The American Association of Pharmaceutical Scientists (AAPS) has announced its 2007 AAPS Fellows, cited for making "remarkable scholarly and research contributions to the pharmaceutical sciences." They will be recognized at the group's annual meeting this week in San Diego, which Bill Swichtenberg will be attending.

Congratulations to each and every one of them.  (If PhRMA would like to launch a new P.R. campaign to improve the public image of the pharma industry, perhaps its marketing types could describe some of these individuals' work in its public affairs material.  It's definitely a nice counterpoint to all the sales and marketing news).

And, for those who remain skeptical about process analytical technologies (PAT), or who think Quality by Design is the FDA's latest "flavor of the month," consider that at least two of these Fellows are very closely involved in both these areas.

 More on each of the fellows below:

Kenneth R. Morris, Ph.D is currently a Professor and the Associate Head of the Industrial and Physical Pharmacy Department at Purdue University . He has worked in the academic, industrial, and governmental sectors in both the pharmaceutical and environmental disciplines. His main research contributions have been in the area of pharmaceutical materials science and engineering. These pursuits led Dr. Morris to develop advanced techniques to monitor processing stress-induced changes for use in developing predictive models, and he emerged as the academic thought leader in the areas of quality by design, PAT and other important pharmaceutical product development initiatives.

Moheb M. Nasr, Ph.D is the Director of the Office of New Drug Quality Assessment, Center for Drug Evaluation and Research , U.S. Food and Drug Administration. He is responsible for providing executive leadership, scientific expertise, and overall technical direction to 150 multidisciplinary pharmaceutical scientists, chemists, engineers, and medical professionals engaged in the regulatory and scientific evaluation of Chemistry, Manufacturing and Controls (CMC) for all Investigational new drugs, and new drug applications intended for human use. Throughout his distinguished career at the FDA, Dr. Nasr has exemplified the spirit of distinguished public service through outstanding scientific and scholarly contributions to improving human health.

Mansoor M. Amiji, Ph.D is a Professor and Associate Chairman of the Pharmaceutical Sciences Department at Northeastern University , and Co-Director of the Nanomedicine Education and Research Consortium (NERC). Over the past 15 years, Dr. Amiji has contributed to the development of novel approaches for surface modification of polymeric biomaterials to improve biocompatibility, micro- and nanotechnologies for target-specific drug and gene delivery, and newer generations of multifunctional nanostructures for biomedical and pharmaceutical applications.

Steven Baertschi, Ph.D is a Research Fellow in Analytical Sciences R&D at Eli Lilly and Company, Indianapolis , Indiana . Over the last 18 years he has made significant contributions to the pharmaceutical sciences in the areas of drug stability, stress testing/degradation chemistry, photostability testing, and the development of analytical methodologies. Dr. Baertschi’s work in delineating degradation pathways has demonstrated the importance of using a "chemistry-guided approach" to solving complex stability problems and to the development of stability-indicating methods.

Ajay K. Banga, Ph.D is Professor and Chair in the Department of Pharmaceutical Sciences at the College of Pharmacy and Health Sciences, Mercer University , Atlanta , Georgia . His research expertise is in non-traditional approaches for transdermal drug delivery. Dr. Banga has investigated transdermal iontophoretic delivery of water soluble drugs for several years and more recently is also using microneedles and other approaches for transdermal delivery of macromolecules. He has just published a theme section on transdermal delivery of proteins in Pharmaceutical Research as a guest editor.

Peter L. Bonate, Ph.D.is currently Senior Director of Pharmacokinetics at Genzyme. His research has involved the exploration of new modeling and simulation methodologies and their application to drug development. He was one of the pioneers in using linear and nonlinear mixed effects modeling of exposure-QTc interval data. Dr. Bonate has been or is currently on the editorial advisory boards of the Journal of Clinical Pharmacology , the AAPS Journal , and Pharmaceutical Research , and he has more than 40 publications in the field of pharmacokinetics and clinical pharmacology

Piet Herdewijn, Ph.D. is one of the founders of the International Society for Nucleosides, Nucleotides and Nucleic Acids and is a member of the Belgian Academy of Medicine. He has taught the course of medicinal chemistry for 20 years at the Katholieke Universiteit Leuven in Belgium and is the head of the laboratory of medicinal chemistry in the Rega Institute for Medical Research, Belgium . Dr. Herdewijn contributed to the medicinal chemistry of nucleosides, oligonucleotides and peptides with applications in the anti-infection and antitumoral field. He has published 500 articles in international journals on these topics and, more recently, he discovered nucleoside triphosphate mimics that are accepted as substrate by HIV reverse transcriptase.

