness.
ii) Methods and timing for evaluating, recording, and analysing the
effectiveness criteria.
8) Assessment of Safety: Description of the methods to be used for monitoring
the study and dealing with the adverse events:
i) Specification of safety criteria.
ii) Methods and timing for evaluating, recording, and analysing the safety
criteria.
iii) Methods for obtaining reports of adverse events and ailments
experienced by the subjects during the study and for recording and
reporting these events and accelerated reporting procedures.
iv) Type and duration of follow -up of subjects who experienced adverse events.
9) Statistics: Description of the strategy for analysing the data obtained during
the study, including:
i) Statistical methods to be used and the timing of any planned interim
analyses.
ii) Total number of subjects to be involved in the study.
iii) Purpose for selecting the spec ific sample size, along with the reflections
on or calculations of the power of the study and clinical justification.
iv) Level of significance to be used.
v) Criteria for ending the study.
vi) Procedure for considering the missing, unused, and false data.
vii) Procedures for reporting deviations from the statistical plan (deviations
from the statistical plan should be described a nd justified in the protocol
and/or in the final report).
viii) Selection of subjects to be involved in the analyses.
10) Direct Access to Source Data or Documents: The sponsor should safeguard
that the protocol or other written agreement states that study investiga tors or
institutions will provide direct access to source data or documents for study -
related monitoring, audits, IRB review, and regulatory inspections.
11) Quality Control and Quality Assurance: A detailed quality assurance plan,
describing the set standards and controls to ensure that each step follows the
accepted plan , is submitted as a separate document. The protocol should
describe the quality assurance methods.
12) Ethics: The ethical considerations related to the study and measures taken to
protect human subjects and maintain the privacy of study data should be
submitted.
* *
13) Data Management: A detailed data management plan describing the

methods of collecting, documenting, submitting, and archiving study data
should be submitted as a separate document. The protocol should describe
the data management activities related to the protocol. The data management
plan describes the procedures that ensure the data reliability during the study
and at all study sites, including:
i) Description of the data system design and development.
ii) Data collection methods and activities.
iii) Methods of data entry and editing.
iv) Procedures for data monitoring, reporting, and transfer.
v) Data recipients and procedures for data distribution.
14) Financing and Insurance: Description of how the study w ill be financed
and insured should be submitted. In some research networks, these issues are
discussed in a separate agreement and are not included in the protocol.
15) Publication Policy: Description of the policies and procedures related to
publication of th e study conclusions should be submitted . In some research
networks, policies and guidelines are established for the researchers for
publications planning process. For example , the publication on primary
outcome data should lead other publications on the study findings. Researchers
should know and adhere to the institutional and sponsor policies and
requirements for publications.As per the FDA Amendments Act, the trial results
will also be published on a public website (i.e., ClinicalTrials.gov.), and this
website will not identify the clinical trial subjects, but will provide a resource for
them, and those seeking clinical trial involvement, to inform themselves.
16) Supplements: Description of any other required information, depending on
the research nature should be submitted. For example, the informed consent
template, the therapy manual, a patient information handbook, etc., may be
attached in the protocol.
6.5. BIOEQUIVALENCE STUDIES

6.5.1. Introduction
If a new product is proposed to be used as an alternative or a p harmaceutical
equivalent for an approved medicinal product, the equivalence with this product
should be shown or justified. Bioequivalence stud ies should be performed for
ensuring the clinical performance of such drug products. Bioequivalence studies
are conducted if there is:
1) A risk of bio-inequivalence, and/or
2) A risk of pharmacotherapeutic failure or diminished clinical safety.
6.5.2. Types of Bioequivalence Studies

Discussed below are the two types of bioequivalence studies:
1) In vivo Bioequivalence Studies: The following sequence of criteria is used
for assessing the need for in vivo bioequivalence studies:
i) Oral immediate release products with systemic action:
a) Directed for serious conditions requiring assured response.
* *
b) Narrow therapeutic margin.

c) Pharmacokinetics complicated by absorption < 70% or absorp tion
window, non-linear kinetics, pre-systemic elimination > 70%.
d) Poor physiochemical properties, like low solubility, metastable
modifications, instability, etc.
e) Documented evidence for bioavailability problems.
f) Non-availability of relevant data, unless justified by the applicant
that in vivo study is not required.
ii) Non-oral immediate release products.
iii) Modified release products with systemic action.
In vivo bioequivalence studies are conducted using the pharmacokinetic and
pharmacodynamic methods.
2) In vitro Bioequivalence Studies: If the above mentioned criteria are not
applicable, comparative in vitro dissolution studies are conducted. These
studies can be used as a substitute to in vivo bioequivalence studies under
certain circumstances, termed as biowaivers (exemptions):
i) The drug product differs in strength of the active substance it contains,
provided all the following conditions hold:
a) Pharmacokinetics is linear.
b) Qualitative composition is the same.
c) Ratio between the active substance and the excipients is same, or in
the case of small strengths the ratio between the excipients is same.
d) Both the products are produced by the same manufacturer at the
same production site.
e) A bioavailability or bioequivalence study has been performed using
the original product.
f) The in vitro dissolution rate is same under the same test conditions.
ii) The original manufacturer has slightly reformulated the drug product or
has slightly revised the manufac turing method in ways that can be
inappropriate for the bioavailability.
iii) The drug product meets the following requirements:
a) The product is in solution form or solubilised form (elixir, syrup,
tincture, etc.).
b) The active i ngredient concentration in the product is same as in the
approved drug product.
c) The product contains no such excipients that will affect the
absorption of active ingredient.
iv) An acceptable IVIVC and in vitro dissolution rate of the new product is
equivalent to that of the approved medicinal product. Furthermore,
a) The product is proposed for topical administration (cream, oint ment,
gel, etc.) to exert local effect.
b) The product is proposed for oral administration but not to be
absorbed (antacid or radio-opaque medium).
c) The product is administered by inhalation as a gas or vapour.
The criteria listed above for drug products indicate that bioavailability and
bioequivalence are self-evident.
* *
6.5.3. Bioequivalence Study Parameters

If two products show similar rate and extent of drug release, i.e., the amount of
drug molecules released and the rate (speed) of release are similar, they are said
to be bioequivalent. These characteristics of two drug products c an be studied
and compared in vivo using the following parameters:
1) AUC: It is the area under the plasma drug concentration -time curve, and it
provides information on the amount of drug in plasma, i.e., extent of release.
2) Cmax: It is the maximum plasma drug concentration, and it partially depends
on the rate of drug released from the formulation.
3) tmax: It is the time required to reach the maximum plasma drug concentration,
and it also depends on the rate of drug released from the formulation.
4) t1/2: It is the elimination half -life, and it provides information on drug
elimination from the body.
Given below are some other parameters used in the bioequivalence study:
1) Normalised C max: Since Cmax and t max show intra -subject variability,
normalised C max is used, wh ich shows comparatively less intra -subject
variability and is calculated as follows:
C max
Normalised Cmax = …..(1)
AUC
2) Mean Residence Time (MRT): It is the time for which a drug molecule
remains in the body before it gets eliminated. To calculate the value of MRT,
Area Under the Moment Curve (AUMC) is calculated as follows:
t
 t C  t i-1  Ci-1 
AUMC0-t    i i t i  t i-1  ..... (2)
i 1  2 
Equation (2) reveals that AUMC calculation is quite similar to AUC, with
the only difference that in the former the drug plasma concentration is
multiplied with time. AUMC 0- can be calculated from AUMC 0-t, and then
MRT can be calculated as follows:
AUMC0-
MRT  ..... (3)
AUC0-
3) Plasma Trough Fluctuation (%): This parameter is used for the

bioequivalence study of sustained release formulations, which are designed
such to maintain steady -state plasma drug concentration for extended time
periods. Hence, bioequivalence study of sustained release formulations
involves comparing the steady-state plasma drug concentrations obtained from
two drug products. Cmin is the lowest plasma drug concentration just before the
next dose and % PTF is the per cent change in the plasma drug concentration
between two dose administrations. These parameters are calculated as:
C max  C min
%PTF  ….. (4)
C average
Where, Caverage = Average plasma drug concentration durin

g the dosing period.
* *
6.5.4. Design of Single Dose Bioequivalence Study

Earlier, generic drug products (pharmaceutical equivalents) did not always give
identical in vivo therapeutic effects in patients. Therefore, bioequivalence studies
are performed to compare the bioavailability of generic drug product with that of
the brand name product. Once bioequivalence is established, same therapeutic
effect will be produced by both the generic and brand name dosage forms. The
following guidelines should be consulted for specific drugs:
1) Design: The design and evaluation of well -controlled bioequivalence studies
require the cooperative input from pharmacokineticists, statisticians,
clinicians, bio-analytical chemists, etc. The basic design for a bioequivalence
study is determined by:
i) The scientific questions to be answered,
ii) The nature of the reference material and the dosage form to be tested,
iii) The availability of analytical methods, and
iv) Benefit-risk considerations regarding the testing in humans.
The branch of biopharmaceutics provides some general guidelines to conduct
bioequivalence studies for some of the generic drugs. For example, the
biopharmaceutics branch has provided “Statistical procedures for
Bioequivalence Studies Using a Standard Two-Treatment Crossover Design”
that addresses three specific aspects:
i) Logarithmic transformation of pharmacokinetic data,
ii) Sequence effect, and
iii) Outlier consideration.
Even if such guidelines are available, the principal investigator should
prepare a detailed study protocol.
Elements of the Design
Some of the protocol elements for an in vivo bioavailability study are:
1) Title iv) Inclusion and exclusion criteria,
i) Principal investigator or study v) Restrictions during study.
director,
5) Clinical procedures
ii) Project or protocol number and
i) Dosage and drug
date.
administration,
2) Study objective
ii) Biological sampling,
3) Study design
iii) Handling of biological samples.
i) Design
ii) Drug products 6) Ethical considerations
a) Test product, i) Institutional Review Board,
b) Reference product. ii) Informed consent,
iii) Dosage regimen, iii) Indications for withdrawal of
iv) Sample collection schedule, subjects,
v) Housing of subjects, iv) Adverse reactions,
vi) Fasting and meal schedule, v) Emergency procedures.
vii) Analytical method. 7) Facilities
4) Study population
i) Subjects, 8) Data analysis
ii) Subject selection i) Validation of analytical
a) Medical history, procedure,
b) Physical examination, ii) Statistical methods used.
c) Laboratory tests. 9) Appendix.
* *
For bioequivalence studies, the test as well as the reference drug formulations
contain the pharmaceutical equivalent drug in same dose strength, do sage
forms (e.g., immediate release or controlled release), and are given by the same
administration route. A single dose and/or a multiple dose (steady-state) study
are conducted before beginning the bioequivalence study. The studyshould be
approved by t he Institutional Review Board (IRB) of the clinical facility
where the study is to be performed. The IRB comprises of professional and
non-professional individuals from diverse background, having clinical
experience and skill and sensitivity to ethical issues and community attitudes.
The IRB safeguards the rights and welfare of human subjects.
The basic guiding principle in performing studies is that unnecessary human
research should not be done. The study is performed in healthy male
volunteers who have g iven informed consent to be in the study. The number
of subjects in the study depends on the expected inter -subject variability.
Patient selection is made according to certain established criteria for
inclusion into or exclusion from the study.
A proper study design and statistical evolution should be considered while
determining bioequivalence. Some study designs are summarised below:
i) Fasting Study: This study is a single dose, two -period, two treatment,
two sequence, open label, randomised crossover des ign in which equal
doses of the test and reference products are compared in fasted, adult,
healthy male and female subjects. This study is conducted for the
immediate release and modified release oral dosage forms. Blood
samples are taken before administer ing the dose (zero time) and then at
specific time intervals after administering the dose to obtain an adequate
profile of plasma drug concentration versus time. The subjects should be
in the overnight fasting state before the drug is administered and shou ld
continue to fast for 4 hours after the drug administration. No other
medication is given to the subject for atleast 7 days before the study.
ii) Food Intervention Study: This study is a single dose, randomised,
three-treatment, three period, six sequence, c rossover, limited food
effects study in which equal doses of the test product given under fasting
conditions are compared with the doses of the test and reference products
given after a standard, high fat content breakfast. This study is conducted
for the modified release dosage forms and immediate release dosage
forms if the bioavailability of the active drug ingredient is affected by
food (e.g., ibuprofen, naproxen).
iii) Multiple Dose (Steady -State) Study: This study is a multiple dose,
steady-state, randomis ed, two -treatment, two -way crossover study in
which equal doses of the test and reference products are compared in
adult, healthy subjects. This study is conducted for the oral extended
release (co ntrolled release) drug products, along with a single dose
fasting study and a food intervention study. Three consecutive trough
concentrations (C min) on three consecutive days should be determined to
ensure that the subjects are at steady state. The last morning dose is given
* *
to the subject after an overnight fast and they continue to fast for 2 hours
after the dose administration. Blood samples are taken similarly as in the
single dose study.
2) Reference Standard: In a bioequivalence study, one drug formulation is
selected as a reference standard against which all other drug formulations are
compared. The reference standard formulation is currently marketed with a
fully approved NDA having valid scientific safety and efficacy data. It is the
innovator‟s or original manufacturer‟s brand name product. The reference
drug should be administered via same route as the other formulations, except
when an alternative route or additional route is required to answer specific
pharmacokinetic questions. For example, if the bioavailability of an active
drug is poor after oral admi nistration, the drug is compared to an oral
solution or an intravenous injection.
Before an in vivo bioequivalence study is started, the total content of the
active drug substance in the test product (generally the generic product)
should be within 5% of the reference product. The in vitro comparative
dissolution or drug release studies under various specified conditions are
performed for the test as well as reference products.
3) Crossover Designs: Subjects abiding by the inclusion and exclusion study
criteria and have given informed consent are randomly selected. A complete
crossover design, in which the test drug product and the reference product are
administered to each subject, is used.In tables 6.3 and 6.4, examples of Latin
square crossover design for a bioequivalence study in human subjects,
comparing three different drug formulations (A, B, and C) or four different
drug formulations (A, B, C, and D) are described. Clinical trial using the Latin
square design is planned such that each drug product is a dministered to each
subject only once, maintaining adequate time gap between the medications to
ensure complete elimination of the drug from the body.
Table 6.3: Latin Square Crossover Design for a Bioequivalence
Study of 3 Drug Products in 6 Human Volunteers
Drug Products
Subjects Study Period 1 Study Period 2 Study Period 3
1 A B C
2 B C A
3 C A B
4 A C B
5 C B A
6 B A C
In this design, each subject is his /her own control, subject -to-subject
variation is reduced, and variation due to seque nce, period, and treatment
(formulation) are also reduced, so that the patients do not receive the same
drug product in the same order and on the same day. The potential carry-over
effects from a drug product can be reduced if the sequence or order in whic h
the drug products are to be given to the subject is changed. Thus as given in
table 6.4, the drug product B is followed by drug product A, D, or C. After
the subjects are administered with a drug product, their blood samples are
* *
withdrawn at specific tim e intervals to yield a valid blood drug level versus
time curve. There should be appropriate gap between the time intervals so
that the peak blood concentration, the total AUC, and the absorption and
elimination phases of the curve can be described. Someti mes, concentration
of drug in urine samples is also measured.
Table 6.4: Latin Square Crossover Design for a Bioequivalency Study of 4
Drug Products in 16 Human Volunteers
Drug Products
Subjects Study Period 1 Study Period 2 Study Period 3 Study Period 4
1 A B C D
2 B C D A
3 C D A B
4 D A B C
5 A B D C
6 B D C A
7 D C A B
8 C A B D
9 A C B D
10 C B D A
11 B D A C
12 D A C B
13 A C D B
14 C D B A
15 D B A C
16 B A C D
Period indicates the time period in which a study is performed. A two-

period or two-legged study signifies that the study is performed on two
different days (time periods) separated by a washout period during which
maximum concentration of the drug eliminates from the body (generally
about 10 elimination half -lives). Sequence indicates the number of different
orders in the treatment groups in a study; for example, a two-sequence, two-
period study is designed as follows:
Period 1 Period 2
Sequence 1 T R
Sequence 2 R T
R = Reference; T = Treatment.
6.5.5. Evaluation of Bioequivalence Data

