Pharmaceutical Manufacturing in America: a Brief History

Pharmaceutical Manufacturing in America: A Brief History

by Arthur Daemmrich*

Abstract: This article reviews the history of drug manufacturing and changes in the compounding of drugs by pharmacies in the United States and outlines opportunities for new research into the making of medicines. The pharmaceutical industry has long been on the vanguard of globalization, and drug companies restructured their international manufacturing footprints frequently in the 19th and 20th centuries. Firms in the prescription drug sector were among the first to market products internationally, to build manufacturing plants around the world, and to integrate research from laboratories across multiple time zones. Yet, issues of quality and safety have arisen repeatedly and the industry has continued to produce its newest medicines in North America even as technological capabilities increased significantly in China, India, and elsewhere since the 1980s. Compounding pharmacies, by contrast, experienced a steady decline during the second half of the 20th century as medicines arrived from producers in final form. The emergence of individualized therapies, however, is now bringing a resurgence in business for biological labs acting in many ways as compounders. Broadly, as pharmaceutical firms turned to a business model built around research and intellectual property production, and as pharmacists shifted from producing medicines to repackaging them for patients, analysts likewise turned to regulation, pricing, and new product innovation as subjects of their research. As a consequence, pharmaceutical manufacturing is largely ignored in the recent historiography of medicine, pharmacy, and pharmaceuticals, an oversight that should be rectified.

Introduction countries, while biotech-based medicines were produced in the United States and Europe. Pharmaceutical firms known today for their In the meantime, the majority of pharma- new drug innovation and worldwide marketing cies experienced a sharp decline in the need for largely grew out of nineteenth-century pharma- drug compounding even as they grew into national cies and chemical manufacturers. On the leading chains between the 1950s and early 2000s. The re- edge of globalization, these companies expanded cent emergence of personalized medicine, typically production around the world between the 1890s involving treatments customized based on a pa- and 1910s, rebuilt in the interwar period, and then tient’s specific cancer or immunological disorder, grew internationally again after World War II. By is sparking new demand for the services of com- the 1990s, manufacturing was highly specialized pounding pharmacies and biotechnology laborato- and involved complex production chains that of- ries. Furthermore, a new wave of concern regard- ten spanned multiple countries. Small molecule ing product quality and counterfeit drugs suggests chemicals, including both generics and active in- that writing an obituary for drug manufacturing in gredients for branded drugs, were typically made the United States is premature. in facilities in China, India, or other developing Published in 1965, Glenn Sonnedecker’s “The Rise of Drug Manufacture in America” of- * Director, Lemelson Center for the Study of Invention and In- novation, Smithsonian Institution, Washington, D.C., email: fers an intriguing snapshot against which to [email protected]. consider subsequent changes to pharmacies

