Pharmaceutical Product Development Insights Into
Pharmaceutical Processes, Management and Regulatory
Affairs 1st Edition
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Contents
Foreword...................................................................................................................vii
Preface.......................................................................................................................ix
Editors........................................................................................................................xi
Contributors............................................................................................................ xiii
Chapter 1 Product Life Cycle Management: Stages of New Product
Development..........................................................................................1
Preshita P. Desai, John I. Disouza and Vandana B. Patravale
Chapter 2 Principal Concepts in Pharmaceutical Product Design
and Development................................................................................. 17
Preshita P. Desai and Maharukh T. Rustomjee
Chapter 3 Regulatory and Intellectual Property Aspects during
Pharmaceutical Product Development................................................ 31
Preshita P. Desai, Sivagami V. Bhatt and Mahalaxmi A. Andheria
Chapter 4 Strategies in Pharmaceutical Product Development........................... 65
Maharukh T. Rustomjee
Chapter 5 Design of Experiments: Basic Concepts and Its Application
in Pharmaceutical Product Development.......................................... 117
Amit G. Mirani and Vandana B. Patravale
Chapter 6 Preformulation Studies: Role in Pharmaceutical Product
Development...................................................................................... 163
Swati S. Vyas, Amita P. Surana and Vandana B. Patravale
Chapter 7 Formulation Development and Scale-Up.......................................... 185
Amit G. Mirani, Priyanka S. Prabhu and Maharukh T. Rustomjee
Chapter 8 Process Validation and Postapproval Changes................................. 237
Amit G. Mirani and Maharukh T. Rustomjee
v
vi Contents
Chapter 9 Case Studies on Pharmaceutical Product Development.................... 257
Ankit A. Agrawal, Manasi M. Chogale, Preshita P. Desai,
Priyanka S. Prabhu, Sandip M. Gite, Vandana B. Patravale,
Maharukh T. Rustomjee and John I. Disouza
Chapter 10 Packaging of Pharmaceuticals.......................................................... 367
Manasi M. Chogale and Maharukh T. Rustomjee
Chapter 11 Quality Management Systems in Pharmaceutical Manufacturing.... 393
Abhinandan R. Patil and Maharukh T. Rustomjee
Chapter 12 A New Era of Drug Products: Opportunities and Challenges..........407
Preshita P. Desai, John I. Disouza and Vandana B. Patravale
Foreword
The pharmaceutical industry is among the most research-intensive and highly regu-
lated industries propelled towards conducting exciting research in various therapeutic
areas using conventional technologies as well as newer technologies and approaches
with application of biotechnology, molecular biology and genetics to address unmet
medical needs towards achieving novel therapies. However, the cost of research is
very high and increasing with time, and the gestation period from research to m arket
launch is long. Hence, getting a respectable return on investment is very challeng-
ing. Any small error or oversight in development or change in regulations can cost
dearly with respect to time and finances. Since the pharmaceutical industry is looked
upon as a ‘zero defects’ industry, achieving efficiency in the product development
process is the key to maximising gains and mobilising resources for fabricating the
next drug product. The pharmaceutical industry demands consistent production
of quality pharmaceuticals with overall quality assurance and continuous quality
improvement. The quality of pharmaceutical products and suitability of drugs for
their intended use are determined by
• Their efficacy weighed against safety as endorsed and judged by regulators
• Their compliance to specifications developed or appropriate pharmacopoe-
ial regulations pertaining to identity, purity and other characteristics
Developing pharmaceutical products in a timely manner and ensuring quality is a
complex process that requires a systematic, scientific approach. Information about the
properties of drug substances and excipients and the interaction between components
of the pharmaceutical dosage forms are obtained in the early stages of research and
development. This knowledge is then applied in different ways, including heuristics,
decision trees, correlations and first-principle models utilising quality-by-design prin-
ciples. These decisions help define the preferred route of administration and the choice
of excipients. Unit operations and equipment needed to manufacture the product can
then be developed. Computer-based techniques are extensively used to assist formula-
tion scientists in managing the vast information, capturing the knowledge and provid-
ing intelligent decision making that supports pharmaceutical product development.
