Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing

By David J. am Ende

This book deals with various unique elements in the drug development process within chemical engineering science and pharmaceutical R&D. The book is intended to be used as a professional reference and potentially as a text book reference in pharmaceutical engineering and pharmaceutical sciences. Many of the experimental methods related to pharmaceutical process development are learned on the job. This book is intended to provide many of those important concepts that R&D Engineers and manufacturing Engineers should know and be familiar if they are going to be successful in the Pharmaceutical Industry. These include basic analytics for quantitation of reaction components– often skipped in ChE Reaction Engineering and kinetics books. In addition Chemical Engineering in the Pharmaceutical Industry introduces contemporary methods of data analysis for kinetic modeling and extends these concepts into Quality by Design strategies for regulatory filings. For the current professionals, in-silico process modeling tools that streamline experimental screening approaches is also new and presented here. Continuous flow processing, although mainstream for ChE, is unique in this context given the range of scales and the complex economics associated with transforming existing batch-plant capacity.

The book will be split into four distinct yet related parts. These parts will address the fundamentals of analytical techniques for engineers, thermodynamic modeling, and finally provides an appendix with common engineering tools and examples of their applications.

• Language: English
• Publisher: Wiley
• Release date: Mar 10, 2011
• ISBN: 9781118088104

Book preview

Part I

Introduction

Chapter 1

Chemical Engineering in the Pharmaceutical Industry: An Introduction

Chemical R&D, Pfizer, Inc., Groton, CT, USA

Although recently several excellent books have been published geared toward process chemistry [1–3] or formulation development in the pharmaceutical industry [4], relatively little has been published specifically with a chemical engineering (ChE) focus. This book, therefore, is about chemical engineering applied to the process research, development, and manufacture of pharmaceuticals. Across the pharmaceutical industry, chemical engineers are employed in R&D through to full-scale manufacturing in technical and management capacities. The following chapters provide an emphasis on the application of chemical engineering science to process development and scale-up for active pharmaceutical ingredients (APIs), drug products (DPs), and biologicals including sections on analytical methods and computational methods. This chapter briefly highlights a few industry facts and figures, in addition to some of the challenges facing the industry, and touches on how ChE can contribute to addressing those challenges. Chapter 2 by Kukura and Thien provides further perspective on the challenges and opportunities in the pharmaceutical industry and the role of chemical engineering.

In general, pharmaceuticals are drug delivery systems in which drug-containing products are designed and manufactured to deliver precise therapeutic responses [5]. The drug is considered the active, that is, active pharmaceutical ingredient, whereas the formulated final drug is simply referred to as the drug product.

In the United States, federal and state laws exist to control the manufacture and distribution of pharmaceuticals. Specifically, the Food and Drug Administration (FDA) exists by the mandate of the U.S. Congress with the Food, Drug & Cosmetics Act as the principal law to enforce and constitutes the basis of the drug approval process [6]. Specifically in the United States, The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health [7].

A review of the structure within the FDA and the drug review process can be found in the cited references [8]. In Europe, the European Agency for the Evaluation of Medicinal Products (EMEA) is a decentralized body of the European Union with headquarters in London whose main responsibility is the protection and promotion of public and animal health, through the evaluation and supervision of medicines for human and veterinary use [9].

According to PhRMA statistics, more than 300 new medicines have been approved in the past 10 years that have contributed to increases in life expectancy. For example, since 1980, life expectancy for cancer patients has increased by about 3 years, and 83% of those gains are attributable to new treatments, including medicines. Death rates for cardiovascular disease fell a dramatic 26.4% between 1999 and 2005 [10]. The value of the biopharmaceutical industry to the American economy is substantial. In 2006, the industry employed over 680,000 people with each job indirectly supporting an additional 3.7 jobs. Thus, as an aggregate, the industry supported 3.2 million jobs in 2006 contributing $88.5 billion in 2006 to the nation's gross domestic product [11]. In terms of the total value that the pharmaceutical sector outputs (sum of the direct value of goods produced, indirect value of goods and services that support the sector, and economic activity induced by the direct/indirect employees), it is estimated to be over $635 billion for 2006 [12].

As an industry, global pharmaceutical sales have steadily increased over the past decade and are now approaching an $800 billion industry based on 2009 revenues. Despite the slowing growth rate over the past decade (Figure 1.1), sales are still expected to grow at 4–7% per year to approach $975 billion by 2013 [13]. This is due, in part, from emerging market countries (China, Brazil, Russia, Mexico, India, Turkey, South Korea) where sales are expected to grow by 13–16% annually over the next 5 years (IMS Health). Amid the uncertainty in long-term growth, as an industry sector, the pharmaceutical industry still ranks near the top of most profitable industries with approximately 19% return on revenues according to Fortune 500 rankings [14]. The top 15 pharmaceutical companies are listed in Table 1.1 according to IMS Health.

Figure 1.1 Top: Global pharmaceutical sales with worldwide pharmaceuticals sales approaching $725 billion for year ending 2008. Bottom: Declining growth rate based on global sales is defined as percentage change in global sales over the previous year. Ref. [15]

Table 1.1 Top 15 Pharmaceutical Corporations in 2008 as Listed by IMS Health [15]

The top 15 global selling drugs are shown in Table 1.2, with Lipitor/atorvastatin topping the list with 2008 global sales of $13.7 billion. The top 15 drugs total nearly $90 billion and comprise approximately 12% of the global market of $724 billion in 2008. Table 1.3 includes some of the top selling small-molecule APIs, including their formulation type and formulation ingredients.

Table 1.2 Top 15 Global Pharmaceutical Products (in 2008)

Table 1.3 Top Selling Marketed Small-Molecule APIs and Dosage Formulations.

With patent expirations and fewer blockbusters on the horizon, the pharmaceutical industry is undergoing a transformation in part through consolidation of drug portfolios via mergers and acquisitions. At the time of this writing, further consolidation of the list in Table 1.1 includes Pfizer's acquiring Wyeth and Merck's acquisition of Schering-Plough in 2009. Patent expirations for branded pharmaceuticals create significant financial exposure to the industry. Specifically, products that generated $137 billion in sales face generic competition from 2009 to 2013 according to IMS Health [15], which represents approximately 17% of current global pharmaceutical sales. In addition, the United States is in the midst of U.S. health care reform (2010). It remains unclear whether the higher volume of prescription drugs that the program intends to ultimately provide coverage for, to the newly insured, will offset the lower price demands and how this will impact the industry as a whole.