Vol. 59 (2017) No. 3 www.aihp.org 63 and the pharmaceutical industry.1 In the article, drawn instead to the arenas of medicinal inno- Sonnedecker captured the sector’s history from vation, human clinical trials, and marketing.7 nineteenth-century apothecary to a modern in- This article begins with an overview of dustry, with manufacturing at the center of its Sonnedecker’s 1965 work and then brings the identity. Written just three years after the major history up to the present by outlining changes regulatory intervention of the 1962 Kefauver- in the manufacture of drugs in America. I find Harris Drug Amendments, Sonnedecker’s es- that the pharmaceutical industry offers a key lo- say in retrospect marked the end of an era for cus for issues of interest to historians of science, compounding pharmacies and the beginning of technology, and medicine as well as to contem- a shift in the industry away from its manufactur- porary policy analysts regarding manufacturing roots. While firms had established research ing more generally. The article concludes with laboratories starting in the early 1900s (and thoughts concerning ongoing tensions in the on- had chemistry labs to test compounds and oc- tological status of the pharmaceutical industry, casionally synthesize new ones some decades an important issue raised somewhat cryptically before), they retained strong manufacturing at the end of Sonnedecker’s article. identities through the 1950s.2 Similarly, while chain pharmacies enjoyed tremendous growth after WWII thanks to sales of prescription drugs Origins and Growth of pre-supplied in pill or tablet form, compounding of medicines remained at the core of their busi- American Drug Manufacturing ness when Sonnedecker wrote his article.3 Both Sonnedecker begins his review with an would change significantly after the mid-1960s.4 intriguing observation concerning both individ- Taking Sonnedecker’s essay as a point of ual and collective (i.e., public health) reliance departure, this article advances a long-range on a “remote industrial complex” that produced history to the pharmaceutical industry’s manu- drugs and medical supplies.8 Treatments that facturing function, with attention also to shifts were historically manufactured or compounded in pharmacies as sites for compounding drugs. locally by a physician or pharmacist were pro- While critical of linear path innovation narra- duced and packaged at a distance by the mid- tives, most recent scholarship nevertheless gives 1960s. Sonnedecker suggests that discomfort dominance to the laboratory and clinic while with this distance was greater than for other underplaying manufacturing. The production of industries; thus even though food was bought medicines is not seen as a place of change over packaged from stores in the 1960s, consumers time or of strategic significance to the industry. maintained some proximity to farms and could Furthermore, few studies connect pharmacy and see the original source of what they were buy- pharmaceuticals as historians like Sonnedecker ing. The claim is an intriguing one; Americans and others had done for decades.5 had bought medicines from Europe and Asia Instead, historians and economists are since colonial times and national marketing examining success or failure with drug dis- of both patent drugs and legitimate medicines covery, clinical trials, marketing, and merg- had separated consumers from the animal, ers to explain the longevity or brevity of indi- plant, or mineral origins of therapeutics since vidual firms.6 For the pharmaceutical industry at least the 1880s. But Sonnedecker was correct writ large, scholars are tracking the industry’s to observe that further distancing patients from strategic shifts when examining knowledge where the ingredients in their prescription production, information management, and medicines were sourced, and who had com- advertising and marketing. As a result, manu- pounded them, was impacting public trust. facturing has been ignored as a potential con- From the early colonial period through tributor to innovation or as a source of com- the mid-nineteenth century, limited medical petitive advantage. Even though the business supplies and the vagaries of shipping constrict- of pharmaceutical firms has been aptly char- ed American pharmacy. Native therapies were acterized as “the manufacture and processing adopted and adapted into folk treatments and of raw materials into medicines,” historians of Americans living and working on large farms in science, technology, and medicine have been the south or on the frontier often had a medi-

64 www.aihp.org Pharmacy in History cine chest with powdered and dried materi- seeking to understand both treatment practices als that they mixed themselves using recipes and changes over time to therapeutics, reveal provided with the kit. A variety of texts sup- a rough balance among botanical medicines, ported home remedies, ranging from practical chemical drugs, and preparations ready to use folk narrative to exotic suggestions. For urban (tinctures and plasters). Superstitious remedies residents, apothecaries grew up in the heart of found in sixteenth-century and seventeenth- cities like Boston, New York, and Philadelphia. century medicine kits were no longer common Some, for example, Smith, Kline & French in by the 1770s. However, concerns about varia- Philadelphia, later grew from small communi- tion in kits, worries about the compounding of ty pharmacies into manufacturers of pills and drugs on the American frontier, and the desire then began doing research into new medicines of pharmacists and the nascent pharmaceutical in the early twentieth century. industry to demonstrate independence from Eu- The Revolutionary War impacted drug rope spurred the development of the first United imports for several years and stimulated do- States Pharmacopeia, published in 1820.9 mestic production in larger pharmacies. The Yet, while some pharmacies turned into Continental Congress even set up a manufac- manufacturing laboratories and later into mul- turing laboratory under an Apothecary General. tinational drug companies, mechanizaion slowly Medicine chests, a useful source for historians impacted their business. Thus, as the industrial

A typical eighteenth-century medicine chest, which were sold widely for use at home and while traveling. Photograph courtesy of the Smithsonian National Museum of American History (M-06371).

