Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

Contract research organizations (CROs) such as Covance (Princeton, NJ) are heading further east through Europe. The company opened new clinical development offices in February 2009, in Kiev, Ukraine, and Bratislava, Slovakia (a third office opened in Tel Aviv, Israel) (1). Covance has provided clinical support services in Central and Eastern European (CEE) countries and the Commonwealth of Independent States (CIS) since 1994, with offices in Poland, Hungary, the Czech Republic, Bulgaria, Romania, and Russia, but these new offices, which will support staff in Ukraine and Slovakia, demonstrate a firm commitment to the developing region. "A comprehensive global presence combined with a balanced approach to leveraging emerging markets is critical...to be able to meet clients' demand in multinational trials, in terms of quality, time, and budget," explains Dr. Yuri Shakhov, executive director of clinical development services in CEE for Covance. "Working with investigative sites in Central and Eastern Europe enables a winning trifecta: The sites are known to be fast enrollers due to patient availability, while at the same time providing high quality data—all at costs that offer a clear competitive advantage over established markets." 

CEE countries, in particular, have additional benefits for CROs that are managing clinical trials. For starters, most countries in the region have a highly centralized medicine system capable of screening a high number of patients per day. There are also large cohorts of patients throughout CEE, including patients with rare indications, which are of increasing interest to pharmaceutical companies looking toward personalized medicine, adds Shakhov. "This is important in these post-Vioxx times considering the increasing demand by regulatory agencies, particularly the FDA, to test drug safety in large patient cohorts," he says. 

CEE countries also tend to have fast enrollment times and lower costs for conducting clinical trials, says Shakhov. And it doesn't hurt that 10 countries in the region are part of the European Union [Bulgaria, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia, Slovenia] and follow well-established EU regulations. Being part of the EU enables them "to offer predictable processes and good quality clinical study conduct," explains Shakhov. "From a regulatory perspective, approval and start-up timelines in Central and Eastern Europe are similar to Western Europe and India, but significantly shorter than in China. This means the countries of Central and Eastern Europe can take their place among the first countries to be active in a clinical trial instead of coming online only once the trial is far progressed." 

But as with any market, challenges exist within CEE and CIS markets, including regional tension and conflicts. Variations in the regulatory requirements of non-EU countries, such as the need to separately import clinical trial materials into each non-EU country, can pose problems as well, notes Shakhov. 

Another example is provided by, Albany Molecular Research (AMRI, Albany, NY). The company experienced some trouble with restrictions on air travel caused by strikes, natural gas shortages precipitated by Russia, and a host of other issues that could not be anticipated when doing business in Hungary, according to Michael Trova, senior vice-president of chemistry at AMRI. 

Yet Trova points out that its operations in Hungary have provided the opportunity to "to establish relationships with the large number of biotechnology companies located throughout Europe." AMRI acquired an existing company in Hungary in 2006 because it "provided an immediate presence in Europe in an EU member state with a significantly lower cost structure than Western European countries," says Trova. It also allowed the CMO to recruit employees from the US and UK. More recently, AMRI completed construction of a new 32,000-ft2 research and development facility in Budapest with capacity that will allow the company to double its synthetic chemistry services over the next five years. The facility also includes a scale-up laboratory for non-GMP synthesis for batch sizes up to 25 L, says Trova. 

Another CRO, PPD (Wilmington, NC), acquired AbCRO, a CRO operating in CEE that focuses on Phase II-IV clinical services, in April of this year, to strengthen its presence in "a highgrowth, emerging region for clinical research," according to a company release. With the acquisition, PPD gained access to Romania, Bulgaria, Serbia, and Croatia. The CRO already had operations in Poland, Russia, and Ukraine. 

, a registry of federally and privately supported clinical trials around the world, Poland had 516 open studies as of Sept. 1, 2009. The Czech Republic had 345, Hungary had 281, and Russia had 394. Looking at overall studies, including open and concluded or terminated studies, the CEE countries had a total of 6943 as of Sept. 1, 2009. Compare this with the total studies reported as of Sept. 1, throughout Western European countries (11,536), the CIS (1333), China (1269), and India (1062) (2). 

