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Girish K. Malhotra
Active Pharmaceutical Ingredient Manufacturing
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Girish K. Malhotra
Active Pharmaceutical
Ingredient
Manufacturing
Nondestructive Creation
Author
Girish K. Malhotra
EPCOT International
29150 Bryce Road
Pepper Pike
OH 44124-5701
USA
E-Mail: girish@epcotint.com
ISBN 978-3-11-070282-8
e-ISBN (PDF) 978-3-11-070284-2
e-ISBN (EPUB) 978-3-11-070289-7
Library of Congress Control Number: 2022930254
Bibliographic information published by the Deutsche Nationalbibliothek
The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie;
detailed bibliographic data are available on the Internet at http://dnb.dnb.de.
© 2022 Walter de Gruyter GmbH, Berlin/Boston
Cover image: © lvcandy / DigitalVision Vectors / Getty Images
Typesetting: Integra Software Services Pvt. Ltd.
Printing and binding: CPI books GmbH, Leck
www.degruyter.com
To Indu my known and unknown friend for her wisdom and encouragement
Preface
For over 25 years, there has been considerable and at times passionate discussion
about “green chemistry” in chemical-related industries, including pharmaceuticals.
“Climate change” and “ net zero emissions” have become “in vogue.” Onus is on
the industry to innovate and lower emissions and to become green. However, to
make a measurable impact, a significant effort is needed. This has been lacking on
industrial scale, especially in pharmaceutical manufacturing. Universities/academ-
ics and the regulators can talk about these and may show some pathways. Unless
the industry takes the necessary steps to curtail emissions through innovative
manufacturing technologies, the stated goal is unlikely to be achieved.
Regulations have to facilitate and promote incorporati on of novel processes
into the existing practices in order to achieve these goals. However, with the current
regulations, and related costs and delays, the industry is hesitant to engage in such
challenges. For public health and safety concerns, both the regulators and the in-
dustry are also constrained by the current regulations. The regulatory agencies
have to rely on the industry for their claims/assertions. Regulators on their part
have not made any effort to understand the environmental impact of their guide-
lines, for example, if a process produces the desired product using excessive sol-
vent or multiple solvents, the industry cannot change the process unless safety and
efficacy of the product is proven again. For the new products, an effort to minimize
solvent use, that is, emissions, has to be the “mantra” from the onset of the product
development. At present, this is not the case.
Pharma companies have to make sure that the technologies that will reduce
emissions by 75–80% from the current levels are incorporated in practice as soon
as the product efficacy and value are recognized. All of the necessary methods
(chemistries, equipment, and processes) have been in existence and have been
used for the last 75+ years in the fine/specialty chemicals, the older cousin of the
API (active pharmaceutical ingredients), and in their formulations. Pharmaceuticals
have not explored and/or adopted many of the available options. Deterrents include
speed to market, profitability, and complexity of regulations. These have prevented
widespread incorporation of better and innovative technologies. Each improvement
in the existing process has to be proven to the regulatory agencies. Companies have
to make sure that the efficacy and performance are not compromised. This process
is expensive and results in delays resulting in lower profits. In addition, lack of under-
standing by the regulators also stands in the way of any improvement of manufactur-
ing processes. The necessary methods/equipment that can significantly lower the
emissions exist and they are practiced by fine/specialty chemicals. Pharma companies
have simply overlooked them.
According to the 2006 Nobel laureate Edmund Phelps, “nondestructive creation”
leads to innovation. This methodology involves alternate ways to apply existing
methods and teachings to simplify the current practices. Since all of the necessary
https://doi.org/10.1515/9783110702842-202
elements that are needed for API manufacturing technology innovation still exist and
are practiced, their incorporation should not be difficult. However, distinctive think-
ing and divergent execution would be required. Chemists and chemical engineers are
familiar with such challenges and have all the tools to apply them. Peter Drucker has
said it rightly that “Innovation can be systematically managed – if one knows where
to look.” However, lack of their application in API manufacturing is startling.
Around Thanksgiving 2019, Mr. Robert Esposito suggested to me to write a
book about pharmaceutical manufacturing. Sometimes good things fall in your lap.
The goal, starting from API manufacturing and their dosage, was narrowed just to
API manufacturing.
Considering the issue of “climate change and global warming,” timing for the
book could not have been any better. The environmental impact of API manufactur-
ing practices is not acknowledged widely. They contribute the highest per kilo of
the product in the chemical manufacturing world. The year 2020 rolled around and
the writing started. Global rumbling of an infectious disease was getting louder. In
mid-March 2020, the world spun but its inhabitants and their activities came to a
screeching halt. With the lockdown, writing became a challenge as references were
not easily accessible. Libraries were shut down. However, most of the scientific
journals could not and would not let the distribution of knowledge to come to
standstill. When Internet became accessible few years ago, we were impressed by
what all it offered. With pandemic, Internet came to bat for all of us. It was the best
blessing. Online access was offered and the world benefited immensely. Thanks to
the “nondestructive creationists” who created the Internet for your vision, creativ-
ity, and imagination. We all benefitted and far exceeded the challenge posed. Cuya-
hoga County Library and the affiliated library systems and others who are my
“nondestructive creationists” were a godsend. Again, thanks to all who helped in
their own ways.