Vol. 59 (2017) No. 3 www.aihp.org 65 revolution unfolded in Britain in the eighteenth World War II and Post-War Growth century and in the United States in the mid- nineteenth century, machine power had modest The interwar period saw a gradual increase impact on the more “delicate and varied hand in international trade and steady growth for U.S. operations required to make drugs,” in pharma- manufacturers, but as the economy endured the cies in Philadelphia, Boston, and elsewhere in shock of the Great Depression, drug production the country.10 Sonnedecker describes Ellis and also slowed. World War II, however, brought Morris, a Philadelphia pharmacy, and the drug about a major transformation for the U.S. phar- producer Squibb as gradually moving into fac- maceutical industry, especially following inno- tories and employing steam-driven stirring and vations in deep tank fermentation for the pro- grinding machines in the 1850s and 1860s. Drug duction of antibiotics. A wartime project to test, manufacturers remained small operations, with mass-produce, and ultimately distribute penicil- only 20 to 30 employees. lin to soldiers on the front featured collaboration The late nineeteenth century brought among government officials, pharmaceutical more significant changes to pharmaceutical pro- firms, and academic researchers. Coordinated duction. Handicraft methods for the extraction by the U.S. government, specifically the War and concentration of active substances and their Production Board, the initiative involved other- combination with inert materials into pills were wise competing firms sharing production knowl- replaced by new equipment. Interestingly, much edge gained as they moved from petri dishes to of it was repurposed or modified from the bak- shallow flasks to deep-tank fermentation.14 As ing industry (mixers), laundries (centrifugal ma- the price of penicillin dropped after WWII, com- chinery), confectionaries (sugar coatings), liquor panied developed accelerated research projects producers (distillation) and the paint and pig- and found dozens of new medicines, produced ment industry (tube-filling). Just as pin-making through the same fermentation processes. machines significantly increased output for an Beyond the booming postwar antibiotic industry once characterized by craft skill, medi- market, a new generation of psycho-pharma- cines production jumped from 5,000 pills per ceuticals moved quickly from invention to mass- day when made by humans to two million per markets. The marketing of meprobamate as machine in a factory process.11 Miltown by Wallace Laboratories (a division of Even though U.S. firms started to hire sci- Carter Products) and as Equanil by Wyeth start- entists from the 1890s on, first in quality control ing in 1955 signaled the start of an era of treat- and then to carry out research into new chemi- ing less severe mental and emotional conditions cal therapies, German dominance in synthetic among significantly larger patient populations. organic chemistry meant that both intermedi- Medicines were newly available to treat not just ates and so-called “finished medicinals” were major psychiatric disorders, but also for use by largely imported.12 World War I blockades the general public with issues of anxiety and forced American chemists to replicate German stress. Physicians drawing on the newly stan- processes for producing drugs such as aspirin, dardized terminology advanced by the Ameri- the antimicrobial salvarsan, and barbital, a pow- can Psychiatric Association could differentiate erful hypnotic useful in easing the pain of battle between psychotic disorders (e.g., schizophre- wounds, among others. American pharmaceuti- nia) and milder psychoneurotic disorders (e.g., cal manufacturing also benefitted tremendously anxiety).15 Miltown quickly became iconic in from the expropriation of German patents. The American life; within months of its market in- U.S. Alien Property Custodian assigned Ger- troduction it was the best-selling drug in the man company held patents to a newly created country and by 1957, one-third of all prescrip- “Chemical Foundation,” which in turn offered tions were for Miltown or Equanil.16 nonexclusive licenses to any firm qualified to International opportunities for the indus- produce the medicines.13 try became apparent gradually in the late 1940s

66 www.aihp.org Pharmacy in History and save customers money, state governments intervened with anti-substitution laws (44 states prohibited the practice by 1959).18 Doctors’ prescriptions were to be filled as written and physicians had sole authority over the choice of medicine. As a result, pharmaceutical firms were separated from direct contact with patients. Physicians acted as authoritative intermediaries, making the collection of data about patients’ ex- periences with drugs, whether positive or nega- tive, subject to their control and oversight.