The bioequivalence data obtained is evaluated by the following methods:
1) Analytical Method: This method for drug measurement should be validated
for accuracy, precision, sensitivity, and specificity. More than one analytical
method should not be used during a bioequivalence study as different
methods yield different values. Data for evaluation should be presented in
tabulated as well as graphic form. The plasma drug concentration versus time
curve should be available for each drug product and each subject.
2) Pharmacokinetic Evaluation of the Data: The pharmacokinetic analyses
for single -dose studies (including a fasting study or a food intervention
study) include calculati on of AUC to the last quantifiable concentration and
* *
to infinity, tmax, and Cmax for each subject. The elimination rate constant ( k),
elimination half -life ( t1/2), and other parameters should also be determined.
The pharmacokinetic analyses for multiple -dose studies include calculation
of the steady -state AUC, tmax, C min, Cmax, and the % fluctuation for each
subject. Proper statistical evaluation should be performed on the estimated
pharmacokinetic parameters.
3) Statistical Evaluation of the Data: Bioequivalence is determined by
comparing the population averages of a bioequivalence metric, such as AUC
and Cmax. This approach is termed average bioequivalence and it involves
calculating a 90% confidence interval for the ratio of averages (population
geometric means) of the bioequivalence metrics for the test and reference drug
products. Bioequivalence can be established by calculating the confidence
interval that should fall within the prescribed bioequivalence limit (80 -125%
for the ratio of the product averages ). The FDA gave another method for the
same purpose, termed as individual bioequivalence that employs a replicate
crossover design to estimate within-subject variability for the test and reference
drug products, as well as subject-by formulation interaction.
Bioequivalence can be proved if no statistical difference exists between the
bioavailability of the test product and the reference product. The bioavailability
of drug from the test dosage form is compared with the bioavailability of the
drug from the reference dosage form using several statistical methods. In many
statistical approaches (or parametric tests), it is assumed that the data are
distributed according to a normal distribution or bell -shaped curve.
Distribution of Cmax and AUC biological pa rameters has a longer right tail
than that in a normal distribution. The true distribution of these parameters is
even difficult to establish as a small number of subjects are used in a
bioequivalence study. The distribution of data that has been converted to log
values closely resembles a normal distribution compared to the distribution
of non-log-transformed data. Therefore for bioequivalence determination, log
transformation of the bioavailability data ( e.g., Cmax and AUC) is performed
before statistical data evaluation.
The obtained data is statistically estimated by the following two methods:
i) Analysis of Variance (ANOVA): This is a statistical method used for
testing the data for differences within and between treatment and control
groups. There should be no significant difference in the tested
pharmacokinetic parameters (AUC (0-t), AUC (0-∞), tmax, and Cmax for each
treatment or dosage form) of the bioequivalent product. Other metrics of
bioavailability can also be used for comparing the bioequivalence o f two
or more formulations.
The ANOVA is used for determining the variability in subjects,
treatment groups, study period, formulation, and other variables,
depending on the study design. In case of large data variability, the
difference in means for each pharmacokinetic parameter may be masked,
and the investigator might by mistake conclude the two drug products to
*
be bioequivalent. *
The probability (p) is used for indicating the level of statistical

significance. The statistical difference between the p harmacokinetic
parameters obtained from two or more drug products is statistically
significant if there is a probability of less than 1 in 20 times or 0.05
probability ( p > 0.05) that these results would have happened on the
basis of chance alone; while if p < 0.05, the differences between the two
drug products are not statistically significant.
ii) Two One -Sided Tests Procedure or Confidence Interval Approach :
This statistical method is used for validating whether the drug
bioavailability from the test formul ation is low or high than that of the
reference product. This method aims to determine if large differences (i.e.,
>20%) exist between the mean parameters. The 90% confidence limits are
estimated for the sample means. The interval estimate is based on
Student’s t distribution of the data. In this test, a 90% confidence interval
about the ratio of means of the two drug products should be within ±20%
for measurement of the rate and extent of drug bioavailability.
A difference of 20% in AUC or Cmax between two drug formulations is not
clinically significant. The lower 90% confidence interval for the ratio of
means cannot be less than 0.80 (80%), and the upper 90% confidence
interval for the ratio of the means cannot be greater than 1.20 (120%). The
90% confidence interval is set at 80-125% when log-transformed data are
used. These confidence limits are also termed asbioequivalence interval.
The 90% confidence interval is a function of sample size and inter - and
intra-subject variability. ANOVA is performed on the log -transformed
AUC and Cmax values for a single -dose, fasting study. No statistical
differences should exist between the mean AUC and Cmax parameters for
the test and reference drug products. The 90% confidence intervals about
the ratio of the means for AUC and Cmax values of the test drug product
should also be not less than 0.80 (80%) and greater than 1.25 (125%) of
that of the reference product based on log-transformed data.
6.6. BIOSTATICS IN PHARMACEUTICAL

PRODUCT DEVELOPMENT
6.6.1. Introduction
Biostatistics involve the use of scientific and quantitative procedures in
descriptive and inferential statistics to evaluate the quality of evidence in
biological sciences. It also involves the statistical processes and methods used for
analysing the biological phe nomena. Biostatistics is a science that includes
designing of biological and experimental study designs as well as synthesis,
analysis, and interpretation of data obtained from such studies. Biostatistics is a
wide branch of biological sciences in which th e theories in statistics are applied
to the living-world problems in health and diseases. It involves various statistical
operations, such as designing and conducting biomedical experiments, clinical
* *
trials, and development of related computational algorit hms. Biostatistics forms

an important part in epidemiological research, development of health policies,
health economics, public health administration, evidence -based practice in
clinical medicine, genomics, proteomics, and development of various
pharmaceutical products.
Biostatistical analysis is an important step in human clinical trials that are

conducted in the last stages of pharmaceutical development. Every drug, device
and biological product should go through this analysis before being introduced to
the market. The p -value is generally used as a substitute for comprehensive
statistical and medical judgment by the scientists and regulators who consider a
wide range of information, measure it all against risks and benefits, and make the
difficult decision either to prevent the harmful effect of a dangerous product or to
provide a new medical miracle to the awaiting subjects.
6.6.2. Experimental Design in Clinical Trials

Before submitting the study data to a regulatory authority for seeking approval,
the clinical trials for a new drug, device or biological product are conducted in
three sequential phases. In each phase, the biostatistician is involved in the design
and analysis of clinical trials.
Sample Size and Experimental D esign: Before designing any trial, a
biostatistician collaborates with medical, regulatory, and data management
experts. Trial designing describes what to measure, how often to measure it, how
to select subjects, randomly assigning treatments to them, and how to analyse the
results. Everything in the clinical protocol, including the expected results, all
analysis strategies, and the rationale for the number of subjects to be studied (i.e.,
the sample size) should be pre -specified. All the above mentioned fa ctors should
be consulted with a statistician at the beginning of a trial to establish the sample
size.
For Phase III trials a clear understanding of the required sample size is critical.
This is because in the final analyses of Phase III trials, the esta blishment of
statistical significance is required to support the submission for marketing
approval.
The results obtained from Phase II trials give evidence to establish the required
sample size for Phase III trials. Factors included in phase II studies a re the
expected size of the clinical benefit of the new drug relative to the control group,
nature of the primary efficacy parameter (continuous, discrete, time -to-event,
etc.), fluctuations in the data from the subjects in the trial, the p -value required to
define statistical significance (termed the alpha level that is set ≥ 0.050 by the
regulatory agency), and the degree of risk the drug‟s sponsor is ready to take that
the trial will fail to obtain the desired alpha level even though the drug has the
magnitude of efficacy predicted by the protocol. The last step is called a s
statistical power , if it is positively described as assurance (and not risk).
Perhaps, it is defined as a probability that a statistically significant outcome of a
single trial will be obtained when the drug activity is as anticipated.
* *
It is not possibl e to accurately predict the response of a human subject to a drug

due to the individual biological characteristics of humans, differences in their
daily lives, and their limited understanding of biology and pharmacology. It also
means that the response of an individual to a drug cannot predict the response of
another individual to the same drug. The unpredictable variations in individual
responses and the need to predict the aggregate responses of a population of
future subjects are the reasons behind the i nvolvement of biostatisticians in
clinical trial design and analysis.
Inferential statistics is the branch of biostatics that makes inferences about

populations by the analysis of data obtained by samples drawn from those
populations in a prescribed manner.
6.6.3. Sensitivity and Cost

Increase in the sample size in a trial increases the assurance that an effective drug
will achieve statistical significance when the trial results are analysed with
normal statistical techniques. Sample sizes are always compromised between
what is ideal and what is affordable as every sponsor of a new drug has some
financial and time limitations. In such case, a biostatistician should define the
parameters around this compromise.
Consequently, the sensitivity of a trial to detect t he statistically significant
efficacy effect for a new drug partially depends on sample size. All other things
being equal, larger the sample size, less effective a drug should be to give a
significant and potentially approvable result. For marketing appro val, the
financial investment is one of the important determinants in clinical trials. But, it
is often misunderstood that this statistical fact has critical societal implications.
Recommendations:For approval of new drugs, a major standard shift is needed in
our thinking regarding the statistical gold standards. It would be consistent with
sound statistical principles to abandon the rigid and ubiquitous alpha = 0.05 hurdle
for regulatory approval. There should be a priority process regarding the
establishment of consistent treatment effect with clinically meaningful benefit, along
with an agreement to both the acceptable width of a confidence interval around that
benefit and the degree of assurance required for that confidence interval. The degree
of assurance could be specified for several confidence intervals, designed to show the
effect of differences in required precision on the interval width. These parameters are
established based on the already known or expected risks, and also on disease
severity and the availability of alternative, effective, and safe therapies.
6.6.4. Random Sampling

The two requirements regarding the random processes include underlying all the
inferential statistics and the ability to forecast population benefits from clinical
trials. At first, the subjects for clinical trials should be randomly selected and
represent the sample of the population of future subjects in the total population that
are approved eligible for the drug use. Secondly, treatments should be randomly
assigned to clinical trial subjects for comparative trials. Although most of the major
trials adhere to the second requirement, a few of them may follow the first.
* *
Recommendations: In case of prospective randomised comparative clinical trial,

the biostatistician should generalise from the trial results, the future population of
subjects who may receive the new drug. In this process, the sampling frame
should be used to represent the properties of that future population, and some
factors of random selection should be present when investigators and subjects are
identified for the trial. If this is not possible due to the limitations on available
subjects, various techniques like advanced approaches to stratified sampling may
be preferred.
In case the relative sizes of st rata differ from that of the population to which
inferences will be made, adjustments should be made during the analysis to gain
the correct balance. Such analysis is not commonly accepted; however, for
pivotal trials, the statistical community should perf orm hard to improve the
relevance of trials to the population of subjects for whom the drugs are designed.
6.7. MANAGEMENT OF CLINICAL STUDIES
6.7.1. Introduction
Many renowned researchers and trialists are convincingly and rec urrently
writing, from the past fifty years, about the need for large, randomised, controlled
trials. Generally, these trials are considered the highest level of evidence for
guiding clinical practice; but, very less about their management is mentioned in
most explanations. Therefore, many clinical trials fail to provide sufficient
information due to the lack of a structured, practical, business -like approach in
trial management. Limited human and financial resources are required for a
randomised trial; therefore, it becomes essential that every possible effort should
be made to ensure that a clinical trial is easily implemented and proficiently
managed. An expert management is required for a randomised trial as it demands
a large investment of time, money, and human resource.
Trial management is an important factor that is required to deliver high -quality

trials. According to the trial management, well -designed trials form the basis for
addressing important clinical questions, but only science is not suffic ient for a
successful trial delivery. The challenge is different if the science is determined
and the trial is accepted through the peer review process. After this, the main
challenges are to establish and implement effective management systems and
techniques that respond to the requirements of the trial and the trialist. Same
coordinated processes and systems are required for clinical trials, irrespective of
the size, scope, costs, or duration.
6.7.2. A Trial Manager

A trial manager plays an important role in th e success of a project. This role is
recognised by the NIHR HTA programme, that recommends all primary research
projects to appoint a dedicated project/trial manager. An ideal condition is that
trial managers should be involved in the early phase of trial design; however, it is
not always possible due to the lack of funding. A good trial manager involved in
* *
trial design and funding application beneficially contributes to the practicalities

of conducting the trial, thereby making the procedure cost -effective and avoiding
unnecessary work. The HTA and UK Trial Managers‟ Network (UKTMN)
identify the following key responsibilities of a trial manager as per the generic
job descriptions:
1) He/she plays a lead role in planning, coordination, and completion of a
project.
2) He/she has to communicate between various departments, and thus should
have remarkable communication and presentation skills.
3) He/she should organise and motivate others.
4) He/she should possess enthusiasm, innovation and leadership qualities when
faced with challenges.
5) He/she should manage the trial budget(s) and maintain the accounts.
6) He/she should possess strategic, tactical and operational management skills
to actively participate in the planning and execution of a project.
6.7.3. Project Planning

According to the project management, the following features of clinical trials are
similar to those of other types of business projects:
1) A clear objective of bringing about a change,
2) Requiring a team,
3) Setting a time scale,
4) Defining resources to achieve its objective, and
5) Tasks that need to be completed to a pre-specified standard.
All the projects include a series of processes and a set of actions, which are
essential to obtain the desired results. Following are the five basic processes:
1) Initiating,
2) Planning,
3) Executing,
4) Monitoring and controlling, and
5) Analysis and reporting.
6.7.4. Collaboration
Good evidence that the clinical question being evaluated is in equipoise, is
important, but it is only part of the equation. The questions should be designed
with the concern of clinicians and nurses as they are the ones who recruit the
participants. Most trials depend on developing some collaborative group for
successful trials. The collaborative group or network focuses on being inclusive,
rather than exclusive.
Proactively ra ising the profile of a developing project and creating a group of
interested people requires commitment and time. This can be performed by
various methods, such as by making personal contacts, through presentations at
relevant conferences, mail shots, news letters from professional colleges, journal
articles and general word of mouth.
* *
The success of a trial, especially the recruitment process, depends on the ability
of thinking „outside the box‟, training, supporting, as well as crediting other
groups (like, nurses, records department staff, ward clerks, radiology staff) who
have no direct involvement in the research process, but still are important for a
trial. The chances of success of a trial increases and the process becomes more
enjoyable, if the collaborative group members work as if the project is their own.
This feeling of ownership can be promoted when the collaborative group
members involve at every stage of the trial projects, i.e., from development of
protocol to publication of results.
6.7.5. Minimal Work for Investigators and Participants

The minimal work for investigators and participants includes assuring that the
procedures of recruitment and the routine practices are being carried parallely.
Site visits and interacting with the staff where recruit ment occurs makes the
recruitment process a part of daily routine.
The recruitment procedure should be real and practical; for example, web
randomisation is not considered practical for a trial being conducted in an Intensive
Care Unit (ICU) or in a tria l of an emergency intervention. It has been observed
that clinical staffs always remain busy and are unwilling to carry out complex
procedures of recruiting participants. The participants may also feel isolated in case
of complicated procedures and extra tests or visits. The recruiting staff should be
readily provided with the data to be obtained to answer the clinical question.
6.7.6. Communication
A regular feedback should be essentially provided to the investigators to ensure
that they feel valuably involved i n an inclusive team answering an important
clinical question. This forms a central of trial‟s communication strategy. The
busy clinicians can identify his/her priorities and maintain trial „buy -in‟ by
remembering the audience being addressed and tailoring all communication
appropriately.
The investigator feels more connected if he/she is communicated through his/her
preferred method (i.e., telephone, email, letter, web site, and personal contact).
Investigators feel contin uously involved if a positive ima ge is made about the
trial progress and also progress within any given site. The confidence of trial and
the trial team can be increased by listening to their problems and quickly
resolving the issues. The feeling of appreciation should be continuously
maintained within the investigat ors and they should not be over -burdened by
involvement in the trial.
6.7.7. Efficient Systems

Large and highly modern computerised systems and procedures are required for a
large trial, so that every aspect of the day -to-day running of the trial can be
monitored. Therefore, it is essential to develop a reliable system for monitoring
recruitment, randomisation procedures, stock control, data management, data
cleaning, and central data monitoring, and for producing useful reports.
* *
All the essential papers that relate to a trial participant should be logged and
tracked through the system. Every process involved in the trial should be logical
and transparent, and should have a brief documentation (standard operating
procedures) and accountability.
In case of international trials, these systems should take account of conflicting
clinical practices, working environments , and governance regulations as per the
country.
6.8. SUMMARY
1) Investigational New Drug (IND) is a pharmaceutical form of an active
substance or placebo being tested or used as a reference in a clinical trial.
2) Investigator IND application is submitted by a physician who initiates and
conducts an investigation, and under whose direction the investigational drug
is administered or dispensed.
3) Emergency use IND application allows the FDA to approve the use of an
experimental drug in an emergency situation that does not allow time for
submission of an IND application.
4) Treatment IND application is submitted for experimental drugs showing
promise in clinical testing for serious or immediately life -threatening
conditions.
5) The process of IND application is used for commercial and research or
non-commercial experimental drug use.
7) Investigators’s brochure includes a summary of the pharmacological and
toxicological effects of the drug in animals and in humans (if known).
6) Investigators’s brochure includes a description of potential risks and side
effects based on the past exp erience with the drug or related drugs under
investigation.
7) The clinical and non-clinical data on investigational product(s) that are
relevant to the study of the product(s) in human subjects are compiled in the
Investigator’s Brochure (IB).
8) The sponsor ca n include an instruction statement to the
investigator/recipients to treat the IB as a confidential document for the
information and use of the investigator‟s team and the IRB/IEC.
9) A summary of the pharmacology of the investigational product and its
significant metabolites studied in animals should be provided.
10) A summary of the pharmacokinetics and biotransformation and disposition of
the investigational product studies should be provided.
11) The NDA is the formal final step a drug sponsor takes, in which he/ she
applies to the Food and Drug Administration (FDA) to get approval for
*
marketing a new drug. *
12) An NDA is a document comprising of 15 sections of data and analyses on

animal and human studies, the drug‟s pharmacology, toxicology and dosage,
and its manufacturing process.
13) The index of NDA should bear the volume and page number for the
summary, the technical sections, and any related information.
14) Archival copy is a complete copy of an application submission.
15) The NDA number (if known), applicant‟s name, and the drug‟s name should
be present on the cover of each folder.
16) The applications should be bound on the left side of the page using the
standard size loose-leaf page (81/2 × 11).
17) “VOLUME __” should be pre -printed on the upper right -hand corner of
each jacket, and should be filled in for original applications and for chemistry
pre-submissions only.
18) Phase 0 trials are the first clinical trials conducted in human subjects and
their objective is to learn the processes a drug undergoes within the body and
the effect it produces in the body.
19) Phase I trials are conducted to determine that dose of a new drug which will
produce the least side effects.
20) Phase II trials evaluate the safety and effectiveness of the drug.
21) Phase III trials compare a new drug to the standard-of-care drug being used.
22) A research protocol is a document that describes the background, rationale,
objectives, design, method, statistical considerations, and organisation of a
clinical research project.
23) In vivo bioequivalence studies are conducted using the pharmacokinetic and
pharmacodynamic methods.
24) AUC is the area under the plasma drug concentration -time curve, and it
provides information on the amount of drug in plasma, i.e., extent of release.
25) Cmax is the maximum plasma drug concentration, and it partially depends on
the rate of drug released from the formulation.
26) tmax is the time required to reach the maximum plasma drug concentration,
and it also depends on the rate of drug released from the formulation.
27) t1/2 is the elimination half -life, and it provides information on drug
elimination from the body.
28) Biostatistics involve the use of scientific and quantitative procedures in
descriptive and inferential statistics to evaluate the quality of evidence in
biological sciences.
29) Biostatistics is a wide branch of biological sciences in which the theories in
statistics are applied to the living-world problems in health and diseases.
30) The minimal work for investigators and participants includes assuring that
the procedures of recruitment and the routine pr actices are being carried
parallely.
* *
6.9. EXERCISE

1) Define IND.
2) Enlist the types of IND.
3) What is invetsigator‟s brochure?
4) What is NDA?
5) Give the objectives of a clinical development of a drug candidate.
6) Define drug dependence and abuse potential.
7) How can you calculate Cmax and MRT?
8) What are the responisbilities of a trial manager in clinical studies?

