OR WAIT null SECS
A review of advancements in areas such as active ingredients, formulation, technology, regulation, and analytical testing.
Birthdays, holidays, and special occasions often seem to provoke retrospection and, sometimes, even introspection. Toward that end, the editors and readers of Pharmaceutical Technology took some time on the occasion of the magazine's 30th anniversary to look back on where the industry has been in order to look forward and make predictions about where it's going. We've converged on three factors that have influenced, indeed shaped the course of the modern pharmaceutical industry: regulation, globalization, and "biologization."
Starting with ingredients themselves—active and auxiliary—we see that biologics-based drugs are expected to be the new growth area. To accommodate these dramatically new products, the industry had to invent dramatically new manufacturing technologies and techniques. And with the advent of new ingredients and classes of ingredients (not to mention some well-publicized failures) comes new regulation. The last couple of years in particular have seen large-scale procedural and philosophical changes at the US Food and Drug Administration, US Pharmacopeia, and other regulatory bodies. These, in turn, necessitated even more technological innovation.
Finally, no one in this industry can deny that manufacturing and research conducted offshore is having and will continue to have a major impact on the way the industry does business. In many cases, offshoring provides for lower labor costs while elevating living standards of overseas workers and creating new consumers. On the other hand, it opens new doors to product counterfeiting and adulteration—issues that can only be addressed through international cooperation and, you guessed it, more regulation.
Still, it's been a remarkable 30 years. The following pages report on this time, based on data from you. Some 320 Pharmaceutical Technology readers responded to our email survey, conducted in April–May 2007. Respondents' primary business activities included: branded pharmaceuticals (35%), biologics or biotechnology (16%), generic drugs (10%), consumer healthcare (4%), contract manufacturing (8%), excipient or chemical supply (3%), diagnostics (3%), equipment manufacturing (3%), analytical testing (3%), and other (15%). Respondents' firms brought in: $50 million or less (26%), $51–250 million (14%), $251–500 million (7%), $501 million–1 billion (10%), $1.1–5 billion (13%), $5.1–10 billion (9%), $10.1–50 billion (14%), and greater than $50 billion (7%).
Survey respondents point to shifting portfolios and production sources for active pharmaceutical ingredients (APIs). Almost half (45%) of survey respondents identified the reduction of late-stage drug candidates and 54% cite the increased number of biologics-based drugs as impact factors in API manufacturing. Even more respondents see this pattern continuing during the next 5–10 years. More than half (56%) point to the reduction of the number of small molecules in the industry's pipeline and almost two-thirds (65%) point to an increase in biologic APIs as factors that will influence pharmaceutical manufacturing.
Historical data and forecasts confirm these trends. Big Pharma's sales of biologics are expected to grow at a compound annual growth rate (CAGR) of 13% from 2004 to 2010, according to Datamonitor PLC (London). In contrast, sales of small-molecule products are expected to increase only at a CAGR of just over 1.0% (1).
Fewer approvals for new molecular entities (NMEs) further highlight the innovation drought in small, nonbiological molecules. An annual average of 22.2 NMEs was approved from 2000 to 2006, with only 18 NMEs being approved in 2005 and 2006 (see Figure 1). While these levels are above NME approvals from 1960–1980, they are below recent peaks. The average number of NMEs approved in the 1960s was 13.7, 17.3 in the 1970s, 21.7 in the 1980s, 25.6 through 1990–1995 (2), and 32.2 from 1996 to 1999, led by a recent peak of 57 in 1996.
Figure 1. Number of new molecular entities (NMEs) approved*
Survey respondents also identify shifting production patterns for APIs. Two-thirds of respondents expect the number of CGMP-compliant API manufacturing facilities to increase in India (68%) and China (66%) during the next 5–10 years.
Industry estimates support this trend, particularly in the merchant market for generic APIs. In 2005, China and India supplied 57% of the generic APIs to Western Europe and 15–16% of generic APIs to the United States on a value basis, according to the Chemical Pharmaceutical Generic Association (CPA, Milan, Italy). By 2010, India and China are expected to hold 67% of the Western European market for generic APIs and 25% of the US market. The market share held by Indian API manufacturers in the global API merchant market (both generic and innovator product) is expected to increase from 7% in 2005 to 10.5% in 2010 and for Chinese API producers from 14% in 2005 to 22% in 2010 (3). For purposes of the analysis, APIs include both active ingredients and advanced intermediates. 30
Looking back at the studies published in Pharmaceutical Technology, some of the major challenges facing formulation scientists during the past 30 years have remained fairly the same, including enhancing the solubility of poorly soluble drugs, improving the stability of unstable drugs (e.g., proteins), controlling and/or sustaining drug delivery, and ensuring accurate drug delivery to the intended target (4).