Knowledge Management Firms From the mid-1960s on, business analysts and pharmaceutical industry leaders began to de-emphasize manufacturing. For example, after John J. Powers assumed the presidency of Pfizer in 1965, he invited the respected management consultant Peter Drucker to evaluate the company’s structure and approach. Drucker concluded that “Pfizer acted like a classic manufacturer,” and he advised the firm, “What you are making and selling is knowledge, and manufacturing is Deep tank fermentation, seen here at Abbott Labo- incidental.”19 Firms across the industry began to ratories in the 1940s, revolutionized the manu- see themselves as in the drug discovery business. facture of antibiotics. Photograph Courtesy of the At the same time, pharmaceutical research Kremers Reference Files [P39(g)]. came to be understood as high risk, especially as new rules for clinical trials took hold in the and then in an accelerating fashion after the mid- late 1960s. One strategy followed by many firms 1950s. Production capacity for both antibiotics involved diversification into a variety of con- (deep-tank fermentation processes) and synthetic sumer health products, including cosmetics, oral organic chemicals (multi-stage industrial synthe- health, and others. When questioned, company sis) and manufacturing know-how enabled firms leaders often suggested there were efficiencies to set up plants in Europe and newly independent of scale in manufacturing that would cut across nations across the developing world. Drug pro- prescription and non-prescription products, ducers also could draw on a boom in academic or that their expertise in core chemistry would chemistry and the ready availability of a new gen- pay dividends.20 These approaches faded in the eration of chemical engineers, both in the United 1990s as firms found the prescription drug mar- States and internationally. ket significantly more profitable than commod- Developments in pharmaceutical manu- ity chemicals or over-the-counter products and facturing and packaging meant that physicians little cross-fertilization occurred in either re- could prescribe branded end dosage forms for search or manufacturing. most ailments by the early 1950s. The percent- Regulatory oversight of drug manufac- age of prescriptions that required compound- turing intensified after the late 1970s. The U.S. ing by pharmacists declined from 75 percent in Food and Drug Administration (FDA) had long 1930 to 25 percent in 1950 and fell further to overseen biologicals, largely through certifica- only 4 percent by 1960.17 tion of antibiotics and certain other treatments. When pharmacists began to substitute However, the introduction of Good Manufac- generic drugs for branded prescriptions in the turing Practices (GMPs) through rules govern- early 1950s in an effort to reduce inventory costs ing drugs (and medical devices) in 1978 set new

Vol. 59 (2017) No. 3 www.aihp.org 67 standards across the industry.21 Specifically, regulations for all over-the-counter human drug the regulations outlined methods for process- products (incorporated into GMPs). In addition, ing, packaging, storing, and shipping drugs that the U.S. Congress passed the Federal Anti-Tam- company employees were required to follow. Fa- pering Act in 1983, making it a crime to tamper cilities were also regulated to specify standards with packaged consumer products. Broadly, the for cleanliness, approaches to recordkeeping, acetaminophen tragedy had an impact across and even the kinds of equipment that could be the pharmaceutical industry as capsules were used to make medicines.22 replaced by tablets. Johnson & Johnson’s rapid One year after GMP rules were finalized, response and strong public communication later the FDA issued policies for Good Laboratory became a case study in corporate communica- Practices (GLPs). The GLP rules initially target- tion and ethical management.24 ed the production of medicines for experimen- In 1986, the heartburn and peptic ulcer tal uses, but would eventually have an impact drug cimetidine (Tagamet) was the first pre- also on personalized (or “precision”) medicine scription drug to generate $1 billion in sales in when it emerged in the early 2000s. GLP rules a single year. Labeled a “blockbuster,” it came specified recordkeeping methods, approaches at a time of rapid growth for the pharmaceu- to sterility and cleanliness, and other dimen- tical industry as prescription drug prices and sions of laboratory work to ensure the safety of sales volumes increased rapidly year-on-year.25 drugs manufactured in small batches, typically With the promised gains from portfolio diver- for clinical research studies. They also covered sification not materializing, pharmaceutical the production of food and color additives, ani- firms sold off their non-prescription drug busi- mal food additives, medical devices for human nesses and engaged in a series of mergers dur- use, and more recently, electronic products.23 ing the 1990s and 2000s. Although challenging Furthermore, the law provided for a sys- to quantify considering the large number of tem of pre- and post-market oversight, includ- confounding variables, some economists found ing FDA inspections, to ensure that companies that the mergers contributed to an innovation follow GMPs, keep appropriate records on the decline across the industry, indicating that it design and manufacture of their products, and was a self-defeating strategy.26 maintain systems for handling complaints. While designed with industry input, rules for Good Manufacturing Practices also locked in Biotechnology and Individualized production to highly specified procedures and Therapies Made in America equipment. Unlike in other sectors, pharmaceutical firms committed to specific manufacturing The targeted creation of genetically modi- approaches and changes, which, even if they fied organisms moved quickly from a labora- saved money or reduced waste, involved addi- tory technique in the mid-1970s to the basis tional regulatory review. for a wave of new biotechnology firms by the In October 1982, a tragic wave of seven early 1980s. Promising not only cures for can- deaths arose from criminal tampering with over- cer and immune disorders, but also a new way the-counter Extra-Strength Tylenol. Once the of conducting research and manufacturing link was established, the manufacturer John- pharmaceuticals, first hundreds and eventu- son & Johnson announced a nationwide recall ally thousands of new biotechnology firms were encompassing some 31 million bottles of the started in the United States.27 Interestingly, the product, and halted all sales for over six months. industry eventually stabilized at between 350- The cost to the company was later estimated 450 publicly traded and approximately 2,000 at over $100 million for the recall and subse- private biotechnology companies in any given quent relaunch of the pain medication. When year from 2010-2016. relaunched, the product featured three security Even as biotech expanded the manufac- layers, namely a glued box, a plastic seal over turing portfolio of the pharmaceutical industry, the neck of the bottle, and a foil seal over the firms took advantage of lowered trade tariffs bottle’s mouth. Regulatory responses included and expanded technical capacity in India and new FDA-issued tamper-resistant packaging China to import ever more active pharmaceu-