Regulators and the pharmaceutical industry together are looking at more holistic
approaches to improve processes to bring new products to the market with acceler-
ated product development and consistent and reliable assurance of the highest level of
quality. The main focus is on product life cycle management, a business transforma-
tion approach to manage products and related information across the industry. This is
challenging because of the complex value chain and business processes required in a
highly regulated environment. Being able to collect and analyse knowledge relating to
all aspects of safety, efficacy and pharmaceutical development, including quality of a
drug and drug product, allows pharmaceutical companies to quickly address industry
challenges and provide solutions for unmet medical needs for our ultimate customers,
patients. Successful commercialisation of the drug thus requires a scientific review
vii
viii Foreword
of pertinent development data that provides the necessary information to assure that
decisions are made regarding the potential in-licensing of a drug. The present book
aims to provide a single comprehensive compilation of pharmaceutical product devel-
opment and management covering all the steps from the very beginning of product
conception to the final packaged form that enters the market in the form of a refer-
ence book that can equip the pharmaceutical formulation scientist with up-to-date,
complete knowledge of drug product development. This book provides an extensive
description of the entire set of processes a potential pharmaceutical product has to go
through in order to qualify as a quality product to appear in the market, and dovetails
pharmaceutical product management with core formulation development and large-
scale manufacturing. Application of core science principles for product development
is thoroughly discussed in conjunction with the latest approaches involving design of
experiment and quality by design with a comprehensive illustration based on practical
case studies of several dosage forms.
Praveen Tyle, PhD
President and Chief Executive Officer
Osmotica Pharmaceutical
Preface
The field of pharmaceutical product development has undergone a significant change
over the years, from an early phase of adopting mostly empirical and unsubstanti-
ated approaches, to a focus on a more structured process that contributes to the
essential and allied processes involved in the creation of a finished product. Today,
the product development process is largely inclusive of aspects related to intellectual
property rights, design and strategy applying principles of quality by design (QbD),
risk management and use of statistical design of experiment (DoE) to enhance the
traditional product development stages, including preformulation, formulation devel-
opment, scale-up and packaging. This book covers all of these aspects using a holis-
tic approach, conceiving the final product from its genesis to market entry. Case
studies discussing the application of these concepts for each type of dosage form
have been presented for a better understanding of the application of these concepts.
Introduction to recent quality improvement trends such as quality metrics and con-
tinuous manufacturing has also been provided for reflection and contemplation. This
book seeks to disseminate the knowledge for pharmaceutical product development in
an easy-to-read mode with simplified theories, case studies and guidelines for both
working professionals in the pharmaceutical industry and students. While the book
presents concepts in their entirety, it mainly identifies and presents realistic, sequen-
tial steps for the assistance of those who wish to work in this field on a practical level.
Given the inadequate number of reference books available in this field, this book
is a considerable resource for pharmaceutical industrialists, academicians and stu-
dents in this area. Although the book is mainly targeted to readers from the field
of industrial pharmacy, intellectual property, pharmaceutical management, pharma-
ceutics and product development, we believe that readers from several allied fields
such as clinical pharmacy, toxicology and even medicinal chemists will profit from
its scope and content.
We are indebted to the authors for investing their time and energy to put forth this
compilation in product life cycle management for pharmaceuticals. We would like
to further extend our deepest gratitude to Dr L. Sesha Rao, Dr Nandkumar Bhilare,
Susan Josi and Suhas Katare for their counsel on technical matters, Mahafrin
Rustomjee for cover page design and to Tanvi Shah for providing valuable inputs and
time towards formatting and language structuring.
Vandana B. Patravale
John I. Disouza
Maharukh T. Rustomjee
ix
Editors
Vandana B. Patravale, PhD, is currently a professor of pharmaceutics at the
Department of Pharmaceutical Sciences and Technology of the Institute of Chemical
Technology, Mumbai, India. She has more than 90 refereed publications, 7 book
chapters, 4 granted patents, 25 patents in the pipeline and 3 trademark registries to
her credit and has handled many national and international projects. Dr Patravale
has worked in close collaboration with industry and holds extensive experience of
approximately 25 years in the field of pharmaceutical sciences and technology. Her
areas of expertise include conventional and modified release dosage forms, formula-
tion strategies to enhance bioavailability and targeting, medical device development
(coronary stents, intrauterine devices), nanodiagnostics and novel nanocarriers with
major emphasis on malaria, cancer and neurodegenerative disorders. Dr Patravale
has recently published a book titled Nanotechnology in Drug Delivery – A Perspective
on Transition from Laboratory to Market by Woodhead (now Elsevier) Publishing
House.