Companies in general are broadly looking for ways to reduce costs to offset the exposure of patent expirations, rising generic competition, and current market pressures. The cost of advancing candidates and entire pharmaceutical portfolios in R&D is significant. In 2001, the average cost for an approved medicine was estimated to be $802 million as reported by Tufts Center for the Study of Drug Development. In 2008, the cost of advancing a drug through clinical trials and through FDA approval was estimated to range from $1 billion to $3.5 billion in 2008 dollars [16]. Although these figures clearly depend on the drug type, therapeutic area, and speed of development, the bottom line is that the upfront investments required to reach the market are massive especially when considering the uncertainty whether the upfront investment will pay back.

Given there might be 10 or more years of R&D costs without any revenue generated on a new drug, the gross margins of a successful drug need to cover prior R&D investments as well as cover the continuing marketing and production costs. Figure 1.2 shows the classic cash flow profile for a new drug developed and marketed. First, there is a period of negative cash flow during development. When the drug is approved and launched, only then are revenues generated, and the drug has to be priced high enough to recoup the investment and provide a return on the investment. The net present value (NPV) calculation is one way to assess return on investment; it considers the discounted revenue minus the discounted costs and is computed over the product development and marketing life cycle. These calculations are used to rationalize investment decisions. For example, a minimum threshold product price can be computed for which the NPV calculation hits a desired return on investment target. If this price is sustained by the market, then the investment can be considered viable. A discount rate of 10–12% is generally chosen in the pharmaceutical industry as the rate to which to value products or programs for investment decisions [17]. Patents typically have a validity of 20 years from the earliest application grant date based on applications filed after 1995, so it is in the company's best interest to ensure that the best patent protection strategy is in place to maximize the length of market exclusivity. Related to this is that patents and intellectual property in general need enforcement on a global basis to ensure fair competition and realize benefit in growth into emerging markets.

Figure 1.2 A hypothetical cash flow curve for a pharmaceutical product includes 10–15 years of negative cash flows of typically $1–3 billion. Reasonably high margins are needed, once the drug is on the market, if it is to recoup and provide a positive return on investment (ROI) over its life cycle.

In some cases, time of market exclusivity can be extended through new indications, new formulations, devices, and so on, which are themselves patent protected. Once market exclusivity ends, generic competition is introduced, which will erode sales. It should be noted that independent of patent position or patent exclusivity, the FDA grants new drug product exclusivity (also known as Hatchman–Wax exclusivity) with specific periods of exclusivity. For example, the following key points are quoted from the FDA on the subject of new drug product exclusivity.

Exclusivity provides the holder of an approved new drug application limited protection from new competition in the marketplace for the innovation represented by its approved drug product. A 5-year period of exclusivity is granted to new drug applications for products containing chemical entities never previously approved by FDA either alone or in combination. A 3-year period of exclusivity is granted for a drug product that contains an active moiety that has been previously approved, when the application contains reports of new clinical investigations (other than bioavailability studies) conducted or sponsored by the sponsor that were essential to approval of the application. For example, the changes in an approved drug product that affect its active ingredient(s), strength, dosage form, route of administration or conditions of use may be granted exclusivity if clinical investigations were essential to approval of the application containing those changes. The Center for Drug Research and Evaluation (CDER) makes exclusivity determinations on all relevant applications. There is a procedure in CDER that provides review of all relevant applications, with or without a request from the applicant, for an exclusivity determination [18].

The pharmaceutical industry invested approximately $60 billion into R&D in 2007. It now takes 10–15 years for a new medicine to go from the laboratory to the pharmacy. Figure 1.3 shows the typical development activity timeline from discovery to launch. From thousands of compounds evaluated for potential therapeutic effect, very few will clear all the safety, efficacy, and clinical hurdles to make it to approval. Figure 1.3 also shows how a general range of volunteers, and therefore clinical supplies, increases for clinical development through phases I to II with clinical development lasting 6–7 years. The cost of product development that includes the cost to manufacture clinical supplies is estimated to be in the range of 30–35% of the total cost of bringing a new chemical entity to market with the following breakdown of development costs: discovery 20–25%, safety and toxicity 15–20%, product development 30–35%, and clinical trials 35–40%. The distribution is graphically displayed in Figure 1.4. Clearly, the distribution will depend on the specific drug, its therapeutic area, dose, and specific company [16].

Figure 1.3 Drug research and development can take 10–15 years with one approval from 5 to 10,000 compounds in discovery. IND: investigational new drug; NDA: new drug application. Pharmaceutical Industry Profile 2009, Pharmaceutical Research and Manufacturers of America (PhRMA) (www.phrma.org)

Figure 1.4 Estimated distribution of product development costs within R&D with the total cost to bring a new chemical entity to market in the range of $1–3.5 billion. Ref. [16]

1.1 Pharmaceutical Development

In general, pharmaceutical product development is different from most other research-intensive industries. Specifically in the pharmaceutical industry, there is a consistent need to ensure that clinical supplies are manufactured and delivered in a timely manner regardless of the current state of development or efficiency of the process. In other words, delivering clinical supplies when they are needed requires using technology that is good enough at the time even if it is not a fully optimized process. Further, process development, optimization, and scale-up historically tend to be an iterative approach [19] —clinical supply demands are met by scale-ups to kilo lab or pilot plant through phase I, phase II, and phase III and it is through this period R&D development teams (including chemist/engineers/analysts, referred to as the ACE model) refine, optimize, and understand the API and DP processes to enable them to be eventually transferred to manufacturing. Manufacturing of clinical supplies in kilo lab, pilot plant, solid dosage plants, and so on occurs under the constraints of current good manufacturing practices (cGMP) conditions, which is discussed further in Chapter 22 by Hamm et al. The pilot plant and kilo lab are also sometimes used to test the scalability of a process. In this way, they serve a dual purpose, which make them unique compared to nonpharmaceutical pilot plants. In terms of cost, however, large-scale experimentation in kilo lab or pilot plant can be significant, so there has been a shift toward greater predictability at lab scale to offset the need for pilot plant-scale technology demonstration experiments. Engineers through their training are well versed with scale-up or scale-down processes and can effectively model the chemical and physical behaviors in the lab to ensure success on scale. This helps to reduce the number of larger scale experiments, thereby lowering costs during R&D. In this way, with the recent trend toward increasing efficiency and continuous improvement, the pilot plant and kilo labs are preferentially utilized to manufacture toxicological and clinical supplies rather than being used to test or verify that the chemistry or process will work on scale. This concept of lean manufacturing will be touched on in more detail later in this chapter.