1) What information should be present on the cover sheet of an IND
application?
2) What pharmacology and tox icology information should be present in an IND
application?
3) Write about the archieval and review copy of NDA.
4) Write a note on clinical reseacrh phase studies.
5) Discuss the types of bioequivalence studies.
6) Write a note on statistical evaluation of bioequivalence data.

1) Enumerate in detail the content and format of an IND application.
2) Mentions the information to be included in an IB.
3) Breifly discuss about clinical research protocols.
4) Write a detailed note on the design of single dose bioequivalence study.
5) Illustarte the biostatics in pharamceutical product develpoment.
* *
CHAPTER Quality Management

7 Systems
7.1. QUALITY MANAGEMENT
7.1.1. Introduction
A management technique used for communicating to employees what is required to
produce the desired quality of products and services and to influence employee
actions to complete tasks according to the quality specifications is termed Quality
Management System (QMS). QMS is a set of policies, processes, and procedures
required for planning and execution (production, development, or service) in the core
business area of an organisation (i.e., area that can impact the organisation‟s ability to
meet customer requirements). Anexample of a QMS is ISO 9001.
A QMS integrates various internal processes in an organisation and provides
a process approach for project execution. With a pro cess-based QMS, an
organisation can identify, measure, control, and improve the various core business
processes that improve the business performance.Quality management is the act of
supervising all the activities required for maintaining a desired levelof quality. The
activities include determination of a quality policy, creating and implementing
quality planning and assurance, quality control, and quality improvement.
7.1.2. Certifications
Management system certification helps in improving an organisation th rough
lessons learnt from the past so that the present can be effectively managed and
efficiently planned to meet the future challenges. A business gains a QMS
certification after proving to the external auditors that the business has a
documented system a nd process for achieving quality outputs and products.
Some of the benefits of QMS certification include:
1) Keeping the existing customers happy by providing quality products,
2) Growing the business with new customers,
3) Applying for government tenders,
4) Having an effective system for documentation and standard procedures,
5) Improved internal and external communication,
6) Reduced costs by identifying cost-saving measures and reducing waste, and
7) Improved work culture.
QMS certification represents an organisation inves tment that has benefits across
every aspect of operation (internally as well as externally). An organisation
should be built on quality management standards to improve efficiency,
performance, safety, and sustaina bility across the board. QMS has a range of
auditor that ensures that the QMS in a specific organisation meets the standards,
so that the business can grow and succeed.
* *
Quality Management Systems (Chapter 7) 153
ISO 9001:2015
ISO 9001:2015 is the primary quality management certification. It sets out the
standard criteria for a QMS that can be used by a large or small organisation,
irrespective of its field of activity. This standard is based on a number of quality
management principles, i.e., a strong customer focus, motivation and implication
of top management, process approach, thinking b ased on risks and opportunities,
and achieving continual improvement.
By implementing the ISO 9001:2015 standard an organisation‟s ability to

constantly provide quality products or services and build customer confidence is
demonstrated.
ISO 9001:2015 standard has the following benefits:

1) It focuses on demonstration of leadership in an organisation.
2) It promotes risk-based thinking in an organisation.
3) It integrates the QMS into business processes, as accountability of QMS, lies
with top management.
4) It result s in more reliable product/services for more effective and efficient
service/product provision processes due to its focus on the desired output of
process and associated risks and opportunities.
5) It enhances efficiency of an organisation.
6) It encourages the employees of an organisation to work for achieving the
vision, mission, and common goal of the organisation.
7) It enhances the performance and productivity of every department in an
organisation.
8) It encourages high morale among the employees.
9) It builds up an excellent brand image.
7.1.3. Concept of Quality

The word quality generally has different meanings. Quality can be defined as
“fitness for use,” “customer satisfaction,” “doing things right the first time,” or
“zero defects.” These definitions are accepted as q uality refers to degrees of
excellence. Quality is defined as “ an inherent characteristic, property or
attribute”. Quality control is the science that keeps these characteristics or
qualities within the limit range.
7.1.3.1. Types of Quality

In a manufacturing or service environment, quality of design and quality of
conformance are the two major categories of quality. If a product is not designed
properly, it will not function appropriately even if it complies with all the standard
specifications. On the other hand, if a product does not conform to excellent design
specifications, it will not perform its intended function in a proper way.
Quality of Design
It refers to the level of characteristic s that the designers specify for a product.
High-grade materials, tight tolerances, special features, and high performance are
the characteristics related to the high quality product.
* *
Quality of Conformance
After determining the quality of design, the product characteristics are formed
into drawings and specifications, which are used by the manufacturing engineers
to develop manufacturing standards and design the operations required for
production. The stand ards and design include the floor layout, machinery, test
sets, tools and other equipment, and a plan for the number of employees required.
The quality and the manufacturing engineers work together to make the quality
system and maintenance of conformance quality an integral part of the
manufacturing process. Any product checks, process checks, or quality
improvement activities are an inherent part of the process. Conformance quality
is the degree of adherence of the product characteristics to the design d rawings
and specifications. The objective of a quality program is to have a system that
economically measures and controls the degree of product and process
conformance.
The quality engineer determines what product or process characteristics are to be

checked, and the type of data to be collected, the required corrective actions, and
the statistical tools or other techniques to be used.
7.1.3.2. Quality Systems

Quality system is a mechanism that coordinates and maintains the activities
required for ensuring that t he characteristics of products, processes or services
are within the limit ranges. A quality system involves every part of an
organisation, affecting these activities in a direct or indirect manner. The quality
system is documented in a quality manual , and the procedures and standards are
specified in the related documents.
Quality system involves the three basic elements:

1) Quality Management: It is the way of implementing and carrying out
quality policy. It aims to plan and manage quality control and qual ity
assurance activities. Quality management ensures that all quality goals and
objectives are implemented and corrective actions have been achieved. It
maintains effectiveness by reviewing the quality system and also identifies
any insufficiencies.
2) Quality Control: It includes various techniques and activities of an
organisation that are involved in monitoring that the products, processes or
services meet the standard specifications, and thus improving the business.
Quality control also involves reviewing the processes and specifications and
make recommendations for their improvement.
It aims to identify and eliminate the causes of sub -standard performance by
removing or reducing the variation sources. The quality control program
works on the objective to define a system in which the products meet the
design requirements and checks and feedback for corrective actions and
process improvements. Quality control also includes selecting and rating of
suppliers to make sure that the products purchased meet the qu ality
requirements.
* *
3) Quality Assurance: It includes all the planned and systematic activities (in
the form of an independent final inspection) required for assuring that a
product or service will meet the specifications. The difference between
quality control and quality assurance is that the former makes quality product
and the latter assures the same. Quality assurance function should represent
the customers and should not depend on the quality control function that
forms an integral part of the manufacturing operation.
7.2. TOTAL QUALITY MANAGEMENT (TQM)
7.2.1. Introduction
Total Quality Management (TQM) involves the management methods used for
improving the quality and productivity of business in an organisation. It is a
comprehensive management approach that works paralle ly with the organisation,
involving all departments and employees and extending backward and forward to
include suppliers as well as clients/customers.
Besides TQM, there are many other abbreviations used t o label management
systems focusing on quality, such as CQI (Continuous Quality Improvement), SQC
(Statistical Quality Control), QFD (Quality Function Deployment), QIDW (Quality
In Daily Work), TQC (Total Quality Control), etc. Alike these systems, TQM
provides a basis for implementing effective quality and productivity initiatives so
that the productivity and competitiveness of the organisations can be increased.
TQM allows the employees to focus on quality (instead of quantity) and strive
hard to give th eir best in whatever they do. According to TQM, the views and
expectations of customers are essential when new strategies are to be framed and
implemented for delivering products that are superior to those of competitors,
thereby yielding higher profits for the organisation.
7.2.2. Concepts
The basic concepts forming the foundation of TQM are:
1) Continuous Improvement of Quality: All the TQM systems should involve
in enhancing the quality of the products and service s an organisation
provides. This improvement in quality increases the productivity and the
organisation‟s ability to remain vital, employ people, and serve customers.
By focusing on continuous quality improvement, the organisation can carry
out its activities appropriately.
2) Central Focus on the Customer: All the TQM systems should focus on the
customer, the internal and external recipients of an organisation‟s products. The
producer should meet or exceed the customer‟s needs and expectations. By
focusing on customers, the organisation can carry out its activities appropriately.
3) Systematic Improvement of Operations: All the operations occur in
processes that account for 80 -85% of the quality of work a nd productivity of
employees. Management is responsible for systems in an organisation;
*
therefore, the managers should take on the blame if something goes wrong *
with the system. TQM employs individuals or teams to study the work
processes quantitatively , t o find places that breakdown or unnecessary
complexities occur in processes, and to identify preventive solutions.
Studying the work processes helps in reducing the costs and ensuring that
quality is built into a service or product since quality cannot be inspected into
it at the end of the processes.
4) Open Work Environments: For continuous quality improvement, an
atmosphere for innovation is required where suggestions for improvement
are asked and respected and where supervisors and managers are open to
disagreement, conflict, and challenge. Activities for improving the work
processes help to break the barriers between the departments or between
supervisors and those being supervised.
5) Long-Term Thinking: TQM also involves long -term thinking to build the
future by understanding the consequences of present activities. This thinking
requires time and decision -making based on data and real problems (not
symptoms). It shies away from quick fixes arrived at by discussion and
intuition. Long -term thinking works effe ctively in organisations where
managers plan to stay, and equally share the consequences of their decisions.
7.2.3. Principles
TQM involves the following eight principles:
1) Leadership: Leaders establish unity of purpose and direction of the
organisation. They should maintain the internal environment where people
involve in achieving the organisation‟s objectives. Steps in application of this
principle are:
i) It should be proactive and lead.
ii) It should understand and respond to changes in the external environment.
iii) It should understand the needs of all shareholders, customers, owners,
suppliers, local communities, and society.
iv) It should establish a clear vision of the organisation‟s future.
v) It should establish shared v alues and ethical role models at all levels of
the organisation.
vi) It should build trust and eradicate fear.
vii) It should provide the required resources and freedom to the people so
that they can act responsibly.
viii) It should inspire, encourage, and recognise people‟s contributions.
ix) It should promote open and honest communication.
x) It should educate, train and coach people.
xi) It should set challenging goals and targets.
xii) It should implement a strategy to achieve these goals and targets.
Role of Leadership in Quality Management

The role of leadership in quality management forms the strength of any
improvement strategy. Leaders provide a unity of purpose and establish the
direction of organisation. The responsibility of leaders includes maintaining
the internal environme nt, in which the employees completely involve
* *
themselves in achieving the organisation‟s objectives. Therefore, good

leadership is required as the leading force that sets objectives and helps the
employees in implementing these objectives, thereby improving the quality
across the organisation.
2) Customer Focus: An organisation depends on its customers, thus should
understand, meet, and strive to fulfil the current and future needs and
expectations of the customers. Steps in application of this principle are:
i) It should understand the customer needs and expectations for products,
delivery, price, dependability, etc.
ii) It should ensure a balanced approach among customers, shareholders,
owners, suppliers, local communities, and society.
iii) It should communicate these n eeds and expectations throughout the
organisation.
iv) It should measure customer satisfaction and act on results.
v) It should manage customer relationships.
3) Process Approach: The desired result is efficiently achieved when related
resources and activities are managed as a process.
Steps in application of this principle are:
i) It should define the process to achieve the desired result.
ii) It should identify and measure the inputs and outputs of the process.
iii) It should identify the interfaces of the process with the fu nctions of an
organisation.
iv) It should evaluate potential risks, consequences, and impacts of
processes on customers, suppliers and other shareholders of the process.
v) It should establish clear responsibility, authority, and accountability for
managing the process.
vi) It should identify internal and external customers, suppliers and other
shareholders of the process.
vii) It should consider process steps, activities, flows, control measures,
training requirements, equipment, methods, information, materials, and
other resources to achieve the desired result when designing processes.
4) Involvement of People: People at all levels form the backbone of an
organisation and their involvement enables their abilities to be used for the
organisation‟s benefit. Steps in application of this principle are:
i) It should accept ownership and responsibility to solve problems.
ii) It should seek opportunities to make improvements, and enhance
competencies, knowledge, and experience.
iii) It should share knowledge and experience in teams.
iv) It should focus on the creation of value for customers.
v) It should be innovative in promoting the organisation‟s objectives.
vi) It should represent the organisation to customers, local communities, and
society in an improved manner.
vii) It should help people derive satisfaction from their work.
viii)It should make people keen and proud to be part of the organisation.
* *
5) System Approach: By identifying, understanding and managing a system of

inter-related processes for a given objective, the organisation‟s effectiveness
and efficiency can be enhanced. Steps in application of this principle are:
i) It should define the system by identifying or developing the processes
affecting a given objective.
ii) It should structure the system to achieve the objective efficiently.
iii) It should understand the interdependencies among the system processes.
iv) It should continually improve the system through measurement and
evaluation.
v) It should estimate the resource requirements and establish resource
constraints prior to action.
6) Continuous Improvement: An organisation‟s permanent objective should
be its continual improvement. Steps in application of this principle are:
i) It should make continual improvement of products, processes, and
systems an objective for every individual in the organisation.
ii) It should apply the basic improvement concepts of incremental
improvement and breakthrough improvement.
iii) It should use periodic assessments against established criteria of
excellence to identify areas for potential improvement.
iv) It should continually improve the efficiency and effectiveness of all
processes.
v) It should promote prevention-based activities.
vi) It should provide appropriate education and training on the methods and
tools of continual improvement (such as the Plan -Do-Check-Act cycle,
problem solving, process re-engineering, and process innovation) to each
member of the organisation.
vii) It should establish measures and goals to guide and track improvements.
viii) It should recognise the improvements.
7) Factual Approach to Decision Making:Effective decisions can be taken based
on the analysis of data and information.Steps in application of this principle are:
i) It should take measurements and obtain data and information relevant to
the objective.
ii) It should ensure that the data and information are accurate, reliable, and
accessible.
iii) It should analyse the data and information with valid methods.
iv) It should understand the value of appropriate statistical techniques.
v) It should make decisions and take actions on the basis of the results of
logical analysis balanced with experience and intuition.
8) Mutually Beneficial Supplier Relationships: An organisation and its
suppliers depend on each other, and a mutually beneficial relationship
enhances the ability of both to create value. Steps in application of this
principle are:
i) It should identify and select key suppliers.
ii) It should establish supplier relationships that balance short -term gains
with long-term considerations for the organisation and society.
* *
iii) It should create clear and open communications.

iv) It should initiate joint development and improv ement of products and
processes.
v) It should establish a clear understanding of customers‟ needs.
vi) It should share information and future plans.
vii) It should recognise supplier improvements and achievements.
7.2.4. Effect
The flowchart below shows the effect of TQM:
Improve Quality (Product/Service)
Increase Productivity (Less rejects, faster job)
Lower Costs and Higher Profit
Business Growth, Competitive, Jobs, Investment
7.2.5. Advantages
TQM has the following advantages for an organisation:
1) It strengthens the competitive position.
2) It provides adaptability to changing o r emerging market conditions and to
environmental and other government regulations.
3) It increases the productivity and profitability.
4) It enhances the market image.
5) It eliminates defects and waste.
6) It reduces costs and provides better cost management.
7) It improves customer focus and satisfaction.
8) It increases customer loyalty and retention.
9) It increases job security.
10) It improves employee morale.
11) It enhances shareholder value.
12) It develops improved and innovative processes.
7.2.6. Disadvantages
TQM has the following disadvantages:
1) It demands initial introduction costs, training workers and disrupts the
current production while being implemented.
2) The workers of an organisation may be resistant to change and may feel less
secure in jobs.
3) It is a long -term process, thus shows results and benefits only after several
years.
* *
7.3. QUALITY BY DESIGN (QBD)
7.3.1. Introduction
Quality by Design (QbD) is a concept developed by Dr. Joseph M. Juran , who
believed that quality should be designed into a product, and most quality
problems are related to the way in which a product was designed. Woodcock
defined a high-quality drug product as a contamination -free product that reliably
produces the expected therapeutic benefit to the consumer.
The US FDA encourages risk -based approaches and implementation of QbD

principles in development, manufacturing, and regulation of drug product. FDA
started emphasising on the acceptance of QbD with the recognition that increased
testing does not improve product quality, and it should be built into the product.
QbD involves designing and developing formulations and manu facturing

processes that ensure predefined product specifications. This concept has been
lately adopted in th e pharmaceutical industries through several initiatives [ e.g.,
ICH Q81, Q92 and Q103, new regulatory documents, Process Analytical
Technology (PAT)5, FDAs cGMP for the 21st Century4].
It aims to shift from the concept of Quality by Testing (QbT, that was previously
implemented in the pharmaceutical industry) to a development that improves the
understanding of the processes and the products, and hence the product quality,
process efficiency, and regulatory flexibility.
7.3.2. Objectives
QbD is a systematic approach to development that begins with predefined
objectives and gives emphasis to understanding and control of products and
processes based on science and quality risk management. The goals of QbD
include the following:
1) To achieve significant product quality specifications based on clinical
performance,
2) To enhance process competence and reduce product variability and defects
by improving the design, understanding, and control of product and process,
3) To increase product development and manufacturing efficiencies, and
4) To enhance root cause analysis and post-approval change management.
QbD helps to achieve these goals by linking the product quality to the desired
clinical performance, and designing a robust formulatio n and manufacturing
process to obtain product of desired quality. Since the QbD has come into
existence, the FDA has significantly progressed to achieve the prime objective
of performance-based quality specifications.
Some examples of FDA policies include tablet scoring and bead sizes in capsules
labelled for sprinkle. However, it should be recognised that ICH documents do
not openly recognise clinical performance-based specifications as a QbD goal.
* *
Another objective of QbD is to enhance process capabilit y and reduce

product variability that may otherwise result in product defects, rejections, and
recalls. To achieve this objective, a robustly designed product and process is
required.
An improved product and process understanding also assists in identify ing and
controlling the factors that influence the drug product quality. After regulatory
approval, efforts should be made to improve the process and to reduce product
variability, defects, rejections, and recalls.
The third objective of QbD is increasin g product development and

manufacturing efficiencies. It also aims to enhance development competence,
speed, and formulation design. It transfers resources from a downstream
corrective mode to an upstream proactive mode. It boosts up the manufacturer‟s
ability to analyse the root causes of manufacturing failures.
The final objective of QbD is to enhance root cause analysis and post -approval
change management. Lack of good product and process understanding limits the
ability to efficiently scale -up and con duct root cause analysis and requires the
generation of additional data sets on the proposed larger scale.
The change guidance of FDA provides a framework for post -approval changes.
Recently, FDA issued a guideline to reduce the regulatory filing requirements for
specific low -risk Chemistry, Manufacturing, and Control (CMC) post -approval
manufacturing changes.
7.3.3. Elements
In QbD approach to product development, an applicant identifies the desired
characteristics of quality from the patient‟s viewpoint, and translates them into
the drug product Critical Quality Attributes (CQAs). Then the applicant links the
formulation/manufacturing variables with the CQAs to offer a drug product with
such CQAs to the patient.
QbD consists of the following elements:

1) A Quality Target Product Profile (QTPP) to identify the CQAs of the drug
product,
2) Product design and understanding including the identification of Critical
Material Attributes (CMAs),
3) Process design and understanding in cluding the identification of Critical
Process Parameters (CPPs) and understanding of scale -up principles, linking
CMAs and CPPs to CQAs,
4) A control strategy including specifications for the drug substances,
excipients, and drug product as well as controls for each manufacturing step,
and
5) Process capability and continual improvement.
* *
Labelled use safety and efficacy
Define quality target product profile
Design formulation and process
Identify critical material attributes and

critical process parameters
Control materials and process
Target Design Implementation

Figure 7.1: Overview of QbD
7.3.4. Tools
The tools for QbD include the following:
1) Prior Knowledge: The term prior knowledge has been widely used in
workshops, seminars, and presentations. In regulatory submissions, the
applicants attempt to use prior knowledge as an authentic reason for substitution
of scientific justifications or conducting necessary scientific studies.
Knowledge
is defined as an awareness of someone or something that can include
information, facts, descriptions, and/or skills attained through experience or
education. The word prior in the term prior knowledgeindicates previous and
also associates with ownership and confidentiality, i.e., not available to the
public. Knowledge gained through education or public literature is termed
public knowledge. Prior knowledge is the exclusive information, understanding,
or skill that applicants acquire through previous studies.
2) Design of Experiments (D OE): It is a structured and organised method of
determining relationship between the factors influencing process
outputs. DOE can offer returns that are four to eight times greater than the
cost of running the experiments in a fraction of time. Use of DOE in QbD
helps in achieving maximum information from a minimum number of
experiments. When DOE is applied to a pharmaceutical process, factors
involve raw material attributes ( e.g., particle size), process parameters ( e.g.,
speed and time), and outputs involve the CQAs such as blend uniformity,
tablet hardness, thickness, and friability.
Each unit operation has many input and output variables and process
parameters, thus experimental investigation of all of them is not possible.
The results of DOE help in id entifying optimal conditions, critical factors
influencing and not influencing CQAs, and the existence of interactions and
synergies between factors.
3) Process Analytical Technology (PAT): It is defined as a system for
designing, analysing, and controlling m anufacturing through
measurements, during processing of CQAs of raw and in -process
*
materials and processes, to ensure the final product quality . The PAT *
aims to enhance understanding and control the manufacturing process, which

is consistent with the current drug quality system. Design space is the key
and critical process parameter (primary focus of on -, in - or at -line PAT
applications) identified from process characterisation studies and their
acceptable ranges.
Principally, real -time PAT assessments pro vide the basis for continuous
feedback and improve process robustness. NIR is a tool for PAT and is
useful in Real Time Release Testing (RTRT) as it monitors the particle size,
blend uniformity, granulation, content uniformity, polymorphism, dissolution
and monitoring the process online, at the line and offline, thus reducing the
release testing of the product.
4) Risk Management Methodology: Quality risk management is defined as a
systematic process for the assessment, control, communication and review
of ris ks to the quality of the drug product across the product lifecycle .
Risk assessment tools are used , based on prior knowledge and primary
experimental data, for identifying parameters (e.g., process, equipment, input
materials) that can affect the product q uality. The initial list of potential
parameters can be long, but can be modified and prioritised through a
combination of DOEs and mechanistic models. After identifying the
significant parameters, they are further studied through a combination of
DOEs, mathematical models, or studies that lead to mechanistic understanding.
This is done to achieve a higher level of process understanding.
The pharmaceutical industry and regulators, with the help of risk
management tools and/or internal procedures, such as basic risk management
facilitation methods (flowcharts, check sheets etc.), evaluate and manage
risks. Some of the well-known models are:
i) Failure Mode Effects Analysis (FMEA),
ii) Failure Mode, Effects and Criticality Analysis (FMECA),
iii) Fault Tree Analysis (FTA),
iv) Hazard Analysis and Critical Control Points (HACCP),
v) Preliminary Hazard Analysis (PHA), and
vi) Risk ranking and filtering.
7.3.5. Advantages
QbD has the following advantages:
1) It focuses on patient safety and product efficacy.
2) It encourages scientific understanding of pharmaceutical processes and
methods.
3) It involves product design and process development.
4) It carries out scientific risk assessment.
5) It identifies critical quality attributes and also analyses their ef fect on final
product quality.
6) It offers robust method or process.
7) Business benefits are also driving force to adopt QbD.
8) Method design concept helps in avoiding cost involved with post-approval.
* *
7.4. SIX SIGMA CONCEPT
7.4.1. Introduction
The Six Sigma concept came in to force as a measurement standard by Carl
Frederick Gauss (1777-1855) who gave the concept of normal curve. This
concept is being used in product variation as a measurement standard since the
1920‟s, when Walter Shewhart described that three sigma from the mean is the
point where a pro cess requires correction. Later, many measurement standards
(Cpk, Zero Defects, etc.) came into existence, but the term Six Sigma was coined
by Bill Smith (a Motorola engineer , incidentally, Six S igma is a federally
registered trademark of Motorola).
In statistics, the term Sigma represents standard deviation that indicates the degree
of variation in a set of measurements or a process or a product. Six sigma is a
statistical concept or a quality management method used for the measurement of a
process or a product in terms of defects at the six sigma level (table 7.1). The
concept also focuses on developing and delivering perfect products and services.
Table 7.1: Six Sigma Level
Sigma Levels Defects per Million Yields
6 3.4 99.99966%
5 230 99.977%
4 6,210 99.38%
3 66,800 93.32%
2 308,000 69.15%
1 690,000 30.85%
7.4.2. Objectives
Following are the objectives of the six sigma concept:
1) It enhances the level of customer satisfaction.
2) It accelerates the process cycle times and time-to market.
3) It reduces defects.
4) It controls variation and improves predictability.
5) It reduces costs without any involuntary consequences.
6) It improves end-to-end process management and measurement.
7) It offers potential to refine current approaches to supply chain improvement.
8) Its project-oriented methodologyis used to solve problemswith statistical tools.
9) It compares different processes according to the sigma levels. The aim of
quality improvement system is to reduce the errors and to maintain t hem at a
low value. Meaning of six sigmais DPMO (Defects per Million Opportunities).
10) It improves effectiveness and efficiency of processes, including e-commerce.
7.4.3. Methodologies
Methodologies of Six Sigma include the key processes, such as DMAIC and
DMADV. The Six Sigma DMAIC process (Define, Measure, Analyse, Improve,
and Control) is an improvement system used for the current processes found
* *
below specifi cation and looking for incremental improvement. While, the Six
Sigma DMADV process (Define, Measure, Analyse, Design, and Verify) is also
an improvement process used for developing new processes or products at Six
Sigma quality levels.
The DMADV can also be used if the on -going process needs more than just
incremental improvement.
1) DMAIC: It is a data -driven quality strategy used to improve processes. It is
an integral part of the company‟s Six Sigma Quality Initiative. DMAIC
denotes five interconnected ph ases, i.e., Define, Measure, Analyse, Improve,
and Control. In the DMAIC cycle, each step ensures the best possible results.
Following are the process steps of DMAIC:
i) Define: It defines the customer, their Critical to Quality (CTQ) issues,
and the business process involved in the following ways:
a) Defining customers, their requirements for products and services,
and their expectations.
b) Defining project boundaries, i.e.,the end and beginning of the process.
c) Defining the process to be improved by mapping the process flow.
ii) Measure: It measures the performance of the business process involved
in the following ways:
a) Developing a data collection plan for the process.
b) Obtaining data from different sources for determining the types of
defects and metrics.
c) Comparing to customer survey for determining shortfall.
iii) Analyse: It analyses the collected data and process map for determining
the root causes of defects an d opportunities for improvement in the
following ways:
a) Identifying the gaps between current performance and the
performance to be achieved.
b) Prioritising opportunities for the improvement.
c) Identifying the sources of variation.
iv) Improve: It prevents and fixes problems of targeting by designing
creative solutions in the following ways:
a) Developing novel solutions using technology and discipline.
b) Developing and organising implementation plan.
v) Control: It controls the improvements to keep the proc ess new in the
following ways:
a) Preventing the process from reverting back to the old way.
b) Developing, documenting and implementing the current monitoring
process.
c) Institutionalising the improvements by modifying the systems and
structures (staffing, training, incentives).
2) DMADV: It is an abbreviated form of Define, Measure, Analyse, Design and
Verify. It is a system of impro vement used for developing new processes or
products at Six Sigma quality levels.
* *
Similarities of DMAIC and DMADV

DMAIC and DMADV are both:
1) Methods of Six Sigma , and are used to reduce defects less than 3.4 per
million opportunities.
2) Data intensive solution approaches.
3) Implemented by Green Belts, BlackBelts and Master Black Belts.
4) Helps to meet the business/financial bottom-line numbers.
5) Used to implement the support of a champion and process owner.
Differences between DMAIC and DMADV

Parameters DMAIC DMADV
Define Define the project goals and Define the project goals and
customer (internal and external) customer (internal and external)
deliverables. deliverables.
Measure Measure the process to determine Measure and determine customer
current performance. needs and specifications.
Analyse Analyse and determine the root Analyse the process options to
cause(s) of the defects. meet the customer needs.
Improve Improve the process by -
eliminating defects.
Control Control future process -
performance.
Design - Design (detailed) the process to
meet the customer needs.
Verify - Verify the design performance and
ability to meet customer‟s needs.
Along with these processes, many manufacturers use DMAICR (Define,

Measure, Analyse, Improve, Control, and Realise) process.
7.4.4. Implementation
Six sigma include the following three basic elements:
1) Process Improvement: It eliminates the root causes of performance
deficiencies in the processes already present in the organ isation. These
performance deficiencies may cause real problems for the organis ation, or
may prevent it from working efficiently and effectively.
2) Process Design/Redesign: Sometimes there is need to design new processes
or to redesign the existing processes, because sometimes just improving the
existing processes is not sufficient. There are many reasons showing why
process design or redesign is required:
i) An organisation may choose to replace (and not repair) one or more of its
core process.
ii) An organisation realise s that the desired level of quality will not be
delivered to the customers by just improving the existing processes.
iii) An organisation pro vides an opportunity to offer a completely novel
product or service.
* *
3) Process Management: It is the most challenging and time-consuming

element of Six Sigma as process management requires a fundamental change
in the structure and management of an organisation. Process management
generally involves the following:
i) It defines processes, key customer requirements, and process “owners”.
ii) It measures performance against customer requirements and key
performance indicators.
iii) It analyses data for enhancing measures and refining the process
management mechanisms.
iv) It controls the process performance by monitoring process inputs,
process operation, and process outputs, and quickly responds to problems
and process variations.
7.4.5. Applications in Pharmaceutical Industry

Some pharmaceutical companies adopted the concept of six sigma in the past few
years for reducing cycle time and cost. To launch a six sigma within a
pharmaceutical industry, the following key strategies are suggested:
1) Six Sigma is used to make c hanges in the traditional ways of performing
clinical trials by campaigning for the impleme ntation of required integration
initiatives with a commitment from top down leadership.
2) Six Sigma is used to integrate the technology and to improve the workflow in
meeting challenges as well as to start new ventures which cannot be initiated
using convent ional isolated implementation of technology or home grown
process improvement methods.
3) Six Sigma provides reliable tested research approaches for quantitative
evaluation of clinical development and proce ss improvement strategies,
which are integrated in correlation with strong financial performance.
Application of Six Sigma can be explained by giving the example of supplier and
material approval process in a company‟s packaging division. The entire process of
identification and certification of a supplier of packaging materials is highly
complex, and thus normally takes 12 months . This process can be simplif ied by
forming a Six Sigma team of 4 pilot products, determining the critical paths, and
analysing and identifying the problems involved in the process . Six Sigma
methodology also helped the team to streamline the process andto reduce the cycle
time from 12 to 5 months, thus making the process less time-consuming.
7.5. OUT OF SPECIFICATIONS (OOS)
7.5.1. Introduction
The term Out of Specifications (OOS) is used for those results of in -process or
finished product testing which are falling out of the specified limits mentioned in
compendia, drug master file, or drug application. The OOS may occur due to
deviations in product manufacturing process, errors in testing procedure, or faulty
analytical equipment. A root cause analysis should be performed for
investigating the causes for OOS.
* *
The reasons for OOS can be grouped as assignable and non-assignable. If the
limits are not within specified range, it is called out of specifications. In case OOS
has occurred, the analyst should inform the QC manager. Then the senior manager
should ask the QA for issuing OOS form to analyst. The responsible personnel
should group the OOS as either assignable cause or non-assignable cause. Each out
of specification is given a unique identification number, e.g., OOS/RM-001/2014;
Where, OOS - out of specification, RM - raw material (department), 001 - OOS for
that year, and 2014 – Year. The OOS investigation involves two phases:
Review of
Phase I (Laboratory
production
investigation)
Investigation of out of
specification
Additional laboratory
Phase II testing
Figure 7.2: Investigation of OOS Results
7.5.2. Phase I (or Laboratory) Investigation

Laboratory investigation is mainly performed to identify the reasons due to which
OOS occur. The reasons may include defect in measurement process or in
manufacturing process. Regardless of the rejection of batches, the results obtained
from OOS should investigate for their trend. The investigation should be
performed for those batches that are resulted in OOS, or also to other batches and
other products associated with OOS.
The OOS investigation should be performed thoroughly, timely, in an unbiased,

well-documented and scientific manner. Before discarding the test and standard
preparations, the phase I investigations should be thoroughly performed. In phase
I investigation, it is necessary to analyse the root cause and to recognise the error
that may have resulted due to:
1) Dilution error of standard and sample solution,
2) Errors in analysis method,
3) Equipment malfunction, and
4) Errors in calculation.
Phase I investigation
QC Investigation
(assignable cause)
Analytical error Calculation or No analytical or

laboratory error Calculation or
Re-analysis of laboratory error
the same sample Rectify
Results within Results OOS

specification
Phase II
investigation
Release
Figure 7.3: Phase I Investigation
* *
7.5.2.1. Phase Ia Investigation

In this phase of investigation, errors like calculation or power outage, testing
errors such as spillages or incorrect setting of equipment paramet er, are
identified. It is expect ed that these issues also occur even when a laboratory
investigation Ib or II was not found.
Phase Ia investigation
No error found
Obvious error
Document and correct Initiate phase Ib

invalid result laboratory
investigation
No further
investigation
required
Figure 7.4: Phase Ia Investigation
7.5.2.2. Phase Ib Investigation

It is the starting phase of investigation , which is performed by the analyst and
supervisor using the laboratory investigation checklist including the related areas
of investigation. In the guidance details of checks , the following checklist
documented are considered:
1) Correct test methodology followed, e.g., Version number.
2) Correct sample(s) taken/tested ( whether or not the check labels were taken
from correct place).
3) Maintenance of sample integrity, correct container and chain of custody (was
there an unusual event or problem).
Phase Ib Investigation
Investigation by
Analyst and Supervisor
No assignable cause or Assignable cause (Root

evidence of error remains cause identified)
unclear
Test data Generate CAPA
Contact – Production/QA/ invalidated repeat
Contract Giver/MAH/QH analysis
Record results
Phase II Investigation
Close investigation
Figure 7.5: Phase Ib Investigation