Donhgho (Robert) Lu, Ph.D. joined the U.S. Food and Drug Administration/ONDQA in 2005. Prior to his FDA career, he was a full professor in pharmaceutics at School of Pharmacy , Temple University , and an associate/assistant professor at College of Pharmacy , University of Georgia . Dr. Lu’s academic research interests have included the development of gene delivery and controlled-release systems, and the syntheses of pharmaceutical compounds with enhanced targeting properties

Tobias Massa, Ph.D. has supervised the regulatory strategy and authoring of chemistry, manufacturing and control sections of 20 globally approved pharmaceutical products and over 150 investigational drug applications. He is currently responsible for managing the CMC regulatory strategy for a portfolio of over 50 products in development and 300 approved products globally for Bristol-Myers Squibb Company. In addition to his corporate responsibilities, Dr. Massa has had a leadership role in efforts to refine regulatory policy for the manufacture and control of synthetic and biological products. He has chaired numerous industry committees on topics such as submission content, change control, specifications, biologics regulations and utilization of biologics manufacturing facilities.

Carlo Rossi, Ph.D.started his research career in the chemistry of natural products field. In particular, he studied the holothurinogenins, toxic saponin principles produced by the Actinopyga agassizi , a marine animal that is very active against its predators. More recently, Professor Rossi turned his scientific interests on the pharmaceutics and drug delivery areas, where he continues to be active. Noteworthy is the research line by which he developed, in a close collaboration with a group of MDs, multifunctional composite microcapsules as potential artificial bio-hybrid organs as a final cure for the type I diabetes mellitus.

Mandip S. Sachdeva, Ph.D.is a professor and section leader for the pharmaceutics activity at Florida A&M, College of Pharmacy . He has made significant contributions to the knowledge and understanding in the area of drug delivery with special emphasis in inhalation/aerosol delivery as applied to lung cancer and topical delivery of neuropeptides. He has used a multidisciplinary approach of not only delivering novel anticancer agents by inhalation drug delivery but also looking into their mechanism of action to look for newer targets. During the last 20 years, besides developing new approaches for improved drug delivery to the lungs and through the skin, Dr. Sachdeva has identified new molecular pathways and mechanisms for therapeutic agents intended for the treatment of lung cancer and skin inflammation.

Robert M. Straubinger, Ph.D Dr. Straubinger’s research in the field of biopharmaceutics focuses primarily upon drug carriers, drug targeting, and drug delivery. His sustained research on the taxane anticancer agents represents a comprehensive exploration of biophysical factors that determine formulation stability, as well as the pharmacological consequences of formulation properties. This work is described in approximately 14 publications and several patents, and resulted in the development of improved, liposome-based formulations of taxol (paclitaxel) having reduced toxicity.

Shinji Yamashita, Ph.D.has conducted continuous research on oral drug absorption and has published many important articles in this field. He is best known for his pioneering work on the development of in vitro and in situSumie Yoshioka, Ph.D. has been involved in fundamental studies with particular emphasis on the difficult and complex area of solidstate stability for more than 25 years. Dr. Yoshioka has published over 100 papers in peer-review journals and provided important leadership in the application of such science to regulatory and health policy issues world-wide. Achievements in her research include: elucidation of the importance of the role played by the physical properties of molecules in the solid state in determining the tendencies for such systems to undergo both physical and chemical instability, and work on solid-state stability using nuclear magnetic resonance to quantitate various types of molecular motions and to demonstrate their role in promoting instability.

Installment 6

Installment 5

ISPE management deserve special praise for inviting a high-ranking engineer from a generic pharmaceutical manufacturing company---in this case, the rapidly growing Teva, to speak at this meeting. 

As  ISPE vice chair Bruce Davis affirmed, generics manufacturers are not "the enemy," but an increasingly important part of the global healthcare system.  They also face margin and profit pressures that present a possible future scenario for pharma innovators---pressures that demand that they embrace new ways of doing things. 

So far, Ajaz Hussain has been fairly quiet about development and manufacturing challenges at Sandoz, so it was interesting to hear from Uri Boneh, director of global engineering at Teva Global Generic Resources, about how the company has applied GMP principles and some Toyota-esque principles to the building of a new oral solid dosage manufacturing plant in Jerusalem.

As Mr. Boneh said, "Tomorrow ---and at least half of the next decade---is already here. We have to think about what we'll do after that point.:

The facility has been designed to facilitate expansion, he said.  I wished that he'd focused a bit more on "how" but assume that would have been considered giving away trade secrets. 

Mr. Bonet devoted a great deal of his presentation to affirming the fact that oral solid dosage manufacturing is still fairly low tech and labor-intensive, and has been operated the same way---using mixing, drying, milling, sieving, blending, tablet compression, filling.... for decades. "The market is growing, people are living longer and need more medications...someone has to make OSDs...

"I was sitting last week with leading tablet press manufacturers who showed how equipment had improved….when I asked him how process had changed in last 150 years he had to admit, "not very much," Boneh said.  "I hear that Novartis is working with MIT on long term 10-year project to change the way we make drugs….I am curious….this should be very interesting….maybe in 10 years