The aim of process development is to drive down the cost contribution of the API to the final formulated pharmaceutical product cost, while at the same time optimizing process robustness. The impact of API costs on overall manufacturing costs is approximated in Figure 1.5. The cost contribution of API is expected to increase with increasing complexity of molecular structures of APIs. It is interesting to note that API molecular complexity can often impact API cost more than formulation or packaging costs. Federsel points out that, Given the importance of ‘time to market’ which remains one of the highest priorities of pharmaceutical companies, the need to meet increasingly stretched targets for speed to best route has come to the forefront in process R&D [20]. Recently, it was considered satisfactory to have a good enough synthetic route that was fit for purpose (i.e., could support the quantities of material needed) but not one having best or lowest cost ($/kg of API). The prevailing view was that the market would bear higher product pricing as compensation for higher cost of goods. Further cost reduction through new routes could be and was pursued post-launch with savings realized later in the life cycle. According to Federsel, and evidenced frequently in contemporary R&D organizations, this approach is no longer viable, at least not as a default position. Instead, the best synthetic route to API (i.e., route with ultimate lowest cost materials) coupled with best process design and engineering (process with lowest processing costs) must be worked out as early as possible in API process development [21]. The best API process developed by the time of launch is necessary to extract additional revenues and respond to reduced cost of goods margins. Achieving this requires continuous improvement in scientific and technical tools as well as multidisciplinary skill sets in the R&D labs, including chemical engineering science. Specific areas of opportunity for engineering are described in more detail in Chapter 2. The implementation of process design principles, drawing on the right skill sets, from both chemistry and engineering perspectives during clinical phase II is considered such an important step toward leaner more cost-effective processes readied for launch that several portions of this book will expand on this concept.

Figure 1.5 Average COG components in final dosage form across a large product portfolio, but for individual drugs this could vary widely (e.g., for API from 5% to 40%). Ref. [19]

1.2 Manufacturing

Pharmaceutical production plants of APIs and drug products can be generally characterized as primarily batch-operated multipurpose manufacturing plants. At these facilities, commercial supplies of API intermediates, APIs, and drug products are manufactured before being packaged, labeled, and distributed to various customers. Pharmaceutical production plants were typically designed to be flexible to allow a number of different products to be run in separate equipment trains, depending on the demand. Further, these facilities have various degrees of automation, relatively high levels of documentation, and change control to manage reconfigurations, with relatively long down times for cleanup and turnover of the plant between product changes [22]. Manufacturing often accounts for more than one-third of a company's human resources and a third of the total costs with expenses exceeding that of R&D [23]. Figure 1.6 shows the major components of revenues based on 2008 annual reports averaged over the 17 pharmaceutical companies shown in Table 1.4. Figure 1.6 shows that the manufacturing costs or costs of goods (COGs) are on average 27% of revenues where R&D represents 17% of revenues. The margin, shown in Figure 1.6, refers to the profit margin at 18%. As an industry with annual sales of over $700 billion, COGs of 27% represent close to $200 billion for the industry. For this reason, COGs have received considerable attention as an area of opportunity for potential savings [24].

Figure 1.6 Distribution of revenue and expenses as a percentage of sales was averaged over 17 major pharmaceutical companies (listed in Table) based on 2008 annual reports.

It has been claimed that through adopting quality by design principles and principles of lean manufacturing, pharmaceutical companies, on average, could save in the range of $20–50 billion/year by eliminating inefficiencies in current manufacturing [25]. This translates to an improvement of 10–25% in reducing current COGs. Another critical factor in API cost determinations is the tax savings provided to companies who manufacture in selected countries. At present, for United States based pharmaceutical companies, significant tax savings are realized by locating production in tax-advantaged locations such as Ireland, Singapore, Puerto Rico, and Switzerland. Manufacturing in tax-advantaged locations can realize tax savings with tax rates of 2–12% versus the U.S. rate of 38% [26], so the cost advantages of any process or operational change need to be carefully determined and location-specific factors taken into consideration.

The principles of lean manufacturing are often cited as an approach to reduce COGs in pharmaceutical development and manufacturing. Lean manufacturing describes a management philosophy concerned with improving profitability through the systematic elimination of activities that contribute to waste; thus, the central theme to lean manufacturing is the elimination of waste where waste is considered the opposite of value. Based on the work of Taiichi Ohno, creator of the Toyota Production System, the following are considered wastes [27]:

Overproduction

Waiting

Transportation

Unnecessary processing

Unnecessary inventory

Unnecessary motion

Defects

All of these wastes have the effect of increasing the proportion of nonvalue-added activities. Lean thinking is obviously applicable to many industries including pharmaceutical manufacturing as well as pharmaceutical development. Continuous processing, for pharmaceutical APIs and DPs, is one application of lean thinking applied to pharmaceutical manufacturing. The challenge that batch processing inherently leads to overproduction (e.g., inventory buildup of intermediates), leading to longer cycle times and excess inventory, is addressed through the concepts of continuous manufacturing.

According to Ohno, The greatest waste of all is excess inventory where in simplest terms excess inventory incurs cost associated with managing, transporting, and storing inventories adding to the waste. Large inventories also tie up large amounts of capital. Implementation of lean manufacturing principles can be used to develop workflows and infrastructures to reduce inventories. One way to reduce inventories is through continuous processing. Chapter 23 by LaPorte et al. discusses the technical benefits of continuous manufacturing. A reliable steady delivery of product API and DP through small product-specific continuous plants could potentially reduce the level of inventory required in a dramatic way if the workflows were designed to ensure consistent delivery of product to packaging and distribution. The facilities of continuous production trains would likely be significantly smaller. Excess inventory represents an opportunity cost where capital is held up in the form of work in process (WIP), API finished goods, and formulated finished goods versus what could be invested elsewhere or back into R&D.

The costs of inventory holdings are significant, including both the carrying cost and the cash value of the inventory. Reductions in inventory equate to a one-time savings of the value of the inventory saved, which represents real savings and positive cash flow. The carrying costs of inventory include two main contributions: (1) weighted average cost of capital (WACC) and (2) overhead [28].