* *
The initial steps of investigation performed by the analyst and supervisor should
include only data/equipment/analysis review. After performing the initial review,
re-measurement is performed to support the investigation testing; this is done
only after the documentation of hypothesis plan . Hypothesis or investigative
testing confirms or discounts a possible root cause. This testing includes further
testing regarding sample, filtration, sonication/extraction, failure of equipment,
etc. During the investigation, multiple hypotheses can also be explored. The
original working stock solutions may also be included in the initial hypothesis
testing; however, another preparation from the original sample cannot be
included.
A test can be cancelled if a clear root cause has been determined, such as:
1) Technician error,
2) Sample/standard preparation,
3) Analytical method,
4) Equipment failure, and
5) Deviation from procedure.
A protocol to conduct phase I investigation of out of specification results is given
in table 7.2:
Table 7.2: Protocol for Phase I Investigation (Assignable Cause) of Out of
Specification Results
S.No. Parameters Observations Sign and Date
1) Check condition of the sample
- Physical examination
- Storage condition
- Storage container
- Labelling
2) Check balance and its calibration
- ID no. of balance:
- Calibration due date:
3) Check instrument calibration
- Name of the instrument:
- ID of the instrument:
- Calibration due date:
4) Check the reagent used for analysis
- Raw data, physical appearance, validity
of reagent used.
5) Check the volumetric standard solution
of standard solution used.
6) Check the indicator solution
of indicator used.
7) Check for dilution, calculation, weighing,
titer volume, readings
8) Check working standard
- ID, Raw data, physical appearance,
validity of working standard used
9) Check chromatograms and TLC plates
* *
10) Check glassware for its accuracy and

calibration
11) Check system suitability (HPLC / TLC)
12) Check bracketing standard for RSD
13) Check method of analysis followed
- Method reference no.:
Discussion with analyst
S.No. Discussion Points Remarks of Investigator
1)
2)
3)
Summary of investigation by investigator:
Re-analysis with same sample (if found genuine analytical error)

S.No. Test Limit Result
1)
2)
3)
RSD
Analysed by: Date & Sign:
Conclusion of phase I investigation:
Corrective action taken:
Senior manager-QC Senior manager-QA
Sign & date: Sign & date:
7.5.3. Phase II Investigation

The phase II in vestigation should be performed if no possible outcome is
obtained from phase I investigation. This phase of investigation is performed to
identify the errors that occurred in manufacturing processes, sampling
procedures, along with other additional laboratory testing.
Phase II investigation is performed when the phase I investigation failed to
expose an assignable laboratory error. These investigations are based on written
and approved ins tructions against hypothesis and should always be performed
with a manufacturing investigation to determine whether there was a possible
manufacturing root cause. The written guidance also includes details on
resampling, retesting, averaging, and written description.
The whole procedure of testing should be written in described manner, and then
approved by QA/Contract Giver/QA equivalent before starting an investigational
testing.
* *
Following are the requirements of investigational testing:

1) A fully documented description,
2) A thoroughly investigated hypothesis,
3) List of samples to be tested,
4) The exact execution of the testing, and
5) Evaluation method of the obtained data.
Phase II investigation
Review of production Additional laboratory

(Assignable cause) testing
Root cause Resampling and new

identified Re-analyse sample by
2nd analyst in duplicate analysis by 2nd analyst
in duplicate
Rejected
All results with in Result out of
specifications specified limits
Investigation and
corrective
Release
Rejected
Investigation and
corrective action Investigation and
corrective action
Figure 7.6: Phase II Investigation
The following additional laboratory testingis involved in phase II investigation:

1) Retesting: It is performed to determine the analytical or dilution error in the
same sample. For retesting, the sample should be taken from the same lot of
the initial test . The qualification and experience of the person retest ing the
sample should be more or equal to that of the first analyst.
If the results obtained from retest are within the limits, the previous test
results should be replaced with the retest results and included in the report
along with explanation regarding the first failure. If the results obtained from
retest are out of lim its, the batches should be re jected and the investigation
should be continued for the related batches and products.
2) Resampling: Retesting includes analysis of the original, homogenous sample
material, while resampling includes analysis of a sample obtained from any
additional units collected as part of the original sampling or from a new
sample collected from the same batch. If the results of resampling are within
the specified limits, the previous tes t results should be replaced with the
resampling results.
If any fluctuation in results occurs due to improper sampling, the sampling
procedures should be validated, and a new sampli ng procedure should be
proposed and documented . A protocol to conduct phas e II investigation of
out of specification results is given in table 7.3:
* *
Table 7.3: Protocol for Phase II Investigation (Review of Production-Assignable

Causes) of Out of Specification Results)
Causes Check for Yes No
I) Personnel 1) Was the person properly trained?
2) Does he know the job properly?
3) Was he wearing the necessary personnel
protective?
4) Were the critical operations supervised by a
supervisor?
II) Equipment 1) Was correct equipment used?
2) Was the equipment condition good?
3) Were the equipment inspected by QA before use?
4) Was the equipment provided with required utilities?
5) Was the equipment calibrated?
6) Was the preventive maintenance carried as per
the schedule?
III) Production 1) Was the correct material used in right condition?
2) Was the right material added as per BMR?
3) Was the total process carried out as per BMR?
4) Were the utilities, e.g., steam, water, air quality,
temperature, humidity, pressure difference, etc., are
as per the requirement throughout the process?
5) Were the in-process checks carried out as per the
BMR?
6) Were the in -process checks results with in
specifications?
7) Were all the steps and results documented in BMR?
8) Was the quality of the intermediate as per the
specification?
9) Were the yields as per the standard?
10) Were the product s or intermediate s stored
properly?
11) Was there any breakdown during process?
IV) Quality 1) Was any material used in manufacturing released
control under deviation?
2) Were there any other observations during
chemical and instrumental analysis, which could
result in OOS?
V) History Have there been similar errors in past?
*- If ticked yes, needs investigation
Phase II investigation (additional laboratory testing)
1) Re-analysis in duplicate with different analysts for the same sample:
RSD
Conclusion:
2) Resampling and retesting induplicate with different analysts:

Justification for resampling:
* *
Resampling authorised by:

Senior manager-QA Sign & date:
RSD
Conclusion of the investigation:
Investigation & corrective action:
Senior manager - Senior manager-QA

QC
Acceptance criteria for retest comparison:
Final conclusion:
Corrective action:
Senior manager - Senior manager-QA

QC
Reporting Test Results

The interpreted results are generally reported by:
1) Averaging: It is recommended only in few conditions:
i) Appropriate Use of Average:
a) Example 1: Weights of 20 tablets are checked in every 30 minutes,
if weight variation is observed during compression stage of tablet
manufacturing. It is not easy to represent the data of every tablet at
every point of sampling time. Therefore, averaging is preferred in
such cases to repre sent the weight variation data with appropriate
relative standard deviation values. During data interpretation, the
limit for standard should be predetermined. In case the standard is
within the specified limit, the compression process is considered
sufficient to produce the product of consistent quality.
b) Example 2: If assay is performed by HPLC method, a single sample
is injected at different times to demonstrate the reproducibility of the
analytical method. Finally, the average of all peak areas is
considered for assay.
ii) Inappropriate Use of Average: When blending is done in octagonal
blender, the samples should be taken from multiple sampling points, such
as 8 sampling points, the assay limit is 90 -110%. Out of the 8 samples, 3
are falling outside limit, l ike 89%, 87%, 90%, 92%, 97%, 99%, 100%,
101%, and the average of all 8 assay s is 94.37%, which is within
specified limits. But 3 samples were out of specified limits, and this
indicates that the content uniformity is not achieved. In such cases ,
averaging is not recommended, as it gives false results.
* *
2) Outlier Test: It rarely occurs that a n obtained value may significantly differ
from others in a series obtained by a validated method. Such a particular
value may qualify as a statistical outlier. These t ests are used for determining
the variation of a value from an array of results. The possible use of outlier
tests should be predetermined, and should be well-documented and written in
to SOPs for data interpretation.
7.5.4. Phase III Investigation

Once the batch is rejected, another batch is investigated to determine whether or
not other batches or products are affected. Phase III investigation is also
performed to identify and implement corrective and pr eventative actions. In
phase III investigation, the completed manufacturing investigation is reviewed ,
along with the combined laboratory investigation into the suspect analytical
results. The factors related to validation methods and possible causes into
fluctuations in the results are also investigated. The guidance also shows that if a
batch is rejected, further testing should be conducted to determine the cause of
failure, so that corrective action s can be taken. Also the decision to reject cannot
be reversed as a result of further testing.
Quality Control (QC) and Quality Assurance (QA) methods are used to
determine the impact of OOS result on other batches, on -going stability studies,
validated processes, and testing procedures. The conclusion obtained by QC and
QA is documented, along with appropriate corrective and preventive actions.
Final decision regarding the release of a batch (despite an initial OOS result that
was not invalidated ) should be taken once a thorough investigation has shown
that the OOS results is not indicative of the quality of batch.
7.5.5. Concluding the Investigation

Once OOS is confirmed from investigation , the OOS investigation may result to
batch failure investigation. These investigations may be extended to other batches
and othe r products. The batches confirmed by OOS will be destroyed and
documented thoroughly. In case the results are not confirmed by OOS, the quality
assurance department will take decision to release the batch in the following
situation – if the results of assay range from 90-110% and the initial assay results
were 89.5%, 90% , 92%, 97%, 99%, 100%, 95%, 93%, a comprehensive
investigation is performed to investigate the cause for OOS result.
Whole investigation can be concluded in the following points:

1) In phase I laboratory testing investigation, the analytical method, sampling
procedure, dilutions were found robust and validated.
2) Then the investigation leads to phase II investigation, where all the
manufacturing procedures were found to be robust and additional tests were
found to be valid.
3) Then QA will be performed which shows that the initial OOS did not reflect
the true quality of the batch.
4) After concluding the investigation, the OOS result should be documented as
*
OOS report for future uses. *
7.6. CHANGE CONTROL
7.6.1. Introduction
Change control is a CGMP concept that manages the change to prevent
unintentional consequences. Some manufacturing changes (i.e., changes altering
the specifications, a critical product attribute, or bioavailability) can be done after
regulatory filings and prior regulatory approval.
Change is an essential part of a pharmaceutical product life cycle. A change

involves an addition to, deletion of, or modification to manufacturing facility,
utilities, process, material, product, procedures or equipment (including software)
that influences quality or regulatory requirements.
The process of change control safeguards that changes are implemented in a

controlled and coordinated manner. The change control program evaluates all
changes that possibly will affect the production and control of drug product,
intermediate, or API. It is the most critical element in the quality management of
pharmaceutical industry. A change control system checks and balances the
quality system by tracking, reviewing and approving the changes. If the change
control procedures are inadequate, it results in regulatory non-compliance.
Change control aims to prevent the unintended consequences that may be

encountered when changing a product or system.
7.6.2. Benefits of Change Control System

The change control system has the following benefits:
1) It provides structured and systematic approach for change management with
proper change evaluation.
2) It helps in documenting and tracking the details of change.
3) It helps in routing of change requests to appropriate individuals or a group of
individuals for approvals.
4) It demonstrates compliance to regulatory agencies.
7.6.3. Change Control Procedure

The change control procedure involves the following steps:
1) A formal and signed request should be made for making a change.
2) The request prompts the question of the influence of change on the product
quality/safety of the population. The major and minor influence on product
quality should be defined, and the treatment of these two options should be
different.
3) Clear rules for the decision, whether the influence of the change on product
quality and/or on study is major or minor, who decides this, and why the
decision is taken, should also be mentioned.
4) For managing the changes, an early decision of who should be involved
needs to be taken by the process owner, who knows best about the influence
of changes on product or study. Double checking should be done at this step.
* *
The technical department should sign. As per the company‟s or sponsor‟s

procedure, the quality unit can act as an approver and conduct periodic
checking by self-inspection audits.
5) If the owner decides that the change is minor and does not influence the
product quality, it can be implemented. The change should be adequately
documented.
6) The changes with minor influence can be implemented rapidly and
efficiently using lists of standard changes (this list should be approved by the
quality unit).
7) If the owner decides that the change will influence the product quality and/or
population safety, an appropriate action plan should accompany such request
to gain approval by the quality unit.
8) After getting approval by the quality unit , the change is implemented. If the
change influences safety aspects, additional release activities are required.
Wherever such activities have been defined, these should be fulfilled before
the release of equipment, that itself is one of the activities.
9) The start of a change control system for technical equipment should be
established after the completion of qualification to maintain the qualified
status.
10) Change control before the completion of qualification does not possesses the
same degree of formality as it can be easily regulated and c an proceed
without an immediate involvement of quality unit. In this case, the required
activities are adequate documentation of the changes and a periodical
adaption of the documentation.
11) The requests for emergency changes can be formalised after the repl acement.
Emergency cases should be appropriately defined by each company.
All the changes should be requested, documented and accepted by
representatives of production, QC/QA, R&D, Engineering and Regul atory
Affairs in a formalised manner. The change control system should make sure that
all the notified or requested changes are investigated, documented, and
authorised adequately.
The changes that may possibly affect the product quality or process
reproducibility should be requested, documented, and accepted formally. The
influence of the change of facilities, systems and equipment on the product
should be evaluated, including risk analysis. The need for re -qualification and re-
validation, and their extent should be determined.
Changes requiring control are documented as a change request, in which the
applicant should define the type of grade/evaluation of the change, specify the
time frames and measures for carrying out the change, and request that the
change is either authorised or declined by the change control committee.
Documentation for the change procedure should prove that the change was
evaluated or has gone through risk assessment, and the subsequently defined
measures were implemented as predetermined.
* *
7.6.5. Change Control Process at Regulatory Submission

Level
The report should contain information about the formulation, including
justification for any and all the changes made in the methods during the
development process. The report should also inc lude information about the
following:
1) Justification for the used ingredients,
2) Justification for the selected analytical methods,
3) Justification for the final manufacturing and analytical processes stated in
application (IND, ANDA, or NDA),
4) Types of equipment used,
5) Description of the manufacturing process,
6) Scale-up to production,
7) In-process results,
8) Test results of the final dosage form,
9) Critical parameters of bulk drug,
10) Acceptance criteria for critical steps,
11) Conclusions with key variables identified,
12) Stability, and
13) Description of pivotal batches.
The purpose of this change control report is to point the authority towards a
document that defines the science and technology used while making the product
and that includes all preliminary studies conducted up t o the regulatory
submission stage.
7.7. ISO 9000 SERIES FOR QUALITY

SYSTEMS AND STANDARDS
7.7.1. Introduction
ISO 9000 is a set of international standards on quality management and quality
assurance. It has been developed to help the companies in ef fectively
documenting the quality system elements to be implemented so that an efficient
quality system can be maintained. They are not specific to any one industry and
can be applied to any, big or small organisation.
ISO 9000 helps a company to satisfy its customers, meet regulatory

requirements, and achieve constant improvement. However, it is only considered
as the first step or the base level of a quality system, and not a complete
guarantee of quality.
ISO 9000 is widely recognised in the world. It aims to implant a quality

management system in an organisation for increasing productivity, reducing
unnecessary costs, and ensuring quality of processes and products.
* *
The table 7.4 describes the standards and guidelines of ISO 9000, along with
their purposes:
Table 7.4: Brief Description About the Standards and Guidelines of ISO 9000
Series
Standards and Guidelines Purposes
ISO 8402: Quality management and Defines the fundamental terms used in the ISO
quality assurance – Vocabulary. 9000 family, which should be known to avoid
internal and external misunderstandings.
ISO 9000 -1: Quality management Establishes a starting point for understanding
and quality assurance standards – and selecting the standards approp riate to
Part 1: Guidelines for selection and needs.
use.
ISO 9000 -2: Quality management Assists in interpretation and application of ISO
and quality assurance standards – 9001, ISO 9002 and ISO 9003.
Part 2: Generic guidelines for the
application of ISO 9001, ISO 9002
and ISO 9003.
ISO 9000 -3: Quality management Provides specific interpretation of the
and quality assurance standards – requirements of ISO 9001 for computer
Part 3: Guidelines for the application software development applications.
of ISO 9001:1994 to the
development, supply, installation and
maintenance of computer software.
ISO 9000 -4: Quality management Provides guidance on how to plan, organise
and quality assurance standards – and control resources to produce reliable and
Part 4: Guide to dependability maintainable products.
programme management.
ISO 9001: Quality systems – Model The requirement standard used to demonstrate
for quality assurance in design, capability for design/development of the
development, production, installation product or service, and also for production,
and servicing. installation and servicing.
for quality assurance in production, capability for production, installation and
installation and servicing. servicing (identical to ISO 9001 except for
design control requirement).
for quality assurance in final capability to control the product or service by
inspection and test. final inspection and test.
ISO 9004 -1: Quality management The requirement standard that provides
and quality system elements – Part 1: guidelines to implement a quality system to
Guidelines. satisfy the customers and fulfil the
organisation‟s needs.
ISO 9004 -2: Quality management This standard is made up in a similar way as
and quality system elements – Part 2: ISO 9004 -1, but the guidelines are designed
Guidelines for services. with special regard to the conditions pertinent
to the service sector.
ISO 9004 -3: Quality management This standard provides quality management
and quality system elements – Part 3: guidelines applicable to a producer of
Guidelines for processed materials. processed materials, which are provided in
bulk.
* *
ISO 9004 -4: Quality management Provides guidelines for implementing

and quality system e lements – Part 4: continuous quality improvement within an
Guidelines for quality improvement. organisation using tools and techniques based
on data collection and analysis.
ISO 10005: Quality management – Provides guidance on how to prepare quality
Guidelines for quality plans. plans for the control of specific products,
projects or contracts.
ISO 10006: Guidelines to quality in Provides guidelines to ensure the quality of the
project management. project processes and the project product.
ISO 10007: Quality management – Provides guidelines to ensure that a complex
Guidelines for configuration product continues to function when
management. components are changed individually.
ISO 10011 -1: Guidelines for Provides guidelines for auditing a quality
auditing quali ty systems – Part 1: system, and for verifying the system‟s ability
Auditing. to achieve the defined quality objectives.
ISO 10011 -2: Guidelines for Provides guidance on education, training,
auditing quality systems – Part 2: experience, personal attributes and
Qualification criteria for quality management capabilities required to carry out
systems auditors. an audit.
ISO 10011 -3: Guidelines for Provides basic guidelines for managing quality
auditing quality systems – Part 3: system audit programmes.
Management of audit programmes.
ISO 10012 -1: Quality assurance Provides guidelines on the main features of a
requirements for measuring calibration system to ensure that
equipment – Part 1: Metrological measurements are made with intended
confirmation system for measuring accuracy.
equipment.
ISO 10012 -2: Quality assurance for Provides supplementary guidance on the
measuring equipment – Part 2: application of statisti cal process control when
Guidelines for control of this is appropriate for achieving the objectives
measurement processes. of Part 1.
ISO 10013: Guidelines for Provides guidelines for the development,
developing quality manuals. preparation and control of quality manuals
tailored to specific needs.
The table 7.5 describes other ISO 9000 publications along with their purposes:
Table 7.5 Description of other ISO 9000 Publications with their Purposes
Publications Purposes
ISO 9000 for Small Provides guidelines and practical examples of how t o
Businesses implement a simple and effective quality system in a
small business environment (also includes full text of
ISO 9001 translated into other languages by ISO
members).
ISO 9000 News This journal has been published 6 times a year in
separate English and Fr ench editions, and includes
updates on ISO 9000 family of quality management
and quality assurance standards, news on their
implementation around the world, and related
developments such as ISO 9000 certification.
* *
Publicising ISO 9000 or This brochure provides guidelines to help certificate