68 www.aihp.org Pharmacy in History panies to advance new therapies through the clinical trial process before acquiring them.30 In some cases, small biotech companies developed drugs that gained FDA approval and then built out manufacturing and marketing capabilities; in effect, joining the ranks of the more established pharmaceutical industry. Although compounding pharmacies had all but disappeared from public or even regulatory awareness by the early 2010s, a tragic case of tainted medicines brought them back into the limelight. The owner and head pharmacist of the New England Compounding Center was later found responsible for fungal contamination of spinal steroid injections that were distributed to 75 facilities in 23 states. Out of 14,000 patients, there were 48 fatalities and some 720 persistent infections that needed lengthy treatment. In- spectors found an unclean and unsanitary facility with standing water and mold and bacteria on worker’s gloves. Reporters covering the story were surprised to learn that compounding pharmacies were only subject to state licensing and inspections not to FDA regulation.31 Starting in the late 1990s, a new wave of entrepreneurs and scientists began to anticipate a future of personalized medicine, also termed precision medicine. Even as the definition of personalized medicine shifted rapidly in its early years, some critics warned it was overpromis- ing and under-delivering. Yet, the first medicine This fermenter was used at Genentech during the widely hailed as a personalized therapy was ap- early 1980s to grow recombinant bacteria from proved by the FDA in May 2017. Merck’s pem- which proteins were extracted to be used in medi- brolizumab (Keytruda) was approved for the cines. Photograph courtesy of the Smithsonian Na- treatment of tumors that express one of two bio- tional Museum of American History (2012.0198.01). markers, regardless of where in the body the tumors are located. The decision marked the first tical ingredients. As a result, the United States time FDA approved a cancer drug based on the shifted from a net exporter to importer of phar- expression of specific biomarkers, rather than maceuticals in 1997.28 Nevertheless, global bio- the tumor’s location in the body. tech drug research and production remained Emerging personalized medicine treat- centered in the United States, where investors ments hold tremendous promise to target at- continued to optimistically fund new firms and tacks on cancers or potentially heal the im- pricing remained unregulated. mune system. Their production, however, Large pharmaceutical firms adopted di- requires remarkably sophisticated controls, verse strategies in dealing with, or ignoring, the since any stray proteins or other contaminants, biotech industry. Some firms drew on their lin- even at a part per million level, can cause fatal eages in antibiotics and other biological-based allergic reactions. As a result, GLP regulations research to develop new manufacturing capa- have gained in salience in addition to the GMP bilities.29 For these firms, research alliances and rules; both were revised numerous times in the joint ventures drew on new in-house expertise. 1990s and 2000s. Yet personalized drugs fall Other large firms opted to wait for biotech com- under the umbrella of drug compounding, with