The weighted average cost of capital for the pharmaceutical industry is estimated to be 12% based on 2007 data and overhead costs are approximately 8% [29]. Estimates for the combined carrying cost of WACC and overhead range from 14% to 25%, which translates to approximately 20% return for every dollar of inventory reduction [28, 30]. In addition, every dollar of inventory reduced yields a one-time cash cost savings that can be invested to bolster the company's bottom line, for example, in R&D. Technology platforms and new workflows designed to minimize the need for stockpiling API and DP inventories across the industry therefore would seem to offer very rapid payback.

Figure 1.7 shows the range of inventories for the 17 pharmaceutical companies profiled in Table 1.4. For a large pharmaceutical company carrying $5 billion in inventories, the holding cost based on the combined WACC and overhead of 20% is approximately $1 billion/year. Considered another way, technologies that ensure a reliable and steady distribution of product with the result of eliminating the need to build and store massive inventories can return the company cost savings equivalent to a blockbuster drug (generating billions of dollars per year). Indeed, one of the three factors having the biggest impact on the profitability of a manufacturing organization is inventory with the other two being throughput and operating expense according to Goldratt and Cox [31]. Continuous processing if designed for reliable operations essentially year-round could potentially eliminate the need to accumulate significant inventories above and beyond 2–4 weeks of critical safety stocks of finished goods. Continuous manufacturing across API and DP integrated under one roof as a platform technology is one long-term approach to transforming the way the industry manages their commercial supply chain.

Figure 1.7 Inventory holdings for 17 pharmaceutical companies (numerical details shown in Table 1.4) based on inventories listed in each individual company's 2008 annual report. FG, Raws, and WIP refer to finished goods, starting materials, and work in process, respectively.

Table 1.4 Financial Data from 17 Pharmaceutical Companies Obtained from 2008 Year-End Reports.

One textbook puts it, Even for very small processes, continuous processes will prove to be less expensive in terms of equipment and operating costs. Dedicated continuous processes often put batch processes out of business [32]. The real point here is that continuous manufacturing is one approach to lean manufacturing and to reducing inventories and costs but certainly not the only approach. Other lean systems can be devised that utilize the existing batch facilities as well.

1.3 Summary

With current cost pressures on the pharmaceutical industry, there is an ever-increasing need for chemical engineering skill sets in process development and manufacturing. Chemical engineers are uniquely positioned to help address these needs in part derived from their ability to predict using mathematical models and their understanding of equipment and manufacturability. As Wu et al. highlighted, chemical engineers can help transform pharma from an industry focusing on inventing and testing to a process and product design industry [33]. Significant pressure exists on what historically used to be a high-margin nature of the pharmaceutical industry to deliver safe, environment-friendly, and economic processes in increasingly shorter timelines. This means fewer scale-ups at kilo and pilot plant scales, with expectation that a synthesis or formulation can be designed in the lab to perform as expected (and right the first time) at the desired manufacturing scale.

From R&D through manufacturing within the pharmaceutical industry, chemical engineering can be leveraged to bring competitive advantage to their respective organizations through process and predictive modeling that lead to process understanding, improving speed of development, and developing new technology platforms and leaner manufacturing methods. The chapters in this book are intended to provide examples of chemical engineering principles specifically applied toward relevant problems faced in the pharmaceutical sciences and manufacturing areas. Further, the broader goal of this work is to promote the role of chemical engineering within our industry, promote the breadth of skill sets therein, and showcase the critical synergy between this discipline and many other scientific disciplines that combine to bring pharmaceutical drugs and therapies to patients in need around the world.

Acknowledgments

I would like to thank our chemical engineering co-op students Steven Modzelewski and Jamie Snopkowski from Northeastern University for their assistance in preparing this chapter.

References

1. Abdel-Magid AF, Caron S, editors. Fundamentals of Early Clinical Development, Wiley, 2006.

2. Gadamasetti KG, editor. Process Chemistry in the Pharmaceutical Industry, Marcel Dekker, 1999.

3. Gadamasetti KG, Braish TF, editors. Process Chemistry in the Pharmaceutical Industry, Vol. 2, CRC Press, 2008.

4. Zheng J, editor. Formulation and Analytical Development for Low Dose Oral Drug Products, Wiley, 2009.

5. Janusz Rzeszotarski, W. Pharmaceuticals Kirk-Othmer Encyclopedia of Science and Technology, 2005.

6. Ibid.

7. http://www.fda.gov/AboutFDA/WhatWeDo/default.htm.

8. Janusz Rzeszotarski, W. Pharmaceuticals Kirk-Othmer Encyclopedia of Science and Technology, 2005, http://www.fda.gov/AboutFDA/WhatWeDo/default.htm.

9. http://www.ema.europa.eu/htms/aboutus/emeaoverview.htm.

10. Pharmaceutical Research and Manufacturers of America. Pharmaceutical Industry Profile 2009, PhRMA, Washington, DC, 2009.

11. Ibid.

12. Burns, LR. The Biopharmaceutical Sector's Impact on the U.S. Economy: Analysis at the National, State, and Local Levels, Archstone Consulting, LLC, Washington, DC, 2009.

13. Ainsworth SJ.Timely transformation, C&E News, December 7, 2009, pp. 13– 21.

14. http://money.cnn.com/magazines/fortune/global500/2009/performers/industries/profits/.

15. http://www.imshealth.com.

16. Suresh P, Basu PK. Improving pharmaceutical product development and manufacturing: impact on cost of drug development and cost of goods sold of pharmaceuticals. J. Pharm. Innov. 2008; 3: 175–187.

17. Gregson N, Sparrowhawk K, Mauskopf J, Paul J. Pricing medicines: theory and practice, challenges and opportunities. Nat. Rev. Drug Discov. 2005; 4: 121–130.

18. www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/.

19. Dienemann E, Osifchin R. The role of chemical engineering in process development and optimization. Curr. Opin. Drug Discov. Dev. 2000; 3(6): 690–698.

20. Federsel H-J. In search of sustainability: process R&D in light of current pharmaceutical R&D challenges. Drug Discov. Today 2006; 11 (21–22): 966–974.

21. Ibid.

22. Behr A, Brehme VA, Ewers LJ, Gron H, Kimmel T, Kuppers S, Symietz I. New developments in chemical engineering for the production of drug substances. Eng. Life Sci. 2004; 4(1): 15–24.