Throughout the years, formulation strategies also have had to adjust because of various political, ethical, and environmental factors. The Montreal Protocol (1987) banned ozone-depleting ingredients from respiratory formulations, for example. And in the late 1990s, vaccine makers faced increased pressures to formulate their products with no or at least reduced levels of thimerosal, a preservative they had been using since the 1930s (5). As the number of new chemical entities declines, industry continues its focus on preformulation, proof of concept (Phase 0) studies. And outsourcing formulation development is not uncommon, even for Big Pharma companies that have formulation groups in house. In fact, our survey noted the growing impact on the industry of outsourcing formulation development and manufacture.
With each decade, the formulator's toolkit has grown to address these challenges. For example, the traditional method when working with poorly soluble drugs was to use water-miscible cosolvents. During the 1980s and 1990s, formulators experimented with particulate carriers including liposomes and polymers as well as micro- and nanosized particle formation, emulsions, novel spray drying methods, complex coating systems, protein precipitation, supercritical fluid technologies, improved milling techniques, and crystallization (6). Formulation ingredients have changed as well. Thirty years ago, excipients were considered "inactive ingredients," mainly fillers and binders purchased from chemical and food supply vendors. In contrast, the industry now has a number of functional excipients, coprocessed excipients, and niche vendors who meet the needs of the pharmaceutical industry specifically.
Today's formulators have a better understanding of pharmaceutical ingredients, novel strategies for facing challenges old and new, computerized modeling methods, an increased interest in controlled and extended-release formulations, and more alternative routes of administration and delivery (see Table I). 30
Table I: Progress in delivery systems*
One of the major stories to emerge during the past 30 years is globalization. In the pharmaceutical industry, this means that drugs are now manufactured, if not discovered, widely throughout the world, and sometimes in countries that are less vigilant than the United States in matters of safety and efficacy. Combine that with the other great phenomenon of the past 30 years—the globalization of information via the Internet—and you end up with a dilemma.
Consumers conducting simple Internet searches discovered that many prescription drugs could be bought more cheaply online from other countries. In addition, as drug products travel increasingly between various countries, it has become easier for counterfeit products to enter the supply chain.
The rise in counterfeiting has led to increased interest in anticounterfeiting technologies. Most attention has focused on radiofrequency identification (RFID). RFID tags are difficult for counterfeiters to copy and, unlike barcodes, do not require a line of sight. This technology also creates an electronic pedigree (epedigree) that records the chain of custody from the point of manufacture to the point of sale, making it easy to identify counterfeit products when they enter the supply chain.
Although RFID is encouraged by the US Food and Drug Administration, and several companies have participated in pilot studies of the technology, there are still some kinks to iron out before RFID can be widely adopted in the industry. One of the main problems is the lack of standardization of the chips so they can be read at every point in the supply chain. Currently, there are more than 100 types of chips with a wide band of frequencies.30
No matter the technology, ingredients, or formulation a company has developed, in the end, it all boils down to regulation if the company wants its innovation on the market. Survey respondents felt that the "finalization of GMPs (21 CFR 210 and 211)" in 1978 and "21 CFR Part 11" in 1997 had an equally high impact (75%) on overall regulation in the past 30 years, with several respondents crediting GMPs as "landmark" policies that "changed the way we do business." Not only did the GMPs clarify standards for manufacturers—providing less room for error and safer drugs for users—but they also enabled FDA to enforce regulations.
Table II: Top 5* Regulatory Actions 1977-2007
Close seconds to the GMPs and CFR Part 11 were the 1987 "Guidelines on General Principles of Process Validation" (70%) and the more risk-based "GMPs for the 21st century" (67%) intiative.
In terms of regulatory organization, respondents felt that the formation of the European Union, which led to one European Pharmacopeia, had the greatest impact on pharmaceutical manufacturing (67%) since 1977 as compared with actions such as the reorganization of the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) (46%). The EU's creation allowed manufacturers to prepare a single submission package for new drugs or devices rather than one for each country. In addition, the EU provided a balance to global regulatory power. The EU "allowed for a second major voice in defining policy and practice for pharmaceutical business," said one respondent. The creation of the International Conference on Harmonization (ICH) in 1990 was also toward the top of the list of important regulatory organization actions, with 61% listing ICH as having "high" or "some" impact.