Chapters review the history and evolution of the API manufacturing and how,
in spite of the technological progress, it is still stuck in the stone age. History indi-
cates that the methodologies used for fine/specialty chemical manufacture in the
first half of twentieth century are still being used today. Methodologies to move it
to the contemporary time are reviewed. They are not earthshakingly complex.
These methods do not call for any alternate science or engineering but their appli-
cation can nondestructively create excellent processes that significantly reduce cur-
rent environmental emissions. They could even convert batch manufacturing of
many products to continuous processes that are inherently more profitable and pro-
duce products of higher quality. Lowering emissions from API emissions and their
formulations will come from “reimagining” chemical engineering fundamentals
that involve physical and chemical properties of chemicals, and their mutual be-
havior along with the equipment use. It requires exploiting social and mutual be-
havior of chemicals. Unit processes and unit operations used would be the same
but their scale could be different from fin e/specialty chemical practi ces. Scale
VIII Preface
would be different. Every which way method/s and some may look like repeats are
reviewed and options discussed. Chemists and chemical engineers have the creativity
and imagination to incorporate these for the chemistries and processes they develop.
It is expected that the reviewed possibilities will invigorate creativity and imag-
ination of chemists and chemical engineers leading to processes that will have sig-
nificantly lower emissions and carbon footprint. It i s very possible that many
products could be produced using continuous processes further lowering emissions.
Most of the regulators do not have hands-on experience of process development, de-
sign, and commercialization, and will have to facilitate innovation. Regulations and
filing processes may have to be modified.
Guidance and help came from unexpected sources. Most of them provided intel-
lectual conversations and that helped me a lot. These conversations planted ideas
that were filed and polished. Dr. Richard Thomas, Dr. Charles E. Kausch, Mr. James
Burton, Dr. Satish Kalhan, MD, and my colleagues at regulatory bodies and the con-
sulting companies offered their counsel and conversation. Due to confidentiality of
the relationships, they are not named here but are acknowledged – they know it.
Dr. Yusuf K. Hamied of Cipla offered conversation time and suggestions. Thanks to
you all.
Drs. Thomas and Kausch, Mr. Lawrence Coven along with my wife Dr. Indu Mal-
hotra proofread, the hardest task, as they have to imagine the writing. They had
their respective input and facilitated the task. I am really grateful. Our family and
friends endured and I am indebted. I gratefully acknowledge Dr. Karin Sora, Vice
President of Science, Technology, Engineering & Mathematics (STEM). Dr. Ria Seng-
busch, project editor for chemistry and materials sciences, needs special thanks for
her suggestions, guidance, and edits to produce and publish this book. Ms. Tharani
Ramachandran, proj ect manager at Integra made this possible. Thanks to you all
and cheers!
Girish K. Malhotra, PE
Friday January 28, 2022
Preface IX
Contents
Preface VII
Chapter 1
History of pharmaceuticals 1
1.1 History of pharmaceuticals: their evolution 1
1.1.1 Beginning 1
1.1.2 GlaxoSmithKline 2
1.1.3 Merck and Merck KGaA 4
1.1.3.1 Merck 6
1.1.4 Pfizer 7
1.1.5 Warner Lambert 8
1.1.6 Parke, Davis 9
1.1.7 Upjohn 9
1.1.8 Bayer AG 10
1.1.9 Eli Lilly 13
1.1.10 Abbott 14
1.1.11 Imperial Chemical Industries (ICI) and AstraZeneca 15
1.1.12 Bristol Myers Squibb 16
1.1.13 E. R. Squibb 16
1.1.14 Novartis, Ciba Geigy, Sandoz 17
1.1.14.1 Ciba 17
1.1.14.2 Geigy 17
1.1.14.3 Sandoz 18
1.1.14.4 Novartis 19
1.1.15 Roche 19
1.1.16 Johnson & Johnson 20
1.1.17 Boots 20
1.1.18 Boehringer Ingelheim 21
1.1.19 Sanofi 21
1.1.20 Aventis 21
1.1.21 Novo-Nordisk 22
1.1.21.1 Novo Industri A/S 22
1.1.21.2 Nordisk Gentofte A/S 22
1.1.22 Other companies 23
1.2 Second half of twentieth century and generic pharma
companies 23
1.3 IG Farben’s contribution 24
1.3.1 Sontochin 25
1.3.1.1 Preparation of sontochin, resochin, and brachysan 25
1.3.2 Salicylic acid 29
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