23. Burns LR. The Business of Healthcare Innovation, Cambridge University Press.

24. The Gold Sheet, Pharmaceutical & Biotechnology Quality Control, Attention turns to the business case of quality by design, FDC Reports, January 2009.

25. Ibid.

26. Kager P, Williams D. How do you solve a problem like manufacturing? Pharmaceutical Executive, PharmExec.com, September 1, 2008.

27. Ohno T. Toyota Production System Beyond Large Scale Production, Productivity Press, 1988.

28. Cogdil RP, Knight TP, Anderson CA, Drennan JK. The financial returns on investments in process analytical technology and lean manufacturing: benchmarks and case study. J. Pharm. Innov. 2007; 2: 38–50.

29. Ibid.

30. Lewis NA. A tracking tool for lean solid-dose manufacturing. Pharm. Technol. 2006; 30(10): 94–108.

31. Goldratt EM, Cox J. The Goal: A Process for Ongoing Improvement, Gower Publishing, 1984.

32. Biegler LT, et al. Systematic Methods of Chemical Process Design, Prentice Hall, 1997.

33. Wu H, Khan MA, Hussain AS. Process control perspective for process analytical technology: integration of chemical engineering practice into semiconductor and pharmaceutical industries. Chem. Eng. Commun. 2007; 194: 760–779.

Chapter 2

Current Challenges and Opportunities in the Pharmaceutical Industry

Joseph L. Kukura and Michael Paul Thien

Global Science Technology and Commercialization, Merck & Co., Inc.Rahway, NJ, USA

2.1 Introduction

The pharmaceutical industry bases its products, strategies, decisions, actions, and ultimately its very existence on the primary challenge of improving human health and the quality of life. The work of this industry uses a foundation of medical science to connect to the most basic struggle faced by all individuals and societies: the struggle for people to live healthy, productive lives. The industry has partnered with governments, health organizations, and society to achieve key successes in human history, including the eradication of smallpox, innumerable preventions of infection through the large-scale production and distribution of antibiotics such as penicillin, and significant reductions in cardiovascular events. Advances in pharmaceutics have contributed to the lower infant mortality rates and longer life spans observed over the past century. When considering the landscape of the pharmaceutical industry, one must retain the perspective that a challenge or opportunity that relates to the improvement of human health is at the core of challenges and opportunities shared by pharmaceutical companies.

2.2 Industry-Wide Challenges

Just as life and the state of human health often undergo significant changes, the pharmaceutical industry is profoundly changing. Fundamental elements that molded past business models are dynamically moving into new realms in a manner that will challenge the continued vitality of pharmaceutical companies much in the same way that changes in environments can influence the health of people. The parallels between diseases that the industry seeks to address and the pharmaceutical business climate are distinctly apparent. Illnesses such as HIV/AIDS are more complex and evolve at a faster pace than many previous diseases, requiring new approaches and advances. Similarly, economic, societal, and scientific forces are rapidly driving changes to the industry's business models. The forces challenging the industry align into four categories: increased costs and risks; revenue/price constraints; globalization of activities; and increasing complexity of pharmaceutical science.

2.2.1 Increased Costs and Risks

Bringing a new medicine to market involves a long, complex process in a highly regulated industry. Estimating accurate or typical costs for successfully launching new pharmaceutical products is difficult. The estimates are a strong function of the success rates assumed for moving a program through various clinical trial stages. Analysis shows that using different time periods to form assumptions for success rates can lead to variations in estimates of an average cost to launch a pharmaceutical product ranging from $900 million to $1.7 billion [1]. Across the industry, costs are trending upward in a manner that forces business practices to adjust.

Developing new medicines for unmet medical needs always involved significant costs and risks. For every product brought to market, pharmaceutical companies have typically invested in several thousands of compounds during the drug discovery stage, hundreds of compounds in preclinical testing, and many (7–12) unsuccessful clinical trials over a period of 9–15 years, as depicted in Figure 2.1. Though the later stage phase II and phase III clinical trials are performed on the fewest number of compounds, they are also the most costly stages of development since they can require testing hundreds of patients in phase II and thousands in phase III in order to get statistically meaningful results. The cost of developing new medicines is therefore particularly sensitive to success rates of late-stage clinical trials. The industry has generally experienced a recent decline in the fraction of compounds proceeding through phase II and phase III clinical trials to a successful regulatory approval and commercial launch of a new product. This decline translates to expending more resources on programs that do not return value on their investment and greater overall spending on research and development.

Figure 2.1 Number of compounds in research and development for every successful launch of a pharmaceutical product.

The lower clinical trial success rates are due in part from the fact that pharmaceutical companies are attempting to treat more complex therapeutic targets. Many diseases with straightforward cause–effect relationships and less sophisticated biological mechanisms have already been addressed, leaving more challenging and intricate problems for the future. The setbacks and frustrations relating to the development of treatments and vaccines for HIV infection serve as a case in point. Numerous articles and presentations have reported that the HIV virus mutates, adapts, and changes features faster than predecessors that were studied for vaccine development. Similarly, the causes of many forms of cancer being addressed in clinical trials have more complex physiological traits in comparison to successfully treated conditions such as high cholesterol and high blood pressure. Treating more complicated illnesses leads to higher risks for clinical trial evaluations.

The pharmaceutical industry research and development costs are also increasing due to greater regulatory hurdles for getting approval of new medication. Many agencies have raised their requirements for approval in comparison to 5–10 years ago, leading to the need for larger and more comprehensive clinical trials and safety assessment testing. Government health agencies are showing a high level of caution with respect to side effects and risk–benefit assessments. This caution creates a need for outcomes data and in turn longer running trials and longer review periods that can delay introduction of a product to market. A more conservative regulatory approach ultimately forces greater spending on development and testing of new medicines to collect the data needed for the higher standards.

2.2.2 Revenue/Price Constraints

Beyond the challenge of increasing costs, the pharmaceutical industry is also facing constraints to income and product pricing. The patents of large revenue blockbuster drugs are expiring faster than they are being replaced by a comparable portfolio of new highly profitable products. The challenges of addressing more complex therapeutic targets previously described in the context of increasing cost also directly affect revenue in the industry. The greater level of complexity not only makes the research and development process more expensive, but also slows the realization of a return on investment in these areas. Many of these more sophisticated research efforts target a narrower patient base than preceding blockbusters. The largest sources of revenue for the industry over the past 20 years improved conditions that were widespread, such as depression, hypertension, and pain. Far fewer people have conditions that many products currently in development aim to improve, such as specific forms of cancer. With a smaller base of potential patients, these new products can be expected to generate less revenue than broadly used products already on the market.