ISO 14000 certification holders avoid the pitfalls of false, misleading or
confusing claims related to ISO 9000 and ISO 14000
certification in advertisements and all forms of
promotional material.
Table of Worldwide This table shows the state of worldwide adoption of
Equivalence of ISO 9000 ISO 9000 in ISO member countries.
Series of Standards
7.7.2. Principles
Discussed below are the eight principles of ISO 9000 series:
1) Customer Focus : Customer is the prime focus of a business. An
organisation should understand and respond to the customer needs by
targeting key demographics. This increases the income by delivering the
products and services the customers are looking for. If an organisation has
the knowledge of customer needs, the appropriate resources can be allocated
efficiently. This makes the customer realise a business‟s commitment, thus
developing customer loyalty, which is return business.
2) Good Leadership : A team of good and successful lead ers can quickly
establish unity and direction in a business by inspiring everyone working on
the project and minimising miscommunication in intra - and inter -
departments. Their role is closely linked to the next ISO 9000 principle.
3) Involvement of People : For a successful business, involvement of all the
organisation members is required. Involvement of substance leads to a
personal investment in a project and creates motivated, committed workers,
who will have a tendency of innovation and creativity by utilis ing their full
abilities to complete a project. If the workers have a vested interest in
performance, they will eagerly participate in the continual improvement that
ISO 9000 facilitates.
4) Process Approach to Quality Management: For achieving the best resul ts,
the activities and resources should be managed together. In this process
approach to quality management, the resources, personnel, and time are
effectively used, thus lowering the costs. If a process is controlled as a
whole, management can focus on im portant goals, and prioritise the
objectives to enhance effectiveness. In figure 7.7, the ISO 9000 process
approach is shown.
5) Management System Approach: Combining management groups is a
difficult task; but an efficient and effective management system can be
obtained with correct methods. The leaders dedicated to the goals of an
organisation help each other in improving productivity. Some results include
integration and alignment of key processes.
The interested parties recognise the consistency, effectiveness, and efficiency

of a management system. The suppliers and customers gain confidence in a
business‟s abilities.
* *
Continual Improvement of the Quality Management System
Customers and Customers and

Other Interested Other Interested
Parties Management Parties
Responsibility
Resource Measurement
Management Analysis and Satisfaction
Improvement
Requirements Input Product Product Output

Realisation
Figure 7.7: ISO 9000 Process Approach

6) Continual Improvement: The principle, being very important, should be the
permanent objective of an organisation. A co mpany by increasing its
performance can increase the profits and overpower its competitors.
If a business is dedicated to continual improvement, different improvement
activities are aligned to achieve a faster and efficient development. When a
business is ready for improvement and change, it will be flexible enough to
quickly react to new opportunities.
7) Factual Approach to Decision Making: Effective decisions rely on data
analysis and interpretation. By making informed decisions, an organisation
makes the right decision. If the companies bring this approach in a habit, it
will be able to validate the effectiveness of past decisions, and will put
confidence in its present and future decisions.
8) Supplier Relationships: A mutually beneficial supplier relations hip should
be established to create value for both parties. A supplier that recognises a
mutually beneficial relationship will quickly react whenever a business
should respond to customer demands or market changes. Through close
contact and interaction wit h a supplier, both organisations will be able to
optimise resources and costs.
7.7.3. Working
ISO 9000 is a collection of guidelines to help a company in establishing,
maintaining, and improving a quality management system. ISO 9000 is not a
rigid set of requirements, and organisations have the flexibility of implementing
the quality management system in their own effective way. This freedom enables
various organisations and large and small businesses to use the ISO 9000
standard.
* *
ISO 9000 is process -oriented. When this approach is implemented by

organisations, they can conduct various audits to check how effective their
quality management system is. Generally, three main types of audits are
conducted, i.e., 1st, 2nd, and 3 rd party audits. An internal audit is a 1st party audit,
which the ISO 9000 requires so that an organisation can get quick feedback from
those who know the value of company.
Since this audit process is partial, 2nd party audits are conducted to allow a
consumer to ev aluate the performance of an organisation. Many companies
choose to become certified with ISO 9000 through a 3rd party audit.
In this case, an independent certification body comes into an organisation and

evaluates that whether or not it meets the standard requirements of ISO 9000. If it
does, the organisation becomes certified in ISO 9000 and carries a seal of quality
recognised throughout the world.
7.7.4. Need for Obtaining ISO 9000 Certification

The software development organisations are in competition with each other to
obtain ISO certification due to the benefits it offers.
Some of these benefits that an organisation acquires by obtaining ISO
certification are:
1) The organisation gains customer‟s confidence when it gets ISO certified.
2) ISO 9000 requires a well-documented software production process that
contributes to repeatable and higher quality of the developed software.
3) ISO 9000 makes the development process focused, efficient, and cost
effective.
4) ISO 9000 certification recognises the weaknesses of an o rganisation and
recommends corrective measures.
5) ISO 9000 sets the basic framework for developing an optimal process and
Total Quality Management (TQM).
7.7.5. Importance
The importance of ISO 9000 is the importance of quality. Many companies offer
products and services, but those efficiently delivering the best products and
services are successful. With ISO 9000, an organisation can recognise the cause
of problem, and find a remedial solution. An organisation can maximise its
profit, by improving its efficiency.
Since a wide range of companies implement the ISO 9000 standards, a supply
chain with integrity is created. Each company participating in the process of
developing, manufacturing, and marketing a product knows that it is part of an
internationally known, reliable system.
Different businesses and even the customers recognise the importance of ISO
9000 and quality. And since consumer is most important to a company, ISO 9000
focuses on the customer.
* *
7.8. ISO 14000
7.8.1. Introduction
The I SO 14000 family of standards provide practical tools for different
companies and organisations who desire to manage their environmental
responsibilities. ISO 14001:2015 and its supporting standards, such as ISO
14006:2011, focus on environmental systems to achieve this. The other standards
of ISO 14000 focus on audits, communications, labelling, life cycle analysis, and
environmental challenges , such as climate change. The ISO 14000 family of
standards is developed by ISO Technical Committ ee (ISO/TC) 207 and its
various sub-committees.
7.8.2. History
Since 1947, the ISO has been developing voluntary technical standards for all
sectors of business, industry and technology. The majority of ISO standards are
highly specif ic to a particular product, material, or process. ISO 14000 is
different from most of the other ISO standards. It is a generic management
system standard. Generic indicates that the same standard can be applied to any
large or small organisation, whatever product or service it provides, in any sector
of activity, and whether it is a business enterprise, public administration, or
government department.
Management system indicates the actions taken by an organisation to manage its

processes or activities. IS O 14000 is concerned with the way an organisation
goes about its work, and not directly with the results of this work. The focus is on
processes and not on products.
ISO 14000 grew out of ISO‟s commitment to support sustainable development as

discussed at the United Nations Conference on Environment and Development in
Rio de Janeiro in 1992. Conversations among 20 countries, 11 international
organisations, and more than 100 environmental experts began in 1991 to define
the basic requirements of a new approach to environment-related standards.
The first standards, i.e., ISO 14004 and ISO 14001, were published in 1996 in the
months of September and October, respectively. The ISO 14000 family of
standards and guidelines are related to environmental managemen t systems and
support standards on terminology and specific tools, such as auditing. The
standards are concerned with the ways in which an organisation reduces the
harmful effects on environment caused by its activities, either during production
or disposal, either by pollution or by depleting natural resources.
7.8.3. Standards
ISO 14000 includes several standards under which the aspects of managing the
practices within facilities, the immediate environment around facilities, and th e
product life cycle are covered. This enables understanding of the influence of raw
materials used in the product and the influence of product disposal.
* *
The most important standard is ISO 14001 that provides guidelines for
implementing an Environmental Management System (EMS). ISO 14004 is
another significant standard that provides additional insight and specialised
standards for implementing an EMS.
Here are the key standards included in ISO 14000:

1) ISO 14001: Specification of Environmental Management Systems
2) ISO 14004: Guideline Standard
3) ISO 14010- ISO 14015: Environmental Auditing and Related Activities
4) ISO 14020 - ISO 14024: Environmental Labelling
5) ISO 14031 - ISO 14032: Environmental Performance Evaluation
6) ISO 14040 - ISO 14043: Life Cycle Assessment
7) ISO 14050: Terms and Definitions
7.8.4. Certification
ISO 14000 certification is achieved either when a qualified auditor verifies that
all the requirements have been fulfilled or when a company self -declares so.
Obtaining ISO 14000 certification is considered as a sign of commitment to the
environment, which can be used as a marketing tool for companies. This
certification also helps the companies to meet some environmental regulations.
Other benefits of certification are that the company is permitted to sell products
to other companies using ISO 14000 certified suppliers. Companies and
customers also pay more for environmental friendly products. If the ISO 14000
standards are met, the product cost is reduced, as it encoura ges the efficient use
of resources and waste limitation. This leads to ways of recycling products or
new uses for previously disposed by-products.
7.8.5. Benefits of ISO 14000 Certification

There are various benefits of obtaining ISO certification. If a company adheres to
the ISO 14000 standards , it results in better conformance to environmental
regulations, greater marketability, better use of resources, higher quality goods
and services, increased safety levels, improved image, and increased profits.
Environmental awareness and documents required by the ISO 14000 standards

help a company to abide by the environmental regulations. Thus, by adhering to
the standards, a company will not violate the environmental regulations and will
always be ready for inspection by a regulatory agency. Certification and
documentation also assist a company in gaining funds, in guarding itself during
environmental litigation, and in receiving insurance or permits.
Certification results in a wider market for the goods and services of a company.
Many corporations and governments look for ISO 14000 certified suppliers to
maintain their own certification and reputation of environment -friendly in
market. If ISO 14000 becomes successful, the already ISO 14000 certified
companies will have an advantage in global markets. The producers of consumer
goods will realise that many consumers purchase goods from environment -
* *
friendly companies, and also spend more if they feel they are helping the
environment. For acquir ing this benefit, a company makes their environmental
efforts acknowledged through advertisements and labelling.
The process analyses that following ISO 14000 certification results in

rationalisation processes and efficient use of resources and raw materials, thereby
reducing a company‟s costs. Finding ways to capture emissions or recycle the
products may reduce the amount of raw materials and utilities used. If the amount
of potentially dangerous substances in an end product is reduced, dangerous
chemicals will be less used in a plant, thus leading to a safer internal environment
for employees and reducing insurance premiums. The employee morale improves
when they feel their workplace is safe and their work contributes to the
environmental effort.
7.9. GLP AND NABL
7.9.1. Introduction
Good Laboratory Practice ( GLP) should be followed in pharmaceutical
laboratories. Given below are the major points to be considered under GLP:
1) The laboratory should be located, designed, customised , and maintained to
suit the performance of all quality control tests and analyses.
2) It should be located conveniently to service the manufacturing department
but separate to avoid vibration, dust, internal and external traffic to protect
the delicate instruments.
3) There should be separate wings for analytical, instruments, microbiology,
sterility, etc., which should be connected with the internal door.
4) There should be an effective airlock, provisions for A.C. and fumigation
chamber. The laboratory should hav e adequate space, and provisions for
utility, water solvent storage, extraction dust collection, etc.
5) The laboratory furniture should provide adaptability. The table top should be
covered with material that is resistant to acids, alkali, solvents, etc.
6) The floor should be smooth, easy to clean, and should have adequate
drainage facility.
7.9.2. Equipment
There should be a written SOP for each instrument. The instruments should be
located in a separate room under controlled temperature. They should be
handled wit h care and should be kept clean. The surrounding area should also
be cleaned. The calibration and maintenance/service record should be done
periodically.
The glassware should be calibrated prior to use. All the necessary instructions
regarding operating, handling and care should be displayed near the instruments.
Adequate light supply should be maintained. The electrical system in the
laboratory should not be overloaded. Voltage stabiliser should be provided for
the delicate instruments.
* *
7.9.3. Chemicals and Reagents

Storage of chemicals and reagents should be done adequately under
recommended storage conditions. The container of all chemicals and reagents
should be properly labelled. The analytical reagents and prepared solutions
should be labelled. Chemicals sh ould be transferred with utmost care. Chemical
reagents should not be pipetted out by mouth, instead rubber bulb should be used.
7.9.4. Organisation and Personnel

There should be a defined organogram of the laboratory, and responsibility and
duties at various levels should be well-defined and documented. Every individual
in the laboratory who is engaged in the conduct of testing should have the desired
educational qualification, training, and experience to perform the assigned
function. A sufficient number of personnel should be available for performing the
studies in accordance with protocols. The personnel should take necessary
precautions to avoid contamination of test and control article of the test systems.
They should be provided with appropriate clothing t hat will prevent

contamination. The personnel should undergo medical examination to know
about their health status and ensure they do not have any infection which might
serve as a source of contamination.
Document is a critical factor of th e GLP as documentation involves recording
information for future reference. The major documents that should be provided
are protocols, logbook for usage, etc. Well -established SOPs should be provided
for the maintenance and calibration of equipment.
Given below are some common information routinely recorded in a laboratory:

1) Receipt and storage of samples, 2) Sampling,
3) Analytical testing, 4) Validation,
5) Calibration, 6) Data recording,
7) Operation of instruments, 8) Reagent preparation,
9) Training records, 10) Organisational charts,
11) Sampling procedure, 12) Analytical testing methodology,
13) Inventory/list, 14) Instrument calibration data,
15) Methods validation data, and 16) Analytical testing results and reporting.
7.9.6. Quality Control

A well-defined procedure should be established, includin g all the aspects related
to the sample, i.e., receipt of the consignment, sampling techniques to be
adopted, storage and handling of samples, recording and reporting of analysis.
Every received sample should have a unique number mentioned on the label, an d
it should be stored under the prescribed conditions. A well -defined sampling
procedure should be followed that should specify the sampling procedure in
detail; for example , if sample blending is allowed, how many can be blended
together, etc.
* *
7.9.7. Protocols and Conduct of a Laboratory Test

The laboratories should develop a well-defined protocol to conduct the tests.
7.9.8. Records and Reports

The laboratories should maintain records of all the tests performed. The graphs
related to IR, HPLC, etc., should also be st ored along with the raw data. The
access to records to an authorised person should be restricted, and these records
should be stored under lock and key.
7.9.9. Safety
Proper facilities and accessories should be provided for the safety of personnel
involved in dr ug testing. Adequate anti -doses should be available for the
accidents that may occur. Suitable equipment should be provided for
extinguishing fire in case of accidental fires.
7.9.10. Auditing Procedure

