May 2006

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-05-02-2006, Volume 30, Issue 5

Gottlieb challenges industry. First GenerationNext Awards. Implementing PAT. Optimizing site risk. RFID in the supply chain. Biodegradable polyketals. Global drug-market growth moderates.


Gottlieb Challenges Manufacturers to Make Processes More Efficient

Each year, the pharmaceutical industry spends about $120 billion dollars on research and development. This spending has resulted in the discovery of many new and innovative drug molecules. "That's the good news," said Scott Gottlieb, deputy commissioner for medical and scientific affairs at the US Food and Drug Administration (Rockville, MD, in his keynote address on the final day of Interphex. "The bad news is that the molecules aren't coming out of the pipeline fast enough . . . For the amount of money we're spending, it's not flowing out the other end."

The drug pipeline has "significant bottlenecks," said Gottlieb. Holdups in the process include the lack of a framework for incorporating new science tools into the drug regulatory process; risks that FDA and industry sponsors are required to take to implement new tools; and approaches to regulation based on tradition, which doesn't allow for innovation.

To help drugs come to market quicker, FDA recently announced updates to its Critical Path Initiative, which included a list of 75 methods to improve clinical trials and a new consortium of eight pharmaceutical companies that will work with FDA to improve the drug-development processes.

Gottlieb also pointed out that the manufacturing industry has not received a lot of attention to facilitate advances in new technologies, though innovation in this area has the potential to help lower drug costs, eliminate drug impurities, and help bring new treatments to market faster. To improve manufacturing processes, he suggested that the relationship between quality, safety, and efficiency must be better understood. In addition, processes must be modernized with analytical tools, particularly process analytical technology. Hand in hand with these issues, the industry must overcome regulatory hesitancy and uncertainty and ask the questions that must be asked.

Questions were raised about the tradeoff between speed to market and consumer safety if drugs are discovered, developed, manufactured, and brought to market faster. Gottlieb suggested that industry must focus efforts on obtaining postmarket data to get information about side effects before they become catastrophic. He suggested that a more active monitoring system that closely tracks patients taking new drugs would be a good way to collect data. Gottlieb admitted, though, that such a system would be difficult to implement.

–Kaylynn Chiarello-Ebner


First GenerationNext Awards at Interphex 2006

Pharmaceutical Technology and the Interphex 2006 Conference and Exhibition (Norwalk, CT, presented the first GenerationNext Awards for Emerging Leaders in Pharmaceutical Science and Technology on March 21, 2006. The winners, Sandy Cope, senior scientist at AstraZeneca Pharmaceuticals (Wilmington, DE,, Derek Y. P. Ung, a senior biopharmaceutical facility design engineer at Johnson & Johnson (New Brunswick, NJ,, and D. Christopher Watts, a staff fellow at the US Food and Drug Administration's Center for Drug Evaluation and Research (Rockville, MD,, were selected for their exceptional ability to lead, to bring constructive change, and to maintain excellence in their work on the technical, scientific, and regulatory aspects of pharmaceutical manufacturing (including all phases from initial process and formulation development through scale-up to full production). In compliance with one of the award's criteria, the winners were younger than 35 years old.

In addition, honorable mentions were given to Michael Fino, a professor of bioprocessing lead at MiraCosta College (Oceanside, CA, and John Thomas Bradshaw, PhD, a senior development scientist at Artel (Westbrook, ME,

Four members of Pharmaceutical Technology's Editorial Advisory Board judged the award: David H. Bergstrom, PhD, senior vice-president and general manager of Cardinal Health; Rory Budihandojo, computer validation manager at Schering-Plough; Ruey-ching (Richard) Hwang, PhD, senior director of pharmaceutical sciences at Pfizer Global R&D; and R. Christian Moreton, PhD, vice-president of pharmaceutical sciences at Idenix Pharmaceuticals.

Sandy J. Cope

Senior Scientist Sandy J. Cope, PhD, has been part of the AstraZeneca formulation team since 2000, first at its Macclesfield, UK facility, and then at its Wilmington, Delaware office. When she joined the US team, she brought with her insight about the principles of solid dosage form development and research tools the company had not typically used in that process (e.g., dry granulation), which made the group more efficient and effective.