Another strong influence on pharmaceutical sales relates to the means by which patients pay for medicine. Organizations responsible to pay for prescriptions, the payers such as insurance companies and health maintenance organizations (HMOs), are influencing the medical options for their membership. Pharmaceutical companies used to focus on physician–patient relationships when marketing products, but the decision-making process to select medicine now involves a more complex set of interactions between physicians, patients, and payers. The pharmaceutical industry must engage all three members of this collective to successfully bring products to those who need them. Payers acquired an increasingly important role in this process in the United States through consolidations that have allowed a few groups to represent a larger number of people. Single payers can control access to millions of patients [2]. Payers can exert their influence on the pharmaceutical industry in several ways. They cannot directly specify which medications a patient may use, but they can make copayments paid by patients much higher for some medications relative to others. If a payer wants to provide incentive for patients to request switching from a current treatment to a less expensive generic alternative, they can make the copayment for the generic version $50–100 per month less expensive. Similarly, payers can also choose to reimburse pharmacists at a higher rate for supplying generics and drive policies at pharmacies to favor the generic options.

In addition to consolidation of private payers, other events elevate the importance of payers to the pharmaceutical industry. The U.S. government became effectively the largest payer to the pharmaceutical industry in January 2006 with the implementation of Medicare Part D prescription plan, covering over 39 million people with that plan alone [3]. Even more people will be eligible for coverage benefits in the coming years. If the U.S. government alters its current policy to not negotiate medicine covered by Medicare or reimportation policies, the changes will create significant challenges to the business models of the pharmaceutical industry. The issue is certainly not limited to the United States. The changing demographics of the world will dramatically affect social medicine policies. The patients themselves in the patient–physician–payer relationship are changing in ways that will challenge the business models of the pharmaceutical industries. Across the world, the fraction of people above age 65 is growing as life expectancy increases. Never will the world have had this many people, this old. Along with economically challenged populations in emerging non-Western markets, this increasing fraction of the planet's population will generally have limited income available for health care, but they will have a disproportionally strong demand for pharmaceutical products. Ensuring access to medicine across the globe and across population sectors will require lower prices. The pharmaceutical industry must adapt to meet the needs of these large segments of customers.

Not only are the demographics of patients changing, but their behaviors and approaches to health care are also differing from the past. Survey results show that health care is a diverse consumer market with people seeking greater access to information to make their own choices with respect to health care needs [4]. With technology advances such as the Internet, patients can get more information to play a larger role in selecting treatment options. In some parts of the world, direct advertising to consumers is prevalent, raising new levels of their awareness of options. Patients are also willing to explore innovative techniques or travel outside their area and even their country to find options that best suit their preferences. To face the revenue and price constraints introduced by patients actions to the patient–physician–payer relationship, pharmaceutical companies need to understand the changing manner in which patient behaviors affect market demand and pricing.

2.2.3 Globalization of Activities

To address financial constraints and meet the global demands of emerging markets, the pharmaceutical industry is increasing the activity levels of its business in these regions, moving away from being primarily located and focused in the United States, Europe and Japan. Like many other industries, a greater fraction of manufacturing and research and development is shifting overseas from a Western base to countries such as China and India. Numerous clinical trials are conducted in these regions to achieve cost savings and to more quickly enroll patients who are not already undergoing another therapy. Development activities such as medicinal chemistry and process scale-up are being performed there as well, leading to an expansion of sophisticated laboratories in these countries. Manufacturing is becoming increasingly well established in regions outside the United States and Europe, supplying global medical needs from truly global locations. Like international efforts in other industries, the globalization of pharmaceutical activities increases challenges associated with logistics, language barriers, and cultural differences but pays dividends in cost and increases in the size of the talent pool.

2.2.4 Increasing Complexity of Pharmaceutical Science

As already mentioned in the context of rising costs and constrained revenues, current research and development of new medicine is attempting to address afflictions and therapeutic categories that are more complex than their predecessors. In order to understand and treat these more complex targets, the industry must use more complex and difficult science. The pharmaceutical industry has always employed a highly talented collection of several scientific disciplines, ranging from biologists and chemists to engineers and statisticians. All of these professions now face harder problems down to the molecular level of their fields to bring forward the next generation of medicines. The scientific challenges take many forms. For example, a larger fraction of compounds in development have low solubility and low permeability in human tissue, making drug delivery within the body more difficult. Highly potent compounds dictate that the amount of drug in the formulation be very small, sometimes in the submilligram ranges, and this also adds to the challenges of formulation development. Innovative and novel delivery systems are required to ensure that new medicines are effective. Advances in the academic understanding of the workings of human genetic code are creating especially challenging questions around how to translate this knowledge into practical improvements in human health. Employees of pharmaceutical companies must be prepared for a future with more difficult challenges.

2.3 Opportunities for Chemical Engineers

The challenges faced by the pharmaceutical industry create several opportunities for its members, including chemical engineers. The pressures to reduce costs connect directly to engineering principles that seek economies of scale and the application of efficient technology. Technological innovation and engineering analysis also enhance products to create meaningful differentiation for patients, which provides value in the face of revenue constraints. The complexities of pharmaceutical science and constraints of approaches that need to be suitable for global use are interwoven with the application of chemical engineering tools to address cost issues and enable product value. Finally, the strategic management of technology used to meet industry challenges by chemical engineers is an additional overarching opportunity in the industry.

2.3.1 Reducing Costs with Engineering Principles

Owing to large margins, engineers in the nongeneric pharmaceutical industry have not had the same traditional focus on product cost as engineers in other businesses. With a renewed emphasis on cost, engineers are increasingly using a wide variety of engineering tools to improve costs and help maintain margins. These tools include modeling of unit operations, employment of efficient laboratory methods and design of experiments, combining the output of models and experiments to define advantageous processing options, and the use of standardized technology platforms. Some of these topics will be highlighted briefly here and discussed in greater detail in subsequent chapters.