The quality assurance department of a laboratory should esta blish a committee
that needs to regularly audit their facilities for ensuring compliance with GLP
requirements.
7.9.11. NABL (National Accreditation Board for Testing

and Calibration Laboratories)
NABL is a Constituent Board of Quality Council of India. Its goal is to provide
Government, Industry Associations and Industry with a scheme of Conformity
Assessment Body‟s accreditation that involves third party assessment of the
technical competence of testing, including medical and calibration laboratories,
proficiency testing providers, and reference material producers.
The laboratory accreditation services to testing and calibration laboratories are

provided according to ISO/IEC 170 25:2005 „General Requirements for the
Competence of Testing and Calibration Laboratories‟ and ISO 15189:2012
„Medical laboratories - Requirements for quality and competence‟. The
accreditation services to proficiency testing providers are based on ISO/IEC
17043:2010 „Conformity assessment - General requirements for proficiency
testing‟ and to reference material producers is based on ISO Guide 34:2009
„General requirements for the competence of reference material producers‟.
NABL offers accreditation servic es in a non -discriminatory manner. It has

established its accreditation system in accordance with ISO/IEC 17011:2004
„Conformity Assessment - General requirements for accreditation bodies
accrediting conformity assessment bodies‟. NABL accreditation system also
considers the requirements of Mutual Recognition Arrangements (MRAs) of
which NABL is a member.
In the current global scenario, a significant pre -requisite of trade is that any
product or service accepted in one economy should be freely circulated i n other
economies without any extensive re -testing. WTO recognises that not accepting
* *
the test results and measurement data forms a technical barrier to trade. Global
sourcing of components calls for equivalence of measurement that can be
facilitated by a series of accredited CABs. Accreditation is the first essential step
for facilitating mutual acceptance of test results and measurement data.
NABL takes steps to remove technical barriers to trade and thus in 2000 achieved
the status of signatory to Asia Pacific Laboratory Accreditation Cooperation
(APLAC), Mutual Recognition Arrangement (MRA), and International
Laboratory Accreditation Cooperation (ILAC) arrangement based on a peer
evaluation by APLAC. This step was majorly taken towards mutual acceptance
of test results and measurement data across Indian borders. NABL went through
the peer APLAC evaluation in 2004, 2008, 2012, and 2016, and confirmed its
APLAC/ILAC signatory status with extension of scope for Proficiency Testing
Providers (PTP) as per the standard ISO/IEC 17043:2010 and Reference
Materials Producers (RMP) as per the standard ISO Guide 34. In the present day,
the test results and measurement data produced by Indian accredited CABs are
accepted by the economies represented by MRA partners.
NABL provides accreditation in all major fields of Science and Engineering such
as Biological, Chemical, Electrical, Electronics, Mechanical, Fluid -Flow, Non -
Destructive, Photometry, Radiological, Thermal and Forensics under testing
facilities, and Electro -Technical, Mechanical, Fluid Flow, Thermal, Optical, and
Radiological under Calibration facilities. It also provides accreditation for
medical testing laboratories. It provides accreditation for proficiency testing
providers and reference material producers.
7.10. SUMMARY
1) A management technique used for communicating to employees what is
required to produce the desired quality of products and services and to
influence employee actions to complete t asks according to the quality
specifications is termed Quality Management System (QMS).
2) ISO 9001:2015 is the primary quality management certification. It sets out
the standard criteria for a QMS that can be used by a large or small
organisation, irrespective of its field of activity.
3) Quality can be defined as “ fitness for use ,” “ customer satisfaction ,”
“doing things right the first time,” or “zero defects.”
4) Quality is defined as “an inherent characteristic, property or attribute”.
5) In a manufacturing or serv ice environment, quality of design and quality of
conformance are the two major categories of quality.
6) Conformance quality is the degree of adherence of the product
characteristics to the design drawings and specifications.
7) Quality system is a mechanism th at coordinates and maintains the activities
required for ensuring that the characteristics of products, processes or
services are within the limit ranges.
* *
8) Quality system is a mechanism that coordinates and maintains the activities

required for ensuring th at the characteristics of products, processes or
services are within the limit ranges.
9) Besides TQM, there are many other abbreviations used to label management
systems focusing on quality, such asCQI (Continuous Quality Improvement),
SQC (Statistical Quality Control), QFD (Quality Function Deployment),
QIDW (Quality In Daily Work), TQC (Total Quality Control).
10) All the TQM systems should involve in enhancing the quality of the products
and services an organisation provides.
11) TQM should establish clear respon sibility, authority, and accountability for
managing the process.
12) TQM should identify internal and external customers, suppliers and other
shareholders of the process.
13) An organisation and its suppliers depend on each other, and a mutually
beneficial relationship enhances the ability of both to create value.
14) Quality by Design (QbD) is a concept developed by Dr. Joseph M. Juran ,
who believed that quality should be designed into a product, and most quality
problems are related to the way in which a product was designed.
15) Woodcock defined a high -quality drug product as a contamination -free
product that reliably produces the expected therapeutic benefit to the
consumer.
16) Another objective of QbD is to enhance process capability and reduce
product variability that m ay otherwise result in product defects, rejections,
and recalls.
17) The third objective of QbD is increasing product development and
manufacturing efficiencies.
18) The final objective of QbD is to enhance root cause analysis and post -
approval change management.
19) Knowledge is defined as an awareness of someone or something that can
include information, facts, descriptions, and/or skills attained through
experience or education.
20) The word prior in the term prior knowledge indicates previous and also
associates with ownership and confidentiality, i.e., not available to the
public.
21) Design of Experiments (DOE) is a structured and organised method of
determining relationship between the factors influencing process outputs.
22) Process Analytical Technology (PAT) is defined as a system for designing,
analysing, and controlling manufacturing through measurements, during
processing of CQAs of raw and in -process materials and processes, to ensure
the final product quality.
23) Quality risk management is defined as a systematic proces s for the
assessment, control, communication and review of risks to the quality of the
drug product across the product lifecycle.
24) The Six Sigma concept came into force as a measurement standard by Carl
Frederick Gauss (1777-1855) who gave the concept of normal curve.
* *
25) This concept is being used in product variation as a measurement standard

since the 1920‟s, when Walter Shewhart described that three sigma from
the mean is the point where a process requires correction.
26) The Six Sigma DMAIC process (Define, Me asure, Analyse, Improve, and
Control) is an improvement system used for the current processes found
below specification and looking for incremental improvement.
27) The Six Sigma DMADV process (Define, Measure, Analyse, Design, and
Verify) is also an improvement process used for developing new processes or
products at Six Sigma quality levels.
28) The phase II investigation should be performed if no possible outcome is
obtained from phase I investigation.
29) ISO 9000 is a collection of guidelines to help a company in establishing,
maintaining, and improving a quality management system.
30) Three main types of audits are conducted, i.e., 1st, 2nd, and 3rd party audits.
31) NABL is a Constituent Board of Quality Council of India. Its goal is to
provide Government, Industry Asso ciations and Industry with a scheme of
Conformity Assessment Body‟s accreditation that involves third party
assessment of the technical competence of testing, including medical and
calibration laboratories, proficiency testing providers, and reference mate rial
producers.
7.11. EXERCISE

1) Define Quality Management System (QMS).
2) What are the benefits of ISO 9001-2015?
3) Give the advantages of QbD.
4) Differentiate between DMAIC and DMADV.
5) Give the benefits of change control system.
6) Give the benefits of ISO 9000.
7) Write about ISO 14000 certification.

1) Discuss the concept of quality.
2) Give the advantages and disadvantages of TQM.
3) Discuss the objectives of QbD.
4) Write the objectives and applications of six sigma concept.
5) Give the procedure of change control system.
6) Give the principles of ISO 9000.

1) Write a detailed note on the principles of total quality management.
2) Write an illustrative note on six sigma concept.
3) Briefly discuss the phase I of out of specifications.
4) Write a detailed note on GLP and NABL.
* *
CHAPTER Indian Regulatory

8 Requirements
8.1. INDIAN REGULATORY REQUIREMENTS
8.1.1. Introduction
In India , the main regulatory bodies responsible for c ontrolling and regulating
pharmaceuticals and medical devices are Ministry of Health and Family Welfare
(MoHFW) and the Centra l Drugs Standard Contro l Organisation (CDSCO). The
CDSCO controls the import of drugs and pharmaceutical devices, and approves
new medical products and clinical trials. The CDSCO also controls the Drugs
Consultative Committee (DCC), the Drugs Technical Advisory Board (DTAB),
and the Central Licensing Approving Authority (CLAA).
Following are some acts, orders, and other regulatory bodies that control
pharmacy practice in India:
1) National Pharmaceutical Pricing Authority ( NPPA): It is a controlling
body under Government of India , which is responsible for enforcement of
Drugs (Price Control) Order 1995.
2) Drugs & Cosmetics ( D & C ) Act, 1940: This a ct controls the import,
manufacture, distribution and sale of drugs in India.
3) GCP Guidelines: The Ministry of Health , Drugs Controller G eneral of
India (DCGI), and Indian Council for Medical Research (ICMR) together
introduced draft guidelines , known as GCP guidelines, for research in
humans. These guidelines are based on Declaration of Helsinki, WHO
guidelines, and ICH requirements for good clinical practice.
4) The Pharmacy Act, 1948:This act regulates the pharmacy profession in India.
5) The Drugs and Magic Remedies (Objectionable Advertisement) Act,
1954: This act controls the advertisements regarding drugs. It also prohibits
the advertisement of remedies, possessing alleged magic qualities.
6) The Narcotic Drugs and Psychotropic Substances Act, 1985: This act
controls and regulates the operations related to narcotic drugs and
psychotropic substances.
8.1.2. Central Drug Standard Control Organisation

(CDSCO)
The CDSCO is a national regulatory authority of India that has 379 staff
members, and works under the Directorate General of Health Services of the
Ministry of Health & Family Welfare. The Drugs Controller General of India
[DCG(I)] heads the CDSCO. A steep rise in recruitment and staffing of CDSCO
* *
Indian Regulatory Requirements (Chapter 8) 193
has occurred from 111 positions in April 2008 to 474 positions at the current
time. CDSCO is a Central Drug Authority that discharges functions assigned to
the Central Government under the Drugs and Cosmetics Act. There are 6 zonal
offices, 4 sub-zonal offices, 13 port offices , and 7 laboratories under the control
of CDSCO.
CDSCO approves drugs and conduct of clinical trials, set standards for drug s,
controls the quality of imported drugs in India, and coordinates the activities of
State Drug Control Organisations. These functions are performed under the
Drugs and Cosmetics Act. To perform these functions, expert advice is provided
so that uniformit y can be maintained in the enforcement of the Drugs and
Cosmetics Act. CDSCO and state regulators together grant licenses for some
specialised class of critical drugs, such as blood and blood products, I.V. fluids,
vaccines, and sera.
8.1.2.1. Structure
The organisational structure of CDSCO is represented in figure 8.1:
National Government
Ministry of Family and Ministry of Environment Ministry of Chemical and

Health Welfare Petrochemical
Central Drug Standard and

Organisation (CDSCO) NPPA DCP
+ GMP Audits
+ Coordination
HQ Zonal Offices (4) With states
+ New Drugs + GMP Audits

+ CLAA Sub-zonal Offices (2) + Coordination
+ Imports With cities
Post-offices (7) + Import

+ Export
+ Testing of drug + CDC-Kolkata

Laboratory (6) + CIPL-Ghaziabad
samples
+ Validation of + CDTL-Mumbai
Test Protocol + CDT-Chennai
Figure 8.1: Organisation of CDSCO
8.1.2.2. Functions
Following are the main functions of CDSCO:
1) It makes policies and procedures for uniform implementation of the
provisions of Drugs & Cosmetics Act, 1940 and Rules, 1945.
2) It assists in setting and implementation of standards for drugs, cosmetics and
medical devices.
3) It coordinates and interacts with international organis ations like WHO, U.S.
FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical
* *
Devices Agency (PMDA) of Japan, European Directorate for the Quality of

Medicines & HealthCare (EDQM), South Asian Association for Regional
Cooperation (SAARC), WHO Regional Office for South East Asia
(SEARO), BRICS nations (Brazil, Russia, India, China and South Afr ica),
etc.
4) It controls the import of medicines, approval of new medicines and clinical
trials, conduct of meetings with the Drugs Consultative Committee (DCC)
and Drugs Technical Advisory Board (DTAB), and function as Central
Licence Approving Authority (CLAA) for approval of certain licences.
5) It performs inspections along with the Zonal Offices and coordinate actions
with the state Drugs Controllers under their authority.
6) It exercises quality control of imported medicines through the port offices.
7) It maintains drugs testing laboratories for sample testing.
Functions of CDSCO
Approval of new drugs and clinical trials
Import Registration and Licensing
License approving of Blood Banks, LVPs,

Vaccines. r-DNA products and some medical
devices (CLAA Scheme)
Amendment to D and C Act and Rules
Banning of drugs and cosmetics
Gant of Test License, Personal License, NOCs

for Export
Testing of new drugs
Oversight and market Surveillance through

Inspectorate of Centre Over and above the
State Authority
Figure 8.2: Functions of CDSCO
8.1.3. State Licensing Authority (SLA)

The state level authorities consist of one Food and Drug Adminis tration (FDA)
for each state, and also certain licensing authorities for the Union Territories (i.e.,
areas directly administered by the Union Government).
It is the duty of state authorities to control the regulation, manufacture, sale and
distribution of drugs. The quality of food articles manufactured and sold within
the state and also outside the state is also controlled by the state FDAs.
8.1.3.1. Procedure for Obtaining Licenses

Food Safety and Standards Authority of India ( FSSAI) issues central licenses
through its regio nal offices (CLA) and state l icenses through its state offices
(SLA). The procedure for obtaining license is given in figure 8.3:
* *
Filing of completed application

Form B with Documents and Fee
Acknowledge application and grant

unique application number
Scrutiny within 15 days’ notice on

any additional information
required or incomplete application,
if any
If no response
from Licensing
FBO files additional required Authority (LA) FBO may
information within 30 days. start the
business
after 60
In case of no
Inspection of premises and issue days
inspection
of inspection report/improvement
notice
If no
Licensee carries out the response
Grant/reject the license within 60
improvements within 30 form LA
days of receipt of completed
days and intimate LA
application or within 30 days of
inspection, whichever is earlier
Figure 8.3: Procedure for Obtaining License
8.1.3.2. Organisation
The organisational structure of the SLA is represented in figure 8.4:
State Drugs Control Organisation
Drugs Controller/Commissioner Drugs Testing Laboratory
Deputy Drug Controller Govt. Analyst
Drugs Inspector Analyst
Supporting Staff
Supporting Staff
Figure 8.4 Organisation SLA
Total No. of Drugs Inspectors = approx. 1,000
Total No. of Drugs Manufacturers = approx.10,000
Total No. of Sales Premises = approx. 50,000
8.1.3.3. Responsibilities or Functions

State licensing authority has the following responsibilities:
1) It controls the licensing of drug manufacturing and sales establishments.
2) It controls the licensing of drug testing laboratories.
3) It regulates the approval of drug formulations for manufacture.
4) It monitors the quality of drugs and cosmetics manufactured and marketed by
state units.
5) It investigates and makes trials on infringement of legal provisions and laws.
* *
6) It takes administrative actions.

7) It conducts pre- and post-licensing inspection.
8) It regulates the recalling of sub-standard drugs.
8.1.4. Certificate of Pharmaceutical Product (CoPP)

The National Health Authorities issue the CoPP upon request from the customer,
the authorities, or the product manufacturer in the importing country. CoPP is
issued for a specific product whether or not it is marketed in the origin country.
The certificate also states that whether or not the manufacturer of the product
complies with GMP, and whether or not they are being inspected often by the
national health authorities. Format of CoPP is designed as per the
recommendations of the WHO.
The CoPP for a pharmaceutical product is asked by the importing country , along
with a special type of certificate that enables a given pharmaceutical product to
be registered and marketed in the desired exporting country and forms parts of
the marketing authorisation application.
The CoPP is issued by both the inspectorate and the fabricator of the product
possessing GMP position and also the position of pharmaceutical,
radiopharmaceutical, biological, or veterinary product. Since the information
approved for various pharmaceutical forms and strengths is different, it is always
issued for a single product.
8.1.4.1. Aim
CoPP mainly focuses on the following aspects:
1) It provides i nformation regarding the imported drug , like whether or not the
drug is of appropriate quality standard, whether or not it is safe and effective
enough to be marketed , whether or not it has undertaken testing and
examination to Regulatory Authorities in the exporting country.
2) It demonstrates that whether or not correct guidelines and p rocedures of
GMP are being followed.
3) It increases the level of quality and safety of the product.
8.1.4.2. Scope
Scope of CoPP can be summarised in the following ways:
1) It is issued at the time of registration or at the time of renewal (licen sing,
authorisation or prolongation) by the importing country, with the possibility
that the product is distributed or commercialised in that country.
2) It helps the small-sized Drug Regulatory Authorities (DRA) or the authorities
without proper Quality Assurance (QA) facilities in importing countries.
3) It enables checking the quality of pharmaceutical products and determining
whether or not it is as per the prerequisites of importation or registration.
4) It recommends the WHO and national authorities to ensure about the
analytical methods followed by the national laboratories.
* *
5) A CoPP, which recommends WHO to national authorities for its

esurient that confirmed method is analytical by the national laboratory,
to view and adapt product information as per labelling requirements,
bioequivalence, and stability data.
8.1.4.3. Inspection
CoPP is issued by the DRA only when inspection of the manufacturing product is
performed. In India , the Pharmaceutical market is of around Rs 65,000 crore, of
which around Rs 30,000 crore accounts for export.
8.1.4.4. Types of COPP

CoPP is of the following three types:
1) WHO 1975 type CoPP: This type of CoPP is issued by exporting country
regulatory authority, and it states that:
i) The authorised product has to be marketed, along with the permit number
and issue date, to be used in the country, or
ii) The non-authorised product has to be marketed, along with the reason for
its requirement, to be used in the country, or
iii) The manufacturer of product conforms to GMP requirements as per the
recommendations of WHO, or
iv) The products are to be sold or distributed within the origin country, or
v) The product is to be exported to the manufacturing plant where it is
produced and at suitable intervals subject to inspections.
2) WHO 1988 type CoPP: According to this type of CoPP, the competent
authority of the exporting country should contain:
i) All labelling copies, and
ii) Product detailed information in the origin country.
3) WHO 1992 type CoPP: This type of CoPP is issued by the competent
authority of an importing country under the following two conditions:
i) If any question is asked about the import and sale license, and
ii) When license renewal, extend, review or changes is required.
At the time of issue of the certificate, the following information is

required:
i) Whether or not there is any requirement to market the licensed
product.
ii) Satisfied information is submitted by the applicant that the certifying
authority of the manufacturer of product undertaken by another party.
iii) Inspection has been performed out of the manufacturer of product.
iv) Whether the certificate is provisional or permanent.
v) Whether any independent company or the applicant has manufactured
the dosage forms, packages and/or labels of a finished dosage form.
vi) Names of the importing and exporting (certifying) countries.
* *
8.1.4.5. Certificate of a Pharmaceutical Product Model

A sample of CoPP is given below:
Certificate of Pharmaceuticals Product-1
Certificate No.:
Valid Up to:
This certificate conforms to the format recommended by the World Health
Organisation
No. of Certificate:
Exporting (Certifying) country:
Importing (requesting) country:
1-Name and dosages form of product:
1-1 Active ingredient(s) 2 and amount (s) per unit dose:
Composition 4:
Ingredients: Starch, micro crystalline cellulose, lactose, methyl paraben, talc,
magnesium stearate, sodium starch glycoate, silicon dioxide, isopropyl alcohol,
PVPK-30 and purified water.
1.2 Is this Product licensed to be placed on the market for use in the
exporting country? 5
1.3 Is this Product actually on the market in the exporting country?
2A
A.1 Number of product licensed 7 and date of issue:
A.2 Product-license holder:
A.3 Status of product-license holder: 8
(A) (B) (C)

A.3 1 For Category B and C the name and address of the Manufacturer producing
the dosage form are: 9
A.4 Is summary basis of Approval appended? 10
A.5 Is the attached, officially approved product
Information complete and consonant with the licence?
3.0 Does the certify authority arrange for periodic inspection of the
manufacturing plant in which the dosages form is product.
If no or not applicable proceed to question 4.
3.1 Periodicity of routine inspection: At least once in a year:
3.2 Do the facilities and operation conform to GMP as recommended by the
World Health Organisation? 15
4.0 Doe s the information submitted by the applicant satisfy the certifying
authority on all manufacture of the Product, If no, explain:
Address of certifying authority:
Drugs Licensing cum controlling authority,
Directorate General of Medical Health Service,
107 Chandar Nagar, Dehradun (Uttrakhand)
Telephone Number: Name of Authorised Person
Stamp and Date Signature:

* *
Prerequisites for Obtaining CoPP

1) CoPP is issued on a request by the Marketing Authorisation Holder (MAH)
to the exporting country’s health authority.
2) CoPP is issued by an authorised person and returned to the MAH.
3) Other required documents, like an application for Export Certificate form,
evidence of a GMP certificate (if applicable), Manufacturing License , and
the last approved Summary of Product Characteristics (SPC) are also
submitted for obtaining CoPP.
Content and Format
1) Importing country.
2) Exporting country.
3) Name, dosage form and composition of the product (API per unit dose).
4) Registration information (licensing).
5) Marketing standards of the product in the exporting country.
6) License number of the product, along with license holder details, involvement
of the license holder in manufacturing (if any), and the date of issue.
7) Summary of the properties of product according to which t he product has
been licensed (if required by the issuing authority).
8) Information on the currently marketed products.
9) Information on the product’s applicant.
10) If there is any lacking in the exporting country, the reasons should be mentioned.
Certificates May Be Issued For
1) Legally marketable drug in the country.
2) Non-authorised drugs, which are legally exported to a foreign country,
should be distributed in the country.
3) For a foreign manufactured drug.
Exportation for Personal Use
Awareness is essential for the drugs which are distributed legally in some
countries and illegally in other countries.
Importation for Personal Use

1) Drugs which are harmful for health should not be imported.
2) Enforcement actions should be taken domestically.
Types of Drugs for which CoPPs may be Issued
1) Approved drug products,
2) Active Pharmaceutical Ingredients (APIs),
3) Over the Counter (OTC) products,
4) Unapproved drug products, and
5) Homoeopathic drugs.
Who can Apply for CPP?