Vol. 59 (2017) No. 3 www.aihp.org 69 small-scale production of medicines by a small duction of early antibiotics could iterate and in- number of laboratory scientists and specialized novate in manufacturing, a mix of regulations, pharmacists. In 2013, the Drug Quality and standards, and strict separation of expertise Security Act (H.R. 3204) moved oversight for changed this dynamic from the 1960s onward. compounding labs from the state level to the Only after products were synthesized and had FDA in response to fatalities and other adverse undergone testing to meet regulatory controls reactions from contaminated compounded did management give consideration to manu- drugs. The FDA’s proposed rules for oversight facturing methods. Manufacturing expanded in were available as “draft guidance” starting in the 1980s and 1990s to adopt new approaches January 2017. Yet, the costs of individualized to biotechnology. Analogous to deep-tank fer- or precision drugs are proving extremely chal- mentation of antibiotics in the 1940s and 1950s lenging for health insurers and patients; the (a method that continues to be used with mod- 50 “targeted” therapies holding FDA approval est changes), new bio-based molecules are now in 2017 were priced between $70,000 and produced in pristine stainless-steel vats, with $130,000 per treatment cycle.32 precise temperature and pressure controls. But emerging approaches to individualized therapies Conclusion for certain forms of cancer–the leading edge of The pharmaceutical industry, Sonnedeck- what may become a broader approach to per- er notes, is a “complex industrial organism”; sonalized medicine–now involve a diverse set of it serves a public purpose when inventing and research, laboratory, and manufacturing exper- manufacturing medicines, but does so in a quest tise in the production of a therapy. for profits and financial returns. Its fundamen- Sonnedecker’s final sentence in a biblio- tal reason for existence, to Sonnedecker, is clear: graphic addendum noted the absence of a “sys- “public health.”33 Whether it fulfills that purpose tematic definitive history of drug manufacture in is a frequent topic of policy dispute in settings America.”34 While no such comprehensive vol- ranging from congressional hearings to street ume has been written since, it would be an im- protests. When outcomes align, there are mea- portant undertaking, especially considering that surable gains in longevity and quality of life for the invention and manufacture of therapeutic millions of people. But incentives are also strong drugs in the United States remains strong, even to convince physicians to write prescriptions by as many other industries shifted production and any means possible, to downplay or ignore ad- even new product research overseas. Sonnedeck- verse reactions, and to focus on diseases impact- er concluded, almost wistfully, “A century ago… ing wealthier people while ignoring those affect- a drug manufacturer understood that his work ing people in poorer regions. was to manufacture, without becoming entan- Under the innovation model that has held gled with unpredictable, often unproductive, but across the pharmaceutical industry for the past always costly, scientific experiments.”35 Had the fifty years, manufacturing has become com- industry not become research-intensive it like- pletely cut off from research and product de- ly would not have survived. At the same time, velopment. Whereas pharmacists who made building a firm around intellectual property medicines in the nineteenth and early twentieth has also proven a challenge, not least for the century and scientists who engaged in the pro- public policy implications.

70 www.aihp.org Pharmacy in History Sprawling manufacturing plants like this E. R. Squibb & Sons facility in New Brunswick, New Jersey (seen here in 1958), helped to supply mass-market pharmaceuticals after World War Two. Photograph courtesy of AIHP Drug Topics Collection.