For more on this topic, see the special report "

, National Library of Medicines, National Institutes of Health (Bethesda, MD), 

Articles

Contract research organizations such as Covance are heading further east through Europe.

CROs and CMOs Go Further East

The National Institute for Pharmaceutical Technology and Education (NIPTE) was formed in June 2007 as an independent nonprofit organization by 11 major US universities. Approximately 30 faculty members from the member universities* are collaborating on various NIPTE projects, as are scientists from Pfizer (New York), Baxter (Bloomington, IN), Abbott Laboratories (Abbott Park, IL), and the US Food and Drug Administration. The institute s research agenda, aimed at improving the quality of drugs and pharmaceutical products, includes the following: 					

Developing an understanding of factors affecting variability in drug development, scale-up, quality, and manufacturing

Improving the scientific basis for understanding the behavior of pharmaceutical materials and the requisite processing steps

Developing tools to predict product performance early in the development process as well as strategies to allow rapid design and scale-up of manufacturing processes

Reducing risk and time-to-market for new drugs.

The US Food and Drug Administration's Center for Drug Evaluation and Research granted NIPTE a $1.19-million contract in September 2008 to help carry out the institute s bold agenda. The funds are to be used to develop quality-by-design (QbD) science for pharmaceutical developers and manufacturers. "The agency plans to make available and use NIPTE s research to develop the science that is badly required for rapid, industrywide QbD implementation," says NIPTE Executive Director Prabir Basu. 

NIPTE researchers are looking at, among other things, how to develop a complete manufacturing process using QbD. This process includes tools that can help develop design space and process analytical technology applications; methodologies for conducting risk analysis and scale-up; design space protocols for unit operations; bioreactor modeling; characterization of excipients (i.e., understanding and predicting their physical and functional properties); pediatric formulations; biotechnology product development; and prediction models for active pharmaceutical ingredient and formulation properties such as solubility, taste, and stability. 

"We are making good progress in designing protocols for scaling up unit operations such as blending, granulation, and fluid-bed drying," says Basu. "We are also making good progress on developing a QbD case study for developing a parenteral freeze-dried dosage form for a small molecule." 

Once the FDA grant period ends in September 2010, NIPTE plans to hold a public workshop about its findings. Although there's no guarantee that the institute's work will lead FDA to revise related guidances, the availability of better science could change some current thinking on the part of regulators, including at the International Conference on Harmonization, says Basu. 

A major component of the institute's work is educating the industry and scientific community. NIPTE is developing educational materials and training programs on QbD-based science and applications with the ultimate goal of creating an academic curriculum. 

"Many scientists in the industry and at our regulatory agency do not have adequate training in the science required or have available all the tools required to implement QbD," explains Basu. "In addition, at our universities, the disciplines such as pharmacy, chemistry, and engineering work in silos. An industry senior vice-president once commented that they have to sometimes hire three people to do one person's job. NIPTE s intent is to take the best educational materials from the entire available curriculum from all the current bachelor and master of science programs in pharmacy and pharmaceutical engineering and develop an integrated curriculum for a pharmaceutical science and engineering program that all the NIPTE schools and beyond can use as a model program." 

Currently, NIPTE operates out of Purdue University in Indiana, but the long-term goal is to have at least one Center of Excellence at each of the member institutions, says Basu. In addition to using a potential new curriculum, each center would specialize in at least one topic or area of research in pharmaceutical process development and manufacturing so that QbD science can continue to develop. 

As for current industry professionals, some retraining in QbD science and processes will be a must, says Basu. NIPTE programs will be available to companies' internal educational programs and to other interested parties. 