Across many industries, engineers are employed to use process modeling and physical/chemical property estimation to maximize the yield and minimize the energy consumption and waste production associated with desired products. Using the broad applicability of this network of techniques is a continuing opportunity. Engineers in the pharmaceutical industry use computational tools originally created for oil refinery processes to optimize distillations and solvent recovery associated with the manufacture of active pharmaceutical ingredients (APIs) [5]. Similarly, thermodynamic solubility modeling can be applied to optimize crystallizations [6]. Computation Fluid Dynamics (CFD) has numerous applications to pharmaceutical flows [7]. The use of sound, fundamental chemical engineering science can eliminate bottlenecks, improve production, and unlock the full potential of biological, chemical, and formulation processes used to make medicine.

Chemical engineers can also use their training and expertise with technology to help reduce costs. In the R&D arena, the use of high-throughput screening tools and multireactor laboratory systems efficiently promotes the generation of data at faster rates. When modeling and estimation techniques cannot provide a complete picture, engineers can get the data they need quickly with high-efficiency technology. It is important to recognize that not all of the advanced laboratory technology works universally well in all situations. A miniature reactor system suitable for homogeneous reactions may have insufficient mixing for heterogeneous chemistry. Selection of the appropriate laboratory technology and proper interpretation of results produced by these laboratory tools benefit from the perspective of combined chemical engineering principles such as mass transfer, heat transfer, reaction kinetics, and fluid mechanics. With the appropriate equipment in hand, engineers can utilize a statistically driven design of experiments to maximize the value of data generated via the experimental methodology.

The process understanding that comes from combining models and experimental data is a key opportunity for chemical engineers. Changes in the regulatory environment contribute to this opportunity. As will be described later in this book, the advent of Quality by Design (QbD) principles (ICH Q8, Q9 and Q10) provides greater freedom after launching a product to modify operating parameters within a defined operating space. These changes can promote higher quality products and reduce process waste by applying the knowledge that comes with increased production experience once a medicine is commercialized. The modeling abilities of chemical engineers and their technology expertise will be able to provide crucial guidance to the definition and refinement of a QbD operating space. A thoughtful, well-conceived operating space will in turn lead to long-term gains in process efficiency and better results for consumers.

A primary method to achieve the benefits of chemical engineering principles at manufacturing scale comes from the development and application of technology platforms that can use a single set of equipment with common operating techniques across a portfolio of processes and products. The platforms not only reduce capital costs by allowing the purchase of a reduced amount of equipment for more applications, but development costs can be lowered as well through a streamlined approach that comes from having a deep understanding and expertise with a technology platform. The familiarity and data obtained from running multiple projects in a single platform will translate into benefits for future projects that share common features. Broad uses of standardized platforms also make processes more portable for global applications. The key challenges of platforms are (1) knowing for which compounds the platform will be applicable and (2) maintaining the knowledge gained about the platform and its underlying technology.

2.3.2 Improving Product Value

Chemical engineers also have opportunities to meet market demands for pharmaceutical products that deliver greater value to patients, payers, and physicians. These customers do not care about the manufacturing process, but they do care about product convenience, safety, and compliance. They are seeking meaningful differentiation in these areas among their options. The remainder of this section will discuss ways engineers can contribute to product value with two examples: drug delivery and diagnostics.

Contributions to improvements in drug delivery vehicles serve as an excellent example of how engineers can improve pharmaceutical product features. The application of particle engineering and convection modeling to inhalers can improve the consistency with which a dose is administered via the respiratory system independent of the strength of the patient's breath [8]. Greater consistency of delivery increases the associated compliance. In orally administered capsules and tablets, engineers can manipulate polymer properties and transport driving forces to afford a consistent extended release of an API [9]. A steady, slow release of medicine from a single delivery vehicle can reduce both the frequency with which the medicine needs to be taken and potential side effects, which can, in turn, improve conveniences for the patient and compliance with the dosing regimen. In order to realize the benefits of controlled release, the pure API particle size distribution usually must be kept consistent prior to formulation. A great deal of engineering effort has been applied to maintain control of crystal sizes during the crystallization, filtration, and drying unit operations for drug substances [10].

Engineering principles can also be used to improve diagnostic tools used to treat diseases. Diagnostics are especially important for payer organizations that want to utilize options that have the highest probability of success for the patient. A diagnostic tool that enables physicians to initially assign the best treatment without going through a trial and error approach reduces the costs charged to the payers through the preemptive elimination of ineffective options. The aforementioned chemical engineering skills that aid the process of making medicines also contribute to improvements in making diagnostic technology. The underlying governing equations that characterize the transport of medicine to a specific target in the body also have applications in the movement of a sample from a patient through a device to the analysis component. Beyond diagnostic effectiveness, the ability for chemical engineers to respond to patient preference and improve the convenience of diagnostics tools used in the home or other areas outside of hospitals and physician offices is a key opportunity with health care becoming an increasingly consumer-driven market [4]. Advances in polymer technology and manufacturing processes can lead to devices that are lighter, smaller, and more resilient to being dropped. Just like new models of an iPod™ garner increased use over their heavier, larger, and more delicate predecessors, delivery vehicles and diagnostics serve as examples of significant opportunities for chemical engineers in the pharmaceutical industry to meet consumer demands for improved products. As will be discussed in greater detail later in this book, the use of Quality by Design principles in the context of ICH Q8/Q9/Q10 guidelines will help ensure that features of the product best match the needs of the patient.

2.3.3 Strategic Technology Management

In addition to direct scientific contributions that reduce costs and improve value for the pharmaceutical industry, engineers have the opportunity to help direct strategic investments in technology. Companies cannot afford to individually develop, implement, and advance all technologies required for their business. Several case studies show how good and poor strategies relating technology to business considerations have affected multiple industries, including computer companies and international distributors [11]. The availability of global development and supply options creates relatively new decisions for the pharmaceutical industry. Technology investment must be managed through a careful balance of internal capabilities, strategic partnerships, and reliance on external vendors. In order for this balance to be established and maintained, a holistic definition and view of technology must first be established. Is any laboratory or production device such as a granulator or a blender considered technology or are they just pieces of equipment? In the context of strategic management, technology can be defined as a system comprising (1) technical knowledge, (2) processes and (3) equipment that is used to accomplish a specific goal. The knowledge encompasses the understanding of fundamental principles and relationships that provide the foundation of the technology. The processes are the procedures, techniques, and best practices associated with the technology. The equipment is the physical manifestation of the technology as devices, instruments, and machinery. The goal for strategic technology management is to make value-driven decisions around investments in the advancement, capacity, and capability with each of the technology components.