Looking forward, survey results showed an overwhelming trend toward going global. Out of a list of 11 factors, including wireless technology and green chemistry, respondents overwhelmingly (83%) ranked globalization as the prime factor to have an impact on the future direction of pharmaceutical manufacturing. This was true across all fields. Not surprisingly, 71% of respondents predicted the practice of outsourcing to increase in the next 5–10 years. This statistic was ahead of 21 other factors, including Big Pharma consolidation (51%) and the number of combination products (58%). Specifically, a majority of participants felt the number of CGMP-compliant manufacturing facilities would increase in both China and India in the next 5–10 years.
Whether these changes will improve relations between the regulatory authorities and industry is unclear. Only a small majority of survey respondents (53%) thought collaboration between FDA and industry would increase in the next decade. Either way, with so many trends pointing abroad, it's inevitable that ICH will have to expand. If outsourcing is to increase as survey participants suggest, common regulatory standards and policies will be necessary to make such partnerships easier and more practical. 30
With greater scrutiny comes greater analysis. Or so it seems when we review the advances in analytical technology. FDA mandates have most famously influenced the process of discovery, but more and more, regulations governing the manufacture of drugs are being regulated. Now, rather than guaranteeing that the finished drug emerging from manufacturing and into the market is perfect, each step in the process itself has to hew to certain standards.
With regard to improvements in techniques, the most prominent new technique during the past 30 years is high-performance liquid chromatography (HPLC). Until the late 1970s, most pharmaceutical analysis was conducted through wet-chemistry testing, and few stability-indicating assays were available. Different drugs required different release-testing techniques. After HPLC testing became a viable option, it gained popularity for its speed and accuracy. The technique also brought uniformity to release testing. HPLC testing has now become the industry standard.
Near-infrared (NIR) spectroscopy is another technique to emerge within the past 30 years. The method and technology evolved, and NIR was introduced to manufacturing facilities. Now NIR is used to quantify materials online.
Atmospheric mass spectrometry (MS) is now widely used, but was unavailable 30 years ago. MS instruments were previously very large and could only be operated by specialists. The instruments required pressurization, and samples had to be introduced one at a time. But today's MS instruments are much smaller, with some models even fitting on the benchtop.
In the automation field, computers have profoundly changed analytical testing. Calculations are no longer performed by hand but by computers and software. Quantification has become more uniform, and accurate results can be obtained more quickly. Testing and sample preparation are now automated as well, eliminating human imprecision and making results more accurate and reproducible.
FDA's process analytical testing (PAT) initiative has been another major influence in analytical testing. The program, initiated in the 1990s, should require manufacturers to collect and analyze data to demonstrate control over their processes. The data must show that the processes will generate results within acceptable specifications. The initiative incited companies to seek real-time analytical results and underscored the need for centralized process data. Manufacturers began focusing tests on characteristics related to product performance, and techniques have shifted toward direct rather than indirect measurement. As testing moved upstream, manufacturing divisions began to perform analytical testing. Quality-assurance personnel now concentrate on auditing test results and ensuring test methods are validated.
In the area of reduced sample sizes, instruments have become more sensitive over the years, and detector technology has improved. As a result, users have been able to generate the same information with smaller sample sizes. Techniques for sample preparation have improved as well, enabling purer samples to be attained. In addition, sample preparation has become largely automated. These developments together brought greater repeatability and more-precise results.
1. S.King, "The Evolving Pharmaceutical Value Chain: Forecasting Growth for Small and Large Molecules," Pharm. Technol. 30 Technology Outlook: APIs, Intermediates, and Formulation suppl. s6–s10 (2006).
2. D.A. Kessler, Presentation at the Food and Drug Law Institute Annual Meeting, Washington, DC, Dec. 10, 1996, www.fda.gov/speeches/kessler.html (accessed May 29, 2007).
3. P.Van Arnum, "The Changing Fortunes of APIs," Pharm. Technol. 31 (1), 52–58 (2007).
4. M.J. Akers, S.L. Nail, and M.J. Groves, "Top 10 Current Technical Issues in Parenteral Science Revisited, 1997," Pharm. Technol. 21 (7), 126–134 (1997).
5. "Thimerosal in Vaccines," www.fda.gov (accessed June 6, 2007).
6. M. Rios, "Bringing Formulations to Size: Strategies for Micro- and Nanoparticle Development," Pharm. Technol. 28 (11), 40–53 (2004).