Industry has endless questions about QbD implementation, many of which boil down to convincing management to support and fund the new risk-based science with the promise of regulatory and operational flexibility as a reward. What some may not understand, however, says Basu, is that to achieve the full benefits of QbD, there must be a full implementation of QbD similar to what other industries do. 

"QbD implementation has to start early in process development. The product and process must be designed using sound scientific principles." In addition, a company's manufacturing plant and systems must be capable of operating a QbD system. 

"A well-designed process will not perform satisfactorily if the manufacturing plant does not have well-developed systems of quality, effectiveness, performance, management, and continuous improvement," says Basu. Only then might companies experience the estimated 25-30% savings in cost of goods sold for implementing QbD.

Industry also wants to know how its day-to-day work will change once QbD processes are in operation. "Today, if we want to heat water in a tank, we do not need to develop a design space or validate that system. If we decide to heat acetone instead of water, we do not need to revise our design space or submit lengthy change requests. This is because the science is available to calculate how long it takes to heat water or acetone," explains Basu. "Our hope is that pharmaceutical science will reach that level someday so that we can develop a manufacturing process in one step from laboratory data and then be able to predict its performance with a high degree of accuracy to be able to control the process in the plant using sound manufacturing science and ensure product quality without requiring FDA approval for every process change we make." 

Basu says that petrochemicals is one industry that has successfully implemented science-and risk-based approaches into its manufacturing processes. "Irrespective of the source of the crude oil, or the season, or the location of the refinery or gas station, the quality of gasoline is always the same. We do not have to readjust our cars everyday or move our cars from one place to the other," he explains. "There is a real need to invest in science and technology for our pharmaceutical process development and manufacturing science. Pharmaceutical companies are trying to save manufacturing costs by outsourcing, but QbD implementation can achieve much greater savings ... and help save our manufacturing jobs," he adds. 

NIPTE is not conducting research simply to satisfy academic curiosity or to be published, says Basu. "Our research should be useful to the regulators and industry to improve pharmaceutical product development and manufacturing. To this end, current good manufacturing practices must be complemented by current good manufacturing technologies. However, this is a big challenge for not only our industry and FDA, but also for academia in terms of working collaboratively with FDA, industry, foreign manufacturers, and regulatory agencies to bring QbD wherever it maybe required to make overall improvement of the quality of our pharmaceutical products."  

*Member universities include Duquesne University, the Illinois Institute of Technology, Rutgers University, Purdue University, and the Universities of Puerto Rico, Connecticut, Iowa, Kansas, Kentucky, Maryland, and Minnesota. 

A review of NIPTE's core projects and its plans for training-and retraining-the pharmaceutical industry.

Academia Tackles QbD Science: NIPTE Carries out FDA Grant and Educational Initiatives

 to clarify the cGMP requirements applicable to combination products in the 

. The proposed rule is meant to set forth "a transparent and streamlined regulatory framework for firms to use when demonstrating compliance with CGMP requirements for 'single-entity' and 'co-packaged' combination products," according to the notice.

21 CFR Part 3 defines a combination product as "any combination of a drug and a device; a device and a biological product; a biological product and a drug; or a drug, a device, and a biological product." Approximately 300 manufacturers of combination products will be affected by the proposed rule, says the notice.

"FDA believes that the absence of clear CGMP requirements for combination products could result in inconsistent or differing application of the various CGMP requirements applicable to the constituent parts, which could affect product safety and the public health," says the notice. According to the proposed rule, combination product manufacturers would be able to demonstrate compliance with either 1: "the specifics of all CGMP regulations applicable to each of the constituent parts included in the combination product containing," or 2: "the specifics of either the drug or the [quality system] regulation, rather than both, when the combination contains both a drug and a device, under certain conditions."