John I. Disouza, PhD, is a professor in pharmaceutics and principal at the Tatyasaheb
Kore College of Pharmacy, Kolhapur, India. He has more than 15 years of teach-
ing and research experience. He also has an executive MBA (higher education)
degree. He has written two books, Experimental Microbiology and Biotechnology
and Fermentation Processes, and has published more than 50 research papers in
peer-reviewed journals. Dr Disouza has worked in diverse research areas, includ-
ing herbal formulations, micro/nanoparticulate, self-emulsifying, liposomal, fast and
modified release drug delivery systems and so on. His research areas of interest are
probiotics, novel diagnostic tools and therapies in cancer and structural modifica-
tions of natural polymers for their pharmaceutical potential. Dr Disouza is an active
consultant to the pharmaceutical industry.
Maharukh T. Rustomjee is a consultant and advisor to the life sciences and health-
care industry. She is one of the founder directors of Rubicon Research Private
Limited, which is an innovation-led drug delivery company in India. Being its chief
operating officer for 15 years, she now continues to serve on the board of directors for
the company. Spearheading Rubicon’s drug delivery technology effort, Rustomjee
has built a strong intellectual property knowledge base, holding numerous patents in
the area of drug delivery systems, developed complex generics and worked on inno-
vative dosage forms as LCM opportunities for multinational innovator pharma com-
panies. She has more than 30 years of experience in dosage form development and
drug delivery platform technologies in all phases of product development from prod-
uct design through commercial manufacturing. Under Rustomjee’s thought leader-
ship, Rubicon developed solutions for bioavailability enhancement, gastric retention,
liquid oral controlled release, taste masking and customised release profiles. Many of
the products using these technologies have already been licensed out/commercialised
to leading generic companies or innovator pharmaceutical companies.
xi
Contributors
Ankit A. Agrawal Amit G. Mirani
Institute of Chemical Technology Institute of Chemical Technology
Mumbai, India Mumbai, India
Mahalaxmi A. Andheria Abhinandan R. Patil
Panacea Biotec Limited Tatyasaheb Kore College of Pharmacy
Mumbai, India Kolhapur, India
Sivagami V. Bhatt Vandana B. Patravale
Panacea Biotec Limited Institute of Chemical Technology
Mumbai, India Mumbai, India
Manasi M. Chogale Priyanka S. Prabhu
Institute of Chemical Technology Institute of Chemical Technology
Mumbai, India Mumbai, India
Preshita P. Desai Maharukh T. Rustomjee
Institute of Chemical Technology Rubicon Research Pvt. Ltd.
Mumbai, India Mumbai, India
John I. Disouza Amita P. Surana
Tatyasaheb Kore College of Pharmacy Jinstar Pharma Consultants Pvt. Ltd.
Kolhapur, India Mumbai, India
Sandip M. Gite Swati S. Vyas
Institute of Chemical Technology Institute of Chemical Technology
Mumbai, India Mumbai, India
xiii
1 Product Life Cycle
Management
Stages of New Product
Development
Preshita P. Desai, John I. Disouza
and Vandana B. Patravale
CONTENTS
1.1 Introduction....................................................................................................... 1
1.2 New Product Development: A Need..................................................................3
1.3 Product Life Cycle Management....................................................................... 5
1.4 Phases of NPD...................................................................................................6
1.4.1 Idea Generation......................................................................................6
1.4.2 Idea Screening....................................................................................... 7
1.4.3 Concept Development.......................................................................... 11
1.4.4 Concept Testing................................................................................... 12
1.4.5 Technical Implementation and Prototype Development..................... 12
1.4.6 Product Development........................................................................... 13
1.4.7 Product Performance Testing/Assessment........................................... 13
1.4.8 Product Commercialisation................................................................. 14
References................................................................................................................. 15
1.1 INTRODUCTION
The pharmaceutical industry is one of the largest, most dynamic and steadily grow-
ing industries. With a cumulative average growth rate of 5.1 per year and estimated
global sales of prescription drugs to cross over a trillion dollars by 2020, it is poised
for a visible rise in its growth trajectory (EvaluatePharma 2014).
The staggering success of this industry is attributed to its ability to offer the most
reliable benefits to society and improve overall public health in terms of life expec-
tancy, quality of life and affordable medical services. An increase in life expectancy
of cancer patients to approximately 83% and a reduction in HIV/AIDS-associated
mortality rate by 85% exemplify these facts reiteratively (PhRMA 2015).
On a macro level, the types of developmental activities performed in the pharma-
ceutical sector can be divided into novel developments, generic (me too) developments,