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Vol. 59 (2017) No. 3 www.aihp.org 71 7. Quoted from Judy Slinn, “The Development of 19. Samuel Mines, Pfizer: An Informal History (New the Pharmaceutical Industry,” in Anderson, ed., York: Pfizer, 1978), 227-229. Making Medicines: A Brief History of Pharmacy 20. Charles Hill and Gary S. Hansen, “A Longitudinal and Pharmaceuticals (Chicago: Pharmaceutical Study of the Cause and Consequences of Changes in Press, 2005), 177-201; see also Jeremy Greene and Diversification in the US Pharmaceutical Industry, Elizabeth Siegel Watkins, eds., Prescribed: Writ- 1977–1986,” Strategic Management Journal 12 ing, Filling, Using, and Abusing the Prescription (1991): 187-199. in Modern America. (Baltimore: Johns Hopkins 21. 21 Code of Federal Regulations parts 210 and 211. University Press, 2012). 22. World Health Organization, Quality Assurance of 8. Sonnedecker, “Rise of Drug Manufacture,” (n.1), 1. Pharmaceuticals: A Compendium of Guidelines 9. Edward Kremers and Glenn Sonnedecker, Kremers and Related Materials (Geneva: World Health and Urdang’s History of Pharmacy (Madison, Wis.: Organization, 2007). American Institute of the History of Pharmacy, 1986). 23. 21 Code of Federal Regulations part 58. 10. Sonnedecker, “Rise of Drug Manufacture,” (n. 1), 4. 24. Dieudonnee Ten Berge, The First 24-Hours (Cam- 11. Arthur Daemmrich, “Invention and Employment: bridge, Mass.; Basil Blackwell, 1990); Stephen Grey- Pin-making Machines and Creative Destruction,” ser, “Johnson & Johnson: The Tylenol Tragedy,” Lemelson Center Blog, July 20, 2017, http:// Harvard Business School Case 583-043 (May 1992). invention.si.edu/innovation-and-employment; 25. Jie Jack Li, Blockbuster Drugs: The Rise and Sonnedecker, “Rise of Drug Manufacture,” (n. 1), 8. Decline of the Pharmaceutical Industry (New York: 12. Kathryn Steen, The American Synthetic Organic Oxford University Press, 2014). Chemicals Industry: War and Politics, 1910-1930 26. William S. Comanor and Frederic M. Scherer, “Merg- (Chapel Hill, N.C.: University of North Carolina ers and Innovation in the Pharmaceutical Industry,” Press, 2014). Journal of Health Economics 32 (2013): 106-113. 13. Maurice Moore, “Medicinal Chemistry,” Industrial 27. Robert Teitelman, Gene Dreams: Wall Street, and Engineering Chemistry 43 (1951): 577-588; Academia and the Rise of Biotechnology (New York: and Dale Cooper, “The Licensure of German Drug Basic Books, 1987); Gary Pisano, Science Business: Patents Confiscated During World War I: Federal The Promise, the Reality, and the Future of Biotech and Private Efforts to Maintain Control, Promote (Cambridge, Mass.: Harvard Business Press, 2006). Production, and Protect Public Health,” Pharmacy 28. IHS Global Insight, Tabulations of World Trade in History 54, no. 1 (2012): 3-32. Service (database), 2015. 14. Alfred N. Richards, “Production of Penicillin in the 29. Louis Galambos and Jeffrey L. Sturchio, “Pharma- United States,” Nature 201 (1964): 441-445. ceutical Firms and the Transition to Biotechnology: 15. American Psychiatric Association, Diagnostic and A Study in Strategic Innovation,” Business History Statistical Manual of Mental Disorders (Washing- Review 72 (1988): 250-278. ton, D.C.: American Psychiatric Association, 1952). 30. Haibin Yang, Yanfeng Zheng, and Xia Zhao, “Explo- 16. Carl Elliott, Better than Well: American Medicine ration or Exploitation? Small Firms’ Alliance Strate- Meets the American Dream (New York: Norton, gies with Large Firms.” Strategic Management 2003), 131; Michael C. Gerald, The Drug Book (New Journal 35 (2014): 146-157. York: Sterling, 2013), 282. 31. Derek Hawkins, “Pharmacist at Center of Deadly 17. Greg Higby, “Evolution of Pharmacy,” in Alfonso Meningitis Outbreak gets 9 Years in Prison,” Wash- Gennaro, ed., Remington: The Science and Prac- ington Post June 27, 2017. tice of Pharmacy (Baltimore: Lippincott Publish- 32. Huub Schellekens, et al., “Making Individualized ing, 2000), 7-18. Drugs a Reality,” Nature Biotechnology 35 (June 18. Dominique Tobbell, “Eroding the Physician’s 2017): 507-513. Control of Therapy: The Postwar Politics of the Pre- 33. Sonnedecker, “Rise of Drug Manufacture,” (n. 1), 13. scription,” in Jeremy Greene and Elizabeth Siegel 34. Sonnedecker, “Rise of Drug Manufacture,” (n. 1), 14. Watkins, eds., Prescribed: Writing, Filling, Using and Abusing the Prescription in Modern America 35. Sonnedecker, “Rise of Drug Manufacture,” (n. 1), 12. (Baltimore: Johns Hopkins Press, 2012), 66-90.

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