There are many specific proposals included in the proposed rule depending on the type of combination product manufactured. Of note, the fact that many facilities may be involved in the manufacture of a combination product, "raises questions about whether and when the proposed streamlined approach to CGMP operating systems could be used," says the notice. The proposed rule would "make clear that when manufacturing of a constituentpart does not occur at the same facility as another type of constituent part, the operating system must be shown to comply with all of the CGMP regulations applicable to that constituent part." In the same regard, when two or more types of constituent parts are in the same facility, a streamlined approach may be used, and when "manufacture of a constituent part occurs at a separate facility from all other types of constituent parts, the manufacture of that part must occur under the regulations applicable to that part," says the notice.

The FDA issued a proposed rule to clarify the cGMP requirements applicable to combination products in the Federal Register.

FDA issues proposed rule on cGMPs for combination drug products

As the pharmaceutical industry moves further into Central and Eastern Europe and the Commonwealth of Independent States, several standard-setting and regulatory bodies are also increasing collaboration in the region, particularly in Russia. 

 In April 2009, the United States Pharmacopeial (USP) Convention signed a Memorandum of Understanding (MOU) with the Federal Service on Surveillance in Healthcare and Social Development of the Russian Federation (Roszdravnadzor, the US FDA equivalent). In addition to implementing the use of the first Russian translation of the 

, the agreement calls for, among other things, organizing joint annual scientific meetings, sharing information—especially during incidents of contamination or accidental adulteration of medicines, developing additional reference materials, and the consideration of a third-party program for auditing active pharmaceutical ingredients manufacturers. 

 "USP is very pleased to cooperate with Roszdravnadzor on improving the quality of drugs in the United States and Russia," says USP CEO Roger Williams. "Both parties are committed to the relationship and collaborative work, which impacts patients in our respective countries and worldwide who rely on quality medicines." 

Since signing the MOU in April 2009, Roszdravnadzor was elected to the USP Convention—a governing body that guides the organization's work—and is exploring scientific exchange opportunities with USP, including a staff exchange in 2010. An updated version of the 

Russian translation is also in the works with an expected 2010 release. 

The International Pharmaceutical Excipients Council of Europe welcomed its first Russian member company, Pharmstandard, in July 2009. Pharmstandard (Moscow), the leading domestic pharmaceutical company in Russia in terms of sales (totaling RUB 14.3 million in 2008; $456,000) according to the Pharmexpert Marketing Research Center. Pharmstandard has manufacturing facilities in Kursk, Ufa, Tomsk, and Nizhny Novgorod. 

 In August, the Parenteral Drug Association (PDA) formed a partnership with Eli Lilly (Indianapolis) and the Purdue Research Park-based Chao Center for Industrial Pharmacy & Contract Manufacturing to help train the Russian Inspectorate on current good manufacturing practices. The program is aimed at advancing Russia's manufacturing and quality control standards and increasing international dialogue between Rozdravnadzor and other regulators with regard to pharmaceutical regulations and inspections, according to an Aug. 3, 2009 Purdue release. 

As the pharmaceutical industry moves further into Central and Eastern Europe and the Commonwealth of Independent States, several standard-setting and regulatory bodies are also increasing collaboration in the region, particularly in Russia.

Standard-Setting Bodies Engage Russia

Across the global pharmaceutical industry, there is a sense of urgency when looking at the pharmerging markets, says David Campbell, senior principal at IMS Consulting. "We're starting to see a lot of movement and interest from companies wanting to enter pharmerging markets or, for those companies already in the pharmerging markets, to expand their opportunities in those markets," he says. "The challenge is that these markets are very complex and the opportunities are different for each BRIC [Brazil, Rusia, India, and China] nation. We're going to see companies rethinking business models—their market strategy and their commercial models—to ensure they remain competitive against entrenched and local competitors in pharmerging markets, while also being able to return value to various stakeholders."  

