Active Pharmaceutical Ingredient Manufacturing

Nondestructive Creation

Girish K. Malhotra

• Publisher: De Gruyter
• Year: 2022
• eBook ISBN: 9783110702897
• Edition: 1
• Topic: Technology & Engineering
• Subtopic: Clinical Chemistry
• Index: Technology & Engineering

The book reviews the history of current brand and generic business in pharmaceuticals manufacturing practices. Based on examples, the reader can interpolate, extrapolate and exploit mutual behavior (physical and chemical properties) of chemicals to design and commercialize processes that fulfi ll the demands, also manipulate chemical unit processes and unit operations to reduce/minimize effl uents and lower environmental impact i.e. reduce global warming. Readers will be able to simplify process development, design and commercialize economic manufacturing processes.

Chapter 1 History of pharmaceuticals

We try to remember that medicine is for the patient. We try never to forget that medicine is for the people. It is not for the profits. The profits follow, and if we have remembered that, they have never failed to appear. The better we have remembered it, the larger they have been.

– George W. Merck Time Magazine August 19, 1952 [1]

1.1 History of pharmaceuticals: their evolution

Going through history, growth and development of the pharmaceutical industry is fascinating from seventeenth century onward. We get to see how various companies will have meaning to history buffs. However, to the current generation, it would be how some companies have appeared and how their names got changed through mergers, demergers, truncations, and change of vision. A short history of some of the companies is presented. Some of the recent mergers (last 5 years) are not included.

1.1.1 Beginning

Different botanical plants were used for remedies of various ailments. Companies started offering soaps, skin care, and distinctive medications for different common diseases. A close look at the companies involved presents an interesting journey. Pharmaceutical industry’s current form really started to take place around late sixteenth and early seventeenth centuries [2, 3, 4]. Wikipedia has been an excellent source of most of the citations. Table 1.1 is a brief compilation of evolution of the pharmaceutical companies. It is difficult to go into the detailed history of each company. The following narrative is an extremely brief summary. Included references are just “tip of the iceberg.” Books can be written about each company’s history.

Tab. 1.1:Pharmaceutical companies from sixteenth century to present.

Company	Current name
Glaxo Smith Kline Beecham Wellcome Research Labs	GlaxoSmithKline
Merck Schering Plough	Merck
Pfizer American Cyanamid (Lederle Labs) Warner Lambert Parke Davis Upjohn Wyeth Pharmacia King Pharmaceuticals Hospira G. D. Searle	Pfizer
Bayer AG	Bayer
Merck KGaA Schering	Merck KGaA
Eli Lilly	Eli Lilly
Abbott Labs	Abbott
	AbbVie
Imperial Chemical Industries (Zeneca) Astra	Astra-Zeneca
Bristol Myers Squibb	Bristol Myers Squibb
Ciba Geigy Sandoz	Novartis
Hoffmann-La Roche	Roche
Johnson & Johnson	Johnson & Johnson
Boots	Walgreens
Boehringer Ingelheim	Boehringer Ingelheim
Sanofi	Sanofi
Aventis
Novo-Nordisk

It is interesting to note that some of these companies got their start as a dye and fine chemical business in the seventeenth century. Researchers found that many of the chemicals could selectively kill bacteria, parasites, and disease-causing microorganisms. With evolution of synthetic organic chemistry, chemists were able to convert many of the coal tar based raw materials to disease curing medicines. Their businesses grew to serve the ever-growing needs of the global population. Development of petroleum-based chemicals, continuous learning, and advances of organic chemistry synthesis facilitated the growth of the pharmaceutical industry. A walk through the major company’s evolution is a fascinating journey and worth a review as it tells us about their roots. One fact that dominates and it is not widely recognized is that a majority of the small-molecule disease-curing compounds (active pharmaceutical ingredients, API) are organic fine and specialty chemicals and their salts that kill disease-causing bacteria. If they did not have a disease-curing value, they could be an additive of some other values.

An important aspect that cannot be forgotten is that the manufacturing practices used in fine/specialty chemicals found use and value for the manufacture of disease-curing molecules. A need to to develop specific manufacturing practices for API was never an issue as these molecules could be easily synthesized in the equipment that was available and used to manufacture other similar organic molecules.

1.1.2 GlaxoSmithKline

Roots of GlaxoSmithKline (GSK) [5] go back to 1873. Joseph Nathan founded a trading company, Joseph Nathan and Co., in New Zealand. Due to excess milk being produced on the dairy farms, it started producing dried milk in 1904 and sold it under the name “Defiance.” They tried to name the product “Lacto” but their trademark was denied. They changed Lacto to Glaxo. It was sold under the slogan “Glaxo builds bonny babies.” Due to vitamin A deficiency, they sold cod liver oil as a supplement. Its first pharmaceutical product was vitamin D. It was extracted from cod liver oil and sold.

Glaxo Laboratories was incorporated as a subsidiary of Joseph Nathan and Co. in the United Kingdom in 1935. However, in 1947 shareholders bought out Joseph Nathan and Co. and reorganized the trading company to make Glaxo, the parent company.

Glaxo acquired Allen & Hanburys [6] in 1958. Glaxo bought Meyer Laboratories in 1978. It expanded its activities in the US market. In 1983, the American arm, Glaxo Inc., moved to Research Triangle Park and Zebulon (US manufacturing) in North Carolina.

Burroughs Wellcome & Company [7] was founded in 1880 in London by the American pharmacists Henry Wellcome and Silas Burroughs. In 1902, the Wellcome Tropical Research Laboratories was established. In the 1920s, Burroughs Wellcome established research and manufacturing facilities in Tuckahoe, New York. It served as the US headquarters until the company moved to Research Triangle Park in North Carolina in 1971. The Nobel Prize-winning scientists Gertrude B. Elion and George H. Hitchings invented drugs such as mercaptopurine [Figure 1.1], which is used for cancer and autoimmune diseases, and are still used many years later.

Fig. 1.1: Mercaptopurine (3,7-dihydropurine-6-...

Table of contents

• Title Page
• Copyright
• Contents
• Preface
• Chapter 1 History of pharmaceuticals
• Chapter 2 Business model: brand versus generics, product demand, process selection, and economics
• Chapter 3 Physical and chemical properties
• Chapter 4 Pharma chemistry/chemical development
• Chapter 5 Manufacturing process development and case studies
• Chapter 6 Active pharmaceutical ingredients (API): innovation, design considerations, and waste reduction
• Chapter 7 Process documentation and operating strategies
• Chapter 8 Road Map
• Index