1) The person/company who exports the drug should submit a compl ete
application for export certification.
2) The certification is meant for a drug that meets the applicable requirements
of the Act or Food Drug and Cosmetic Act 801 requirements.
* *
Process to Apply for a CoPP

1) Form no. 3613b is submitted.
2) Requirements for CoPP application include:
i) Information on applicant contact,
ii) Trade name of the drug product,
iii) Generic name of the bulk substance,
iv) Applicant’s name,
v) Status of the product license holder,
vi) Complete address of the manufacturing facility,
vii) Facility registration number,
viii) List of importing countries,
ix) Authorisation to release information,
x) Number of certificates requested,
xi) Certification statement,
xii) Billing contact, and
xiii) Marketing status in the exporting country.
Attachments to CoPP
1) For a single country, two sets of attachments are required; one set is attached
to the certificate package and the second set is for FDA files.
2) Attachments should not be more than five pages per certificate.
3) Applicant should consult with the importing country to determine the type of
the information required.
Process Time
Drugs in compliance are issued within 2 0 government working days of receipt of
complete and an accurate CoPP application.
Certificates may not be Issued

1) Returned: If any information is missing in the application with a letter
identifying the missing information.
2) Rejected: If the manufacturing facilities are not in compliance with GMPs.
3) Denied: If drug products are not in compliance with the regulations (e.g.,
misbranded drug).
Coloured Ribbons Designate the Type of CoPPs

1) Red: For approved drug product, API, OTC marketed as per monograph, and
export only drugs.
2) Blue: For unapproved drug product not marketed in the country.
3) Yellow: For drug manufactured with foreign manufacturing sites.
CoPP Fee Schedule

1) First Certificate (original) – `11025.
2) Second Certificate – `5670.
3) Third and subsequent certificates – `2520.
* *
Expiration of CPP
1) Certificate expires in 2 years from the notarisation date or as noted.
2) A new CoPP application has to be submitted after the expiry date.
Benefits
The CoPP certificates are obtained by pharmaceutical companies to start business
in foreign country.
8.1.5. Regulatory Requirements and Approval

Procedures for New Drugs
For the approval of new drug , different regulatory requirements are being
followed in different countries. Sometimes, a single regulatory approach is
applicable in various countries for Marketing Authorisation Application (MAA),
which is a very difficult task. Therefore , it is essent ial to have knowledge about
regulatory requirement for MAA of each country.
Each country has its own regulatory requirements ; therefore, it is a challenging

task for the companies to develop a single drug that can be simultaneously
submitted in all the co untries for approval. Before starting the developmental
work, the regulatory strategy for product development should be established, so
that major obstacles can be passed after the submission of application.
It is the role of the regulatory authorities to ensure the quality, safety, and
efficacy of all medicines being circulated in their country. It includes the process
of controlling and monitoring the drugs, along with the process of manufacturing,
distribution and promotion of the drug s. The biggest cha llenge of regulatory
authority is to ensure that the pharmaceutical products are developed according
to the regulatory requirement s of the specific country. This process includes
evaluation of critical parameters during product development.
If an Indian company wishes to manufacture or import a new drug, it has to get

permission from the licensing authority ( i.e., DCGI) by filing the Form 44 and
also submitting the data as per Schedule Y of Drugs and Cosmetics Act 1940 and
Rules 1945. For proving its efficacy and safety in India , clinical trials are
conducted as per the guidelines specified in Schedule Y. The report of such
clinical trials should be submitted in the specified format.
But, Rule-122A of Drugs and Cosmetics Act 1940 and Rules 1945 states that the
licensing authority may waive certain trials , if he considers that with respect to
public health, he may permit the import of new drugs as per the data of the trials
conducted in other countries. Same provisions are made in Rule-122A, according
to which the clinical trials may be waived for new drugs that are approved and
are in use for several years in other countries.
As per the Section 2.4 (a) of Schedule Y of Drugs and Cosmetics Act 1940 and
Rules 1945, all phases of clinical trials should be cond ucted for the drug s
discovered in India.
* *
As per the Section 2.4 (b) of Schedule Y of Drugs and Cosmetics A ct 1940 and
Rules 1945, for th e drug s discovered in countries other than India, the data
obtained from other countries should be submitted by the applicant. The licensing
authority may either ask the applicant to perform all the studies again or allow
him/her to proceed directly from Phase III clinical trials.
According to the Section 2.8 of Schedule Y of Drugs and Cosmetics Act 1940
and Rules 1945 , the licensing authority may need pharmacokinetic data
(bioequivalence data) to show that the data obtained from India is equivalent to
the data obtained from countries other than India. Then, the licensing authority
grants permission to the applicant to proceed with Phase III trials.
In India, it is essential to demonstrate the safety and efficacy of the drug products
meant for human use before approving their import or manufacture by the
applicant by Central Drugs Standard Control Organisation (CDSCO).
For conducting clinical trials in India, an application along with the data of
chemistry, manufacturing, control and animal studies should be submitted to
DCGI. Also, the data regarding t he trial protocol, investigator’ s brochures, and
informed consent docu ments should be submitted. A copy of the application
should be submitted to the ethical committee. The clinical trials should be
conducted only when granted approval by the DCGI and ethical committee.
Phase I clinical trials are conducted on healthy human subjects to determine the
maximum tolerated dose in humans, adverse reactions, etc. Phase II trials are
conducted in 10 -12 patients to determine the therapeutic uses and effective dose
ranges at each dose level.
Phase III trial s (confirmatory trials) are conducted to obtain data regarding the
efficacy and safety of the drug. The se trials are performed in 100 patients (in 3 -4
centers) to confirm the efficacy and safety claims made by the drug . If the new
drug substance is not marketed in any other country , Phase III trials should be
conducted on at least 500 patients in 10-15 centres.
Application for the registration of new drug in Form 44, along with pre -clinical
and clinical testing information is submitted, once the clinical trials are
completed. Along with the information on safety and efficacy, complete
information on the marketing status of the drug in other countries is also
submitted. Information regarding the prescription, samples and testing protocols,
product monograph, labels, and cartons should also be submitted.
Review of the application should be performed within 12 -18 months of its

submission. Once the NDA grants approval for a drug product, a company is
allowed to distribute and market the product. This step is considered as Phase
IV trial s, in which new uses, new populations, long -term effects, etc. are
explored. Figure 8.5 explains the whole process of drug approval in India.
* *
Applicant
Application to ethical IND application filing to CDSCO

committee head quarters
Report of ethical committee Examination by new drug

division
If Positive
Detailed review by IND
committee
Within 12 Recommendation to DCGI

weeks
IND application approved
Clinical trials started
Application for new drug

registration to CDSCO
If not complete
Review by DCGI
Refused to grant license If complete
License is granted
Figure 8.5: Drug Approval Process in India
8.2. SUMMARY
1) In India, t he main regulatory bodies responsible for controlling and
regulating pharmaceuticals and medical devices are Ministry of Health and
Family Welfare (MoHFW) and the Central Drugs Standard Control
Organisation (CDSCO).
2) The CDSCO also controls the Drugs Consultative Committee (DCC) , the
Drugs Technical Advisory Board (DTAB), and the Central Licensing
Approving Authority (CLAA).
3) The Drugs Controller General of India [DCG(I)] heads the CDSCO.
4) In April 2008 to 474 positions at the current time. CDSCO is a Central
Drug Authority that discharges functions assigned to the Central
Government under the Drugs and Cosmetics Act.
5) There are 6 zonal offices, 4 sub -zonal offices, 13 port offices, and 7
laboratories under the control of CDSCO.
6) The state level authorities con
sist of oneFood and Drug Administration(FDA)
*
for each state, and also certain licensing authorities for the Union Territories. *
7) It is the duty of state authorities to control the regulation, manufacture, sale

and distribution of drugs.
8) The National Heal th Authorities issue the CoPP upon request from the
customers.
9) Food Safety and Standards Authority of India (FSSAI) issues central
licenses through its regional offices (CLA) and state licenses through its state
offices (SLA).
10) The Certificate of Pharmaceutical Product (CoPP) states that whether or
not the manufacturer of the product complies with GMP, and whether or not
they are being inspected often by the national health authorities.
11) CoPP is issued by the DRA only when inspection of the manufacturing
product is performed.
8.3. EXERCISE

1) Write the full form of CDSCO and name the person who heads the organisation.
2) What is SLA?
3) Give the aims of CoPP.

1) Mention the organisation and responsibilities of SLA.
2) Mention the types and scope of CoPP.

1) Discuss about the structure and functions of the CDSCO.
2) Briefly discuss about regulatory requirements and approval procedure for new drugs.
* *
Index 205
Index
A G
Approved Regulatory Bodies and Good Laboratory Practice (GLP), 186
Agencies, 57
Applications, 167 H
Advantages, 163
Application in Pharmaceuticals, 45 History, 184
APCTT (Asian and Pacific Centre for Hot Melt Extrusion, 35
Transfer of Technology), 64 Historical Overview, 79
Advantages, 159
I
B Investigational New Drug (IND), 113
Bioequivalence Studies, 135 Investigator’s Brochure (IB), 120
Bioequivalence Study Parameters, ISO 14000, 184
137 ISO 9000, 178
Biostatistical analysis, 144 Implementation, 166
Benefits, 176 Importance, 183
BCIL (Biotech Consortium India Inhalation Technology, 35
Limited), 66 Working, 182
C M
Central Drug Standard Control Management of Clinical Studies, 146
Organisation (CDSCO), 192 Memorandum of Understanding, 75
Certificate of Pharmaceutical Product Microsphere, 34
(CoPP), 196 Methodologies, 164
Change Control, 176
Clinical Research, 127 N
Confidentiality Agreement, 72 NABL (National Accreditation Board
Content and Format, 114 for Testing and Calibration
Certification, 185 Laboratories), 188
Concepts, 155 New Drug Application (NDA), 124
Non-Clinical Drug Development, 93
D Nanotechnology, 34
Drug Approval Process in India, 90 Need, 79
Documentation, 177 NRDC (National Research
Disadvantages, 159 Development Corporation), 65
E O
Evaluation of Bioequivalence Data, Out of Specifications (OOS), 167
141 Objectives, 14
Elements, 161 Oral Disintegrating Formulations
Effect, 159 Technology, 35
Objectives, 160
Objectives, 78
* *
P S
Pilot plant scale up studies, 13 Scale Up and Post Approval Changes
Pilot Plant Scale Up Studies (SUPAC), 27
Procedure, 176 Six Sigma Concept, 164
Principles, 156 Objectives, 164
Principles, 181 State Licensing Authority (SLA), 194
Phase I (or Laboratory) Investigation, Standards, 184
168 SIDBI (Small Industries Development
Phase II Investigation, 171 Bank of India), 68
Phase III Investigation, 175 Significance, 13
Platform technologies, 34 Steps, 14
Platform Technologies Sprinklers, 35
Sustained Release Formulations
Q Technology, 35
Quality by Design (QbD), 160
Quality Management System (QMS) ,
T
152 Technology Transfer, 38
Quality Risk Management, 44 Technology Transfer Agencies in
Quality Risk Management:, 45 India, 64
Quality of Conformance, 154 TBSE (Technology Bureau for Small
Quality of Design, 153 Enterprises), 67
TIFAC (Technology Information,
R Forecasting and Assessment Council),
65
Regulatory Affairs, 78 Technology Transfer Protocol, 43
Regulatory Authorities, 81 Total Quality Management (TQM),
Regulatory Requirements and 155
Approval Procedures fo r New Drugs, Types of Quality, 153
201
Responsibility of Regulatory Affairs
Professionals, 84
Role of Regulatory Affairs
Department, 83
* *
Bibliography 207
Bibliography
 Remington: The Science and Practice of Pharmacy Pharmaceutical
Sciences Vol. I and III, Mack Publishing Company, U.S.A.
 Avis R.E., Pharmaceutical Dosage Forms: Parenteral Medication,
Vol-I, Marcel Dekker-Inc, New York & Basel.
 Ansel H.C., Introduction to Pharmaceutical Dosage Forms , Lea &
Febiger, Philadelphia, U.S.A.
 Khar R. K., Vyas S.P., Ahmad F., Jain G. K., The Theory and
Practice of Industrial Pharmacy, 4th Edition, CBS Publishers and
Distributors.
 Dinda S. C., Advances in Pharmaceuti cal Technology, PharmaMed
Press.
 Ansel H.C., Pharmaceutical Dosage Form and Drug Delivery
System.
 Sankar, V. Ramesh S., Shanmugam V., A Text book of Novel Drug
Delivery System, PharmaMed Press.
 Subrahmanyam C.V.S., Setty T. J., Pharmaceutical Engineering ,
Vallabh Prakashan.
 Bentley’s (E. A. Rawlins), Textbook of Pharmaceutics , AITBS
Publishers.
 McCabe W. L., Smith J. C., Unit Operations of Chemical
Engineering, MGH.
* *

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According to the syllabus based on ‘Pharmacy Council of India’

Dr. Vikesh Kumar Shukla

Dr. Sameer H. Lakade

Books are Available for Online Purchase at: tppl.org.in

THAKUR PUBLICATION PVT. LTD., LUCKNOW

Copyright © All Rights Reserved

- Dr. Vikesh Kumar Shukla

-Dr. Sameer H. Lakade

Please e-mail us at, thakurpublication@gmail.com

Chapter 2: Technology Development and Transfer

2.3.3. NRDC (National Research Development Corporation) 65

Chapter 3: Technology Transfer Related Documentation

Chapter 4: Regulatory Affairs

Chapter 5: Regulatory Requirements for Drug Approval-I

Chapter 6: Regulatory Requirements for Drug Approval - II

6.7. Management of Clinical Studies 146

Chapter 7: Quality Management Systems

7.7.1. Introduction 178

Chapter 8: Indian Regulatory Requirements

CHAPTER Pilot Plant Scale Up

1.1. PILOT PLANT SCALE UP TECHNIQUES

In this technique, a formula is examined and shifted to a most suitable

Pilot plant scale up studies is essential in pharmaceutical research for preventing

1.1.2. Rationale for Pilot Plant Studies

1.1.3. Significance of Pilot Plant Studies

1.1.4. Objectives of Scale Up

1.1.5. Steps Involved

Laboratory studies and scale up planning are conducted at

Key rate-controlling steps are defined in the proposed

Preliminary larger-than-laboratory studies with equipment to

A pilot plant including provisions for process and

Pilot plant results (product and process) including process

1.2. GENERAL CONSIDERATIONS FOR

1.2.2. Reporting Responsibility

1.2.3. Personnel Requirements

The personnel should be aware of the appropriate scale up conditions to be used

1.2.4. Space Requirements

1.2.5. Raw Materials

1.2.6. Review of the Formula

1.2.7. Processing Equipment

Upon development of a practical process on the pilot plant equipment, medium -

1.2.8. Process Evaluation

1.2.9. Production Rates

1.2.10. Preparation of Master Manufacturing Procedure

1.2.11. Good Manufacturing Practice (GMP) Considerations

1.2.12. Transfer of Analytical Methods to Quality Assurance

1.3. PILOT PLANT SCALE UP

1.3.2. Material Handling

1.3.3. Dry Blending or Mixing

Figure 1.2: Dry Blending Method

Problems Associated with Improper Blending

Equipment Required for Blending

Parameters to be Considered for Improving the Blending Process

Functions of Granulation Process

Different processes involved in granulation mechanism are wetting,

1.3.6. Reduction of Particle Size

Equipment Involved in Particle Size Reduction

According to objective 1, blending should attain uniform size distribution of all

1.3.8. Dry Compaction

1.3.9. Direct Compression

Drying of material Milling Mixing Compression

1.4. PILOT PLANT SCALE UP

1.4.2. Steps of Liquid Manufacturing Process