Sandy J. Cope

Cope—who received her BA and PhD from the University of Nottingham's School of Pharmacy (Nottingham, UK)—also trained her colleagues in many new techniques for the manufacture of clinical supplies that were not familiar to the department because of its emphasis on solid dosage form development. She also motivated the staff to work efficiently and effectively in completing the studies needed to finish projects on time. "The training programs were quite good and used materials from many sources that made the training effective. Now, we can manufacture more than just solid dosage forms for early development and have increased the effectiveness of our clinical manufacturing program," said J. Richard Creekmore, manager of process analytical technology and physical sciences at AstraZeneca, in his nomination.

Cope also completed projects that reduced the facility's operating costs while increasing its level of compliance and product quality. Some projects served as models for other facilities throughout the company and were completed at other AstraZeneca locations using the procedures and practices that she used. Cope designed these innovative projects by finding potential solutions or parts of solutions to problems inside and outside the company and putting them together to provide unique solutions to the Delaware facility.

Said Creekmore, "If the pharmaceutical industry had more people like Dr. Cope, many of the challenges and shortcomings of the industry today would not exist or would be more easily solved."

Derek Y.P. Ung

Derek Y.P. Ung, a senior facility design engineer at Johnson & Johnson, was named a recipient of the GenerationNext Award for his technical leadership while working at the human genome sciences manufacturing facility of CDI Life Sciences.

Derek Y.P. Ung

According to Ung, the facility was designed to support the various expression technologies of human genome sciences. "Most biotech facilities have some flexibility in the downstream processing area. This facility is very flexible in the upstream as well. Whatever emerges as their lead candidate, this facility will be able to support. It's also one of the earliest adopters of disposable technology in terms of disposable bag wave bioreactors and disposable in-process bag containers," said Ung.

Ung worked for three years as the lead process engineer on that project. He previously worked as an industry consultant on the Fourth Year Design Project at the University of Pennsylvania, where he provided industry insight and mentorship for biotech design projects. Ung also worked as a commissioning and validation specialist for DowPharma, a technical cell culture specialist at Lonza Biologics, and modeled deionized water and water-for-injection generation and storage systems at GlaxoSmithKline, where his recommendations saved the company more than $500,000.

"It's definitely an honor to be selected by industry peers for an award like this," the 34-year-old Ung said. "The challenge now is to live up to the expectations, but it's definitely nice to be recognized early in life."

Ung currently is working at Johnson and Johnson Worldwide Engineering, where he plans to stay for a while. "There's more and more of a bio focus in the whole pharmaceutical world, and I plan to provide leadership and guidance in that area," Ung said.

In addition, Ung has spent time working on clean utilities water systems and is a member and J&J representative on ISPE's Critical Utilities Community of Practice Steering Committee that's in the process of writing an ISPE baseline guide, of which he is a contributing writer.

"I did my masters in biomaterials and drug delivery, where I was exposed to the biopharma world, and it just seemed like a very challenging area to be in," Ung said. "It's something that is constantly challenging, so it keeps me interested."


D. Christopher Watts

D. Christopher Watts is a staff fellow in the Office of Pharmaceutical Science (OPS) at the US Food and Drug Administration's Center for Drug Evaluation and Research (CDER). He received the GenerationNext Award for his outstanding work on the process analytical technology (PAT) team and for his exceptional ability to communicate, motivate, influence, and guide his peers. Watts directs his talents toward the improvement of the pharmaceutical industry and the betterment of public health.

D. Christopher Watts

"It's exciting to see that the work we've done at the agency has really helped foster innovation within industry," said Watts. He also said he felt honored by the ceremony, "especially when I met my fellow recipients. It was a humbling experience, to say the least."

Watts was a member of the team that developed FDA's PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance guidance for the industry, which lays a regulatory foundation for encouraging industry to pursue innovative development, manufacturing, and quality assurance. He actively engages with industry leaders to explain, promote, and create a common understanding of the PAT initiative. Watt also has led the way in creating a workforce within FDA that has expertise in various fields of pharmaceutical science such as analytical chemistry, chemical engineering and information, and inspection and testing techniques. His work as a leader and trainer has brought valuable knowledge and greater efficiency to FDA.