To make those investment decisions, industrially relevant technology can be assigned to categories. The concepts of core technology and noncore technology and associated subcategories are useful in this regard:

Core Technology: Core technology is sophisticated technology that makes critical contributions to the core business. As such, it justifies investment in all three components of the technology (knowledge, process, equipment) to afford a competitive advantage. Options for core technology include maintaining internal capability for all three components as a primary technology or managing the technology via external capacity as a partnered technology. The distinguishing feature of all core technology is that internal capability in the knowledge component of the technology is typically required to ensure that the technology is adequately controlled to meet core business needs.

Primary Technology: Primary technology is a category of core technology that offers competitive advantage by maintaining internal capability for the complete technology system. The investment in internal capacity does not need to meet all business uses of the technology but ensures that adequate resources can be provided for critical projects.

Partnered Technology: Partnered technology is a technology that contributes to the core business, but the company can maintain a competitive advantage while relying on external partners to be primarily responsible for parts of the technology system. The company may invest in knowledge and process development for a partnered technology while utilizing external equipment capacity and potentially outside process expertise.

Noncore Technology: Noncore technology does not warrant investment or control in all three components of the technology system. The subcategories of emerging technology and commoditized technology characterize the most relevant noncore technology.

Emerging Technology: Emerging technology has potential to contribute significant business value in the future but generally requires additional investment in the knowledge base before it can be applied in practice to the core business. Emerging technology is not necessarily brand new technology but its application to the core business may be atypical or speculative.

Commoditized Technology: Commoditized technology is mature technology that is reliable, well established within the industry, cost efficient, and available in the market such that little investment in the technology is required.

To determine if a technology of interest is core or noncore, the connection of the technology to business value must be assigned as well as risks associated with the technology's ability to meet business requirements. Business value (BV) can be determined by identifying the revenue enabled by products made via the technology. Risk (R) can be calculated or estimated by assessing the fraction of attempts that a technology fails to deliver intended results within predetermined specifications for both quality and efficiency. A minimum business value (BVmin) and minimum risk tolerance (Rmin) for being a core technology should then be assigned based on a strategic business and financial perspective. If either the business value or risk associated with a technology is below the corresponding minimum, the technology should not be considered for core technology investment. When a technology meets the minimum risk and business value requirements, a threshold value (TV) can serve as the primary criteria for determining the core technology designation as follows:

The underlying principle of this approach is that the core technology investment ensures the value benefit of the technology to the core business and mitigates the risk of a severe failure in the application of the technology. This insurance and mitigation come from the direct investment and maintenance of expertise in all three components of the technology, whereas noncore technology takes more appropriate risks with lower investments. As technology evolves in importance and reliability, it can transition between the core and noncore regimes by regular assessment of the business value and risk associated with the technology.

Technology progression and the evolution of a concomitant investment approach can be illustrated graphically on a plot of business value versus risk. On such plots, core technologies fall into the upper right regions. Risk generally decreases as time progresses and experience with the technology increases. A life cycle thus moves from right to left on the value–risk plot, and two examples are shown in Figure 2.2. In both cases, the technologies start with a relatively high risk as emerging technologies and transition from noncore to core technology when the business value becomes sufficiently high. In case 1, the technology sustains business value long enough for the technology to become a low-risk commoditized technology. Though the business value remains high, the reduced risk drives the transition from core to noncore technology in this case. Technologies that make sterilized vials serve as an example here. At one point, the pharmaceutical industry needed to invest internal resources to ensure vials for vaccines would be sterile, but they are now readily available as a commodity made from reliable, established technology managed by vendors. In contrast, case 2 illustrates a decreased business value driving the transition from core to noncore technology, perhaps due to the introduction of a better replacement. Obsolete open-top vacuum funnel filters that have been replaced by centrifuges and sealed filter dryers in manufacturing environments to improve industrial hygiene and efficiency provide an industrial example of case 2. Technologies relating to crystallization, spray drying, and roller compaction are representative of current chemical engineering core technology at several pharmaceutical companies.

Figure 2.2 Examples of progression along a technology life cycle between core and noncore regimes.

Engineers have opportunities to substantially contribute to several facets of technology management as outlined above. Due to the complex nature of pharmaceutical processes, assigning a failure event to specific technology can be a challenging multivariant problem during risk assessment and risk management endeavors. Fundamental process understanding and technology expertise are vital to evaluating quantitative contributions to risk. Similar skills are useful for objectively determining whether value is enhanced through the use of internal capabilities versus external options. The understanding of a technology is important for determining the reliability of a prospective partner using that technology for critical business needs. Engineers can also contribute to investment choices among various emerging technologies with technical assessments of probabilities of success and potential applicability across a company's portfolio of products.

2.4 Prospects for Chemical Engineers

Chemical engineers have made enabling contributions to health care that serve as a strong foundation for future success. However, the pharmaceutical industry is profoundly changing and the role of engineers must change with it. The industry challenges described in Section 2.2 translate into the opportunities for chemical engineers in Section 2.3. The use of modeling, standardized technology platforms and a sound technology strategy will allow engineers to help reduce costs. The platform technology will also assist with the challenges of making processes portable in an era of globalization. The need for greater product value to enable future revenues can partially be met by engineering enhancements to delivery devices and diagnostic tools. In addition, engineers may also be able to improve the stability of formulated products, thereby reducing the need for expensive cold storage and enhancing access options for patients in severe environments. As the underlying science and supporting academic chemical engineering research evolve toward an increasingly molecular basis, the perspectives and training of engineers must move from macroscopic and continuum foundations to a combined macroscopic, continuum, and molecular view. Chemical engineering will continue to integrate with the rest of scientific disciplines beyond a confined role in processing realms. The work of engineers must progress beyond connecting process contributions to production efforts to integrating the processes with the product itself. These efforts will be performed in the context of changing business models and pricing constraints on an increasingly global stage.

Acknowledgments

The authors wish to acknowledge the contributions of the Merck Commercialization Technical Forum, most notably Anando Chowdhury, Louis Crocker, James Michaels, Lawrence Rosen, and Cindy Starbuck, to Section 2.7.

References

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