Several multinational companies have already laid this groundwork in Central and Eastern Europe (CEE) and Commonwealth of Independent States (CIS) countries by establishing official emerging-market strategies. Sandoz (Holzkirchen, Germany), the generic-drug division of Novartis (Basel), got in early and now leads the CEE market for generic pharmaceuticals with a presence in nearly every CEE country, excluding Montenegro and Slovenia, as well as in Belarus, Ukraine, and Uzbekistan. The company's acquisition of Slovenian generic-drug manufacturer Lek (Ljubljana), which operates all over the CEE and CIS regions, in 2002 provided a major stepping stone into the region. Today, Sandoz is the second-largest generic-drug company in the world based on sales (1) and Novartis is the primary player in Eastern Europe with 2007 sales of $1.5 billion (2). 

Another European major, sanofi aventis, is also gaining ground in CEE and the CIS. "Most companies are already announcing strategies to get away from small molecules in the rich countries. We're already there. We're already the leader in emerging markets," said sanofi aventis CEO Chris Viehbacher in an April 2009 video presentation (3). These markets are undergoing major economic growth, which means their consumers are spending more on healthcare, he explained in the presentation. 

sanofi aventis' focus has been on Russia, where its retained a presence since 1970. Today, the company has two offices in Moscow and 31 sourcing plants throughout the country. sanofi aventis' 2008 sales in Russia grew 34.4% to EUR 380 million ($541.5 million) according to a company investor-relations seminar on Emerging Markets in July 2009 (4). Looking ahead, the company aims to be a leader in Russia's prescription generic-drug market and its over-the-counter drug market. sanofi aventis wants to expand its vaccines business to other CIS countries as well (4). The company's recent acquisition of Zentiva in the nearby Czech Republic and Sanofi Pasteur's 20% share of Russia's vaccines market (GSK, Novartis, and Merck have smaller but significant shares) should help in this regard (4). 

Looking ahead, Viehbacher hopes that 64% of sanofi aventis's volumes will be sold in emerging markets this year and that sales in those markets will double between 2008 and 2013 (4). 

Pfizer (New York) reorganized in 2008 to create five major business units, one of which is Emerging Markets (5). The new unit is focused on capturing greater revenue, particularly in Latin America, Asia, and Eastern Europe (6). The company wants to add $3 billion in annual sales by 2012 from emerging markets, namely, the BRIC countries plus Mexico and Turkey (6,7). Glaxo-SmithKline (London) also established a strategy in spring 2008 to "unlock the potential of emerging markets" by placing a priority on investments in capacity and regulatory expertise in those counties (8,9). And in August 2009, as a result of its recent merger with Schering-Plough, Merck & Co. (Whitehouse Station, NJ) announced a new structure that includes an Emerging Markets group. The group is being established under the company's Global Human Health division—the largest of five divisions in the newly merged company—and is charged with, among other things, identifying ways to take advantage of significant growth opportunities in emerging regions, including Eastern Europe, according to an Aug. 31 company release. 

Specialty pharmaceutical company Nycomed (Zurich, Switzerland) recently expanded its product portfolio by purchasing 20 branded generic products, including several betablockers and the profitable Hypnogen (Zolpidem), from sanofi aventis and Zentiva in several CEE countries this past August. Pleased with its activity in Russia and the CIS region since the mid-1980s, Nycomed is now turning to Eastern Europe. The markets in that region "sustain solid growth as increased spending power continues to translate into demand for pharmaceuticals," explains a Nycomed spokeswoman. "Nycomed has shown that it can thrive in such conditions by combining local entrepreneurial activity with strong central support from Nycomed's global brands and European manufacturing network. The strategy has been highly successful in Russia and shows every sign of being just as productive for Eastern Europe." The company's Russia/CIS division had a net turnover of 3.6% to EUR $78.7 million ($112 million) during the first quarter of this year, according to the company's financial statements, and plans to invest EUR $60 million ($85.5 million) into a new manufacturing plant in Russia. 

Another specialty firm, Meda Pharmaceuticals (Solna, Sweden), acquired Valeant s (Aliso VIeja, CA) business in Western and Eastern Europe, including Russia, in September 2008. And in June 2008, Mylan (Pittsburgh, PA) acquired Merck KGaA's CEE generic-drug business, including operations in Poland, Hungary, Slovakia, Slovenia, and the Czech Republic. 