A consistent theme of Watts's career has been a spirit of teamwork. CDER and FDA separately awarded him for his intercenter collaboration. In turn, Watts believes he is lucky to have worked closely not only with FDA's reviewers at CDER, but also with investigators in the field. "I'm proud of what I've done to this point," he says, "but I'd like to think that the [GenerationNext] award is more a reflection of some of the amazing people I've worked with and what they've done, rather than what I've done."

Watts takes the mission of promoting and protecting the public health seriously, and enjoys working with FDA to achieve that mission. He singled out the good manufacturing practices initiative, question-based review, and the quality-by-design pilot program as initiatives he feels fortunate to have participated in: "Hopefully, we can just continue to maintain that momentum that we've been able to build."

Michael Fino

Michael Fino received an honorable mention for his work at MiraCosta College ( in Oceanside, California. In 2004, the college hired Fino as the lead instructor of its bioprocess technology program and asked him to supervise its reorganization. Until that point, the program had focused primarily on the research-oriented aspects of biotechnology. Because of his eight years in the industry, Fino recognized that companies were seeking individuals with practical experience of biotechnology processes. He selected the necessary equipment and process tools and established a state-of-the-art biotechnology training facility to expose students to the full breadth of biopharmaceutical production. “It’s a very immersive experience for the students,” Fino remarks. Fino also developed a course called “Qualification and Validation in Biotechnology” that teaches biotechnology methods, cleaning, software, and process validation.

In addition to his activities at the college, Fino founded the first Southern California student chapter of the International Society for Pharmaceutical Engineering (Tampa, FL, and became its advisor. He has traveled to local high schools to raise awareness of biotechnology and to encourage students to pursue careers in science. Fino’s goal is “to change people’s expectations of what is possible at a community college.” Through all of his activities, Fino has demonstrated a commitment to spreading knowledge and an enthusiasm for biotechnology.

John Thomas Bradshaw

In recognition of his work as a senior development scientist at Artel (, Pharmaceutical Technology gave John Thomas Bradshaw an honorable mention. Bradshaw was the lead scientist during the development of Artel’s “Multichannel Verification System” (MVS). The system uses a ratiometric absorbance methodology to calibrate, troubleshoot, and measure the performance of automated liquid handlers. “We … presented the first viable commercial system for calibrating multichannel devices,” Bradshaw says.

After he started at Artel, Bradshaw learned the theory behind MVS, which the company’s founder had already elaborated. Bradshaw was intimately involved in early research for MVS and ultimately built prototypes and demonstrated them to people in the field. He “was involved clear up to the launch and beyond,” he explains. Because Artel is a small company, Bradshaw benefited from participating in “some parts [of the project] that traditionally a research and development scientist wouldn’t get to touch.”

Bradshaw has begun research in fluorescence to extend MVS’s capabilities to picoliter volumes and higher-density applications. He believes that 1536-well applications will eventually become the standard, and is preparing the company to adapt to that environment. Bradshaw also is the coholder of patents for an apparatus and method for spectrophotometer calibration, and for a method of testing and validating nonaqueous pharmaceutical solutions.

–Kaylynn Chiarello-Ebner,

Erik Greb, and George Koroneos

Implementing a PAT Strategy

Many companies want to implement process analytical technology (PAT) in their manufacturing lines to better understand their processes, but there are no established best practices for doing so. During the March 21 session, "Establish and Implement a PAT Strategy," Connie Langberg Heinze, manager of PAT Center of Excellence at NNE, Inc. (Soeborg, Denmark, discussed what it takes to implement PAT and recommended a step-by-step strategy for companies to follow.

According to Heinze, a common PAT implementation pitfall is that companies buy a new analyzer for PAT and then decide how to use it in their processes. But to best integrate PAT into processes, "You need to know what you're looking for and how you want to use [the analyzers,]" she said. Ideally, Heinze noted, it's best to implement PAT on new processes to "give you the full benefit of PAT and less regulatory burden," although PAT principles also can be extended to existing systems. In all cases, following a clear implementation plan is the best way to define how and why to bring such technology on-line.

Heinze recommended a seven-step implementation methodology: organize a core PAT team, identify opportunities for improvement with PAT, define a pilot project, investigate possible PAT applications, define control strategies and prepare an implementation plan, communicate with regulatory bodies, and implement PAT.

Discussions about how and why to implement PAT are a vital part of PAT implementation. These conversations should involve cross-functional teams comprising representatives from several departments (e.g., quality control, development, and manufacturing), and input from all team members should be obtained. "Spending days together talking is a productive and easy way to start PAT implementation," said Heinze.

–Kaylynn Chiarello-Ebner


FDA's Risk-Based Model Leads to Strategies for Optimizing Site Risk Potential

Site risk potential (SRP) for a pharmaceutical manufacturing facility is an often-overlooked element of the US Food and Drug Administration's (Rockville, MD, major initiative of a risk-based approach for pharmaceutical current good manufacturing practices (CGMP). Justin O. Neway, PhD, executive vice-president and chief scientific officer at Aegis Analytical Corp. (Lafayette, CO,, outlined at Interphex 2006 how FDA calculates SRP and the approaches that drug and fine chemical manufacturers can use to improve their SRP scores.

FDA inaugurated its risk-based inspection program in September 2004 with the release of the report, Risk-Based Method for Prioritizing CGMP Inspections of Pharmaceutical Manufacturing Sites—A Pilot Risk Ranking Model (

"FDA realized that it did not have sufficient resources to meet the rapidly growing demand for facilities' inspections and initiated the SRP program in response to that," explained Neway. "It is part of the overall shift by the FDA moving from rule-based thinking to a science-based approach as part of the agency's risk-based CGMP initiative."

Last year, FDA piloted a risk-based inspection model for prioritizing inspections based on SRPs. "All manufacturing sites in the United States have been assigned an SRP score," explained Neway. "These scores have been supplied to FDA field offices. Field offices used these scores to prioritize roughly 40 percent of their site inspections in 2005. The goal is to direct resources to areas of highest risk."

The SRP is composed of facility risk, product risk, and process risk. The year of the last CGMP inspection also is factored into the total score. Facility risk takes into account the production volume and the history of inspection, compliance, and previous CGMP violations of that particular facility. Product risk looks at elements such as whether the product is a prescription drug or is over the counter, sterile or not sterile, and the therapeutic significance of the drug. Process risk assesses the process controls and contamination potential of the processes within that facility.

For pharmaceutical manufacturers in 2006, the key is to understand ways in which to minimize the SRP score for a given facility and to have the supporting processes and data access and analysis capabilities in place and in use before the next inspection.

"You can't change the fundamental business or production processes you're already running that dictate the facility and product portions of your SRP score or change your record of past inspections," said Neway. "But, you can improve your understanding of your current processes and use that to identify and improve control of variability going forward and to make better choices when you design your next manufacturing process, thus reducing the process-risk portion of your SRP score and improving your future inspection record." To that end, Neway stressed the need for effective collaboration and information sharing between process development and manufacturing to improve process understanding collaboratively as early as possible in the product life cycle.

–Patricia Van Arnum


RFID and the Future of Pharmaceutical Supply Chains

Interphex 2006 had an upsurge of products and vendors focusing on radio frequency identification (RFID). An entire section of the exhibit hall and several conference sessions were dedicated to the emerging technology focusing on track-and-trace solutions to help combat counterfeiting and diversion of drug product.

In a March 21 session entitled, "RFID and the Future of Pharmaceutical Supply Chains," Mark Roberti, founder and editor of RFID Journal, explained how pharmaceutical executives and IT personnel can implement RFID to secure their supply chain and provide strong e-pedigree systems.

RFID is a general term that defines the ability to identify an object remotely using radio waves to transfer information. Data are usually stored on microchips using active or passive tags that can be read using a variety of frequencies.

Active tags include a power source and transmitter for broadcasting with a typical range of 300 ft. Tags can track high-value assets and can be traced with real-time locating systems.

Far cheaper are passive tags, which have no battery, draw power from the reader, and reflect back a signal. These tags also have a far shorter signal with a typical read range of 15–20 ft.

Roberti explained that the passive tag is made up of several parts, including a microchip that stores data and modulates an antenna that gathers energy and reflects back signals. Tags also are made up of a protective layer and packaging.

Information on passive and active tags can be transcribed by a reader that emits radio waves. The tag converts the RF electricity to power the microchip that then modulates and demodulates the antenna and reflects back a signal. The reader then converts these waves into readable data.

"The technology has been around since the 1970s, but several things have changed," Roberti said. "Prices of RFID tags are falling, standards are emerging, and the Internet and other infrastructure make it possible to share data. RFID is taking off now because of the ability to connect to the Internet . . . It's about information constantly moving."

According to Roberti, the pharmaceutical industry is at the forefront of adoption for several reasons. First, counterfeiting is a growing problem for the industry. In addition, states are introducing regulations requiring drug e-pedigrees. And, retailers are requiring their wholesalers and distributors to use RFID technology.

Purdue Pharma (Stamford, CT, is one of the first companies to put item-level tagging into production. In 2005, Purdue and H.D. Smith (Springfield, IL, ran a three-month e-pedigree pilot in which an e-pedigree was created at the point-of-goods issue. All items were scanned and their electronic product codes (EPC) were recorded and associated with shipment to H.D. Smith. The EPC numbers, product information, and transaction data were stored in the e-pedigree document.

Now, Purdue tags bottles of the highly counterfeited "Oxycontin" for retail juggernaut Wal-Mart. Purdue checks all labels after application to ensure 100% readability. If there is a problem, then the line stops and the bottle is relabeled.

In addition, Purdue puts a digital signature on the e-pedigree when it's sent to H.D. Smith with the product code. H.D. Smith then confirms the authenticity of pedigree. When the product is received, the EPC numbers are checked against the pedigree, and the pedigree is again signed digitally. The chain of custody is then transferred to H.D. Smith.

For adoption of RFID to take off, e-pedigree standards must be established, and the pharmaceutical industry must agree on which frequency to use. Said Roberti, "The price of tags and readers must fall further, and companies must agree on standards and sharing data."

Other challenges lie ahead for RFID to be integrated into pharmaceutical manufacturing. IT systems must be modified to handle e-predigrees, business processes need to take advantage of RFID data, and collaborations with supply-chain partners must be established. And, according to Roberti, as many as 20% of all tags fail because of damage in shipment and temperature flux.

According to recent reports, industry has been very slow in adopting RFID. But according to Roberti, FDA is well on its way to mandating RFID. With individual states creating their own laws for electronic pedigree, the agency will want to reign in legislation at the national level, Roberti said, citing recent legislative proposals as examples.

Brad Todd, a product manager at Escort Memory Systems (Scotts Valley, CA,, told Pharmaceutical Technology that several companies within the pharmaceutical industry use RFID internally for pill dispensing and monitoring, but a full-blown vertical supply-chain rollout is pending the adoption of standards. "Until FDA moves—until we have some broader consensus in the industry—we don't see anything more than pilots going on," Todd said.

Some vendors said that it would take a pandemic to jump-start an industry-wide RFID implementation. Some even stated, off-the-record, that "Tamiflu" may be the drug that sets things off, when or if bird flu strikes the United States. "If people become afraid that they will get sick, they will start hoarding vaccines, and counterfeit drugs will start appearing left and right," one vendor said. "That's when RFID will be taken seriously."

–George Koroneos


New Biodegradable Polyketals Developed for Drug Delivery

Scientists have developed a new family of biodegradable polyketals for the intracellular delivery and sustained release of drugs targeted for acidic environments, including those of tumors and inflammatory tissues. Researchers from Georgia Institute of Technology (Atlanta, GA,, Emory University (Atlanta, GA,, and the University of Rochester (Rochester, NY, have synthesized the polyketal nanoparticles to hydrolyze into FDA-approved hydrophilic compounds.

"One of the interesting polyketals we've made degrades into cyclohexane dimethanol, which is an indirect food additive, and acetone, which is on FDA's list of generally regarded as safe compounds," says Niren Murthy, assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. "The polyketals will degrade into almost any aliphatic carbon with two hydroxols on it."

This process offers significant advantages over the degradations of current polyester-based biomaterials, whose byproducts tend to generate acids that lead to inflammation.

Moreover, current biodegradable polyesters are notoriously slow in their degradation. The process can take months, thereby requiring frequent injections when used to treat chronic illnesses. The newly developed polyketals, however, can hydrolyze in a week.

Some of the polyketals are membrane permeable and can be taken up by cells. When cells take up particles, they naturally move them to a part of the cell with a low pH. A polyketal that goes inside a cell will degrade in the cell's acidic environment and the degradation products such as cyclohexane dimethanol and acetone will then diffuse out of the cell. Therefore, there is no accumulation outside of the cell that can cause inflammation.

The polymers were developed using a straightforward acetal exchange reaction process. "It's normally a reaction used to protect alcohols, but when you make it react with a molecule with two alcohols, it makes this polymer," says Murthy.

Murthy also explains that the polymer's hydrolysis rates and mechanical properties can be tailored to modify drug-release rates. "With acute liver failure, you want drug release in one to two days, whereas with arthritis, you want release over one to two months."

Polyketal-based delivery would be suitable for antioxidants to treat acute liver failure. Murthy also says there is a potential application for protein-based vaccines or protein-based therapeutics such as insulin.

"We've already been able to encapsulate proteins in polyketals and we have been able to get beautiful SEM images showing that protein is active," says Murthy.

The researchers currently are investigating the treatment of chronic and acute inflammatory diseases and hope to start animal studies in three months.

–Maribel Rios


Global Pharmaceutical Market Shows Moderate Growth

The global pharmaceutical market experienced moderate growth in 2005, with North American sales* increasing slightly more than 5% from 2004, according to a recent analysis by IMS Health Inc. (Fairfield, CT, Other key trends are continued strong growth in China, a rise in the number of drugs reaching blockbuster status, projected strong growth in generics, and an increase in the number of biologic-based drugs in the pipeline.

Total global pharmaceutical sales increased 7% to $602 billion in 2005, IMS said. In the ten major markets, which account for 81% of total global pharmaceutical sales, growth increased 5.7%, compared with 7.2% in 2004.

North America, which accounts for 47% of global pharmaceutical sales, grew 5.2% to $265.7 billion, while Europe experienced a somewhat higher growth of 7.1% to $169.5 billion in 2005. Sales in Latin America grew 18.5% to $24 billion, while Asia Pacific (outside of Japan) and Africa grew 11% to $46.4 billion. Japan—the world's second largest market, which has historically posted slower growth rates—performed strongly in 2005, growing 6.8% to $60.3 billion, its highest year-over-year growth since 1991, according to IMS Health.

Pharmaceutical sales in China grew 20.4% to $11.7 billion in 2005, representing the third consecutive year that the market has achieved growth of 20% or more. IMS estimates that China will be the world's seventh largest pharmaceutical market by 2009.

Overall, IMS forecasts that the total pharmaceutical market will expand at a compound annual growth rate of 5–8% over the next five years. North America and Europe are projected to grow 5–8% each, Asia Pacific and Africa to grow 9–12%, Latin America to grow 7–10%, and Japan to grow 3–6%.

Increased number of blockbuster drugs

The number of blockbuster products (those with sales exceeding the billion-dollar level) reached 94 in 2005, compared with 36 in 2000, according to IMS Health. This included 17 new drugs reaching blockbuster status."The end of blockbusters is not upon us, despite what some analysts are saying," says Murray Aitken, IMS's senior vice-president for corporate strategy. "In fact, we expect that blockbusters will continue to be an important part of pharmaceutical market growth over the next five years, due to new uses for existing therapies, the emergence of niche and specialty products, and the ongoing demand for chronic disease treatments."

Six blockbusters are expected to lose their patents in 2006, which will contribute to further growth in the generics market. In 2005, combined sales of generics in the top eight markets (Unites States, Canada, France, Germany, Italy, Spain, United Kingdom, and Japan) exceeded $55 billion, and are expected to experience double-digit growth by 2011, according to IMS.

Pipeline increases

In 2005, more than 2300 products were in clinical development, up 9% from 2004 levels, and up 31% over the past three years, according to IMS. A breakdown of drugs in Phase III clinical trials or preapproval stage shows 96 oncology products, 51 products for treating cardiovascular disease, 37 for viral infections and HIV, and 28 for arthritis and pain. Of the total pipeline, 27% of these products are biologic in nature—an all-time high, according to IMS.

–Patricia Van Arnum

*The data in the IMS analysis reflect pharmaceutical sales figures measured in current US dollars, include prescription and certain over-the-counter data, and reflect ex-manufacturer prices. Growth in sales is measured in constant dollars.