Even Indian-based companies are staking a claim in CEE. Mumbai's Sun Pharmaceuticals bought ICN Hungary (now known as Alkaloida Chemical Company), a producer of controlled-substance APIs, in 2005. And Strides Polska, a subsidiary of Strides Arcolab (Bangalore), a leader in finished generic drugs, purchased a sterile manufacturing unit from ICN Valeant in Warsaw, Poland, in 2006. "This addition further strengthens Strides' presence in Europe and allows us to focus on developing the Polish operations into a strategic part of our manufacturing network, as well as allowing us to promote our products and services in the 'New Europe,'" said President of Global Manufacturing Paul Moore in a company release. 

1.   Sandoz Company Information, January 2009, 

2.   S. Sutton, "Pharma Boom in Eastern Europe," 

3.   C. Viehbacher, "The New Strategy for Sanofi-Aventis," transcript from sanofi aventis TV, interview taped Apr. 17, 2009 with 

4.   Sanofi Aventis, Emerging Markets IR Seminar, July 2, 2009,  

http://en.sanofi-aventis.com/investors/events/corporate/2009/090702_Emerging-Markets.asp

5.   Chairman's Report, Pfizer Annual Review 2008, 

6. Pfizer Press Release, "Pfizer Presents New Opportunities for Global Growth," Mar. 5,2008. 

7. J. Irish, "Pfizer Eyes Deals to Raise Emerging Markets Presence," Reuters, June 14,2009. 

8.   GSK Press Release, "GSK's Emerging Markets Strategy Advances With Acquisition in Egypt," Oct. 15,2008. 

9.   GSK Press Release, "GSK to Drive Growth in Emerging Markets with Acquisition of UCB Products," Jan. 23,2009.

This article is part of a Special Report on the Emerging Markets of The East, October 2009

Multinational Firms Stake Claims

The US Food and Drug Administration issued a 

 to clarify the current good manufacturing practice (CGMP) requirements applicable to combination products in the Sept. 23, 2009, 

. The proposed rule is meant to set forth “a transparent and streamlined regulatory framework for firms to use when demonstrating compliance with CGMP requirements for ‘single-entity’ and ‘co-packaged’ combination products,” according to the notice.

 Part 3 defines a combination product as “any combination of a drug and a device; a device and a biological product; a biological product and a drug; or a drug, a device, and a biological product.” Approximately 300 manufacturers of combination products will be affected by the proposed rule, says the notice.

“FDA believes that the absence of clear CGMP requirements for combination products could result in inconsistent or differing application of the various CGMP requirements applicable to the constituent parts, which could affect product safety and the public health,” says the notice. According to the proposed rule, combination-product manufacturers would be able to demonstrate compliance with either 1: “the specifics of all CGMP regulations applicable to each of the constituent parts included in the combination product containing,” or 2: “the specifics of either the drug or the [quality system] regulation, rather than both, when the combination contains both a drug and a device, under certain conditions.”

  There are many specific proposals included in the proposed rule depending on the type of combination product manufactured. Of note, the fact that many facilities may be involved in the manufacture of a combination product, “raises questions about whether and when the proposed streamlined approach to CGMP operating systems could be used,” says the notice. The proposed rule would “make clear that when manufacturing of a constituent part does not occur at the same facility as another type of constituent part, the operating system must be shown to comply with all of the CGMP regulations applicable to that constituent part.” In the same regard, when two or more types of constituent parts are in the same facility, a streamlined approach may be used, and when “manufacture of a constituent part occurs at a separate facility from all other types of constituent parts, the manufacture of that part must occur under the regulations applicable to that part,” says the notice.

The US Food and Drug Administration issued a proposed rule to clarify the current good manufacturing practice (CGMP) requirements applicable to combination products in the Sept. 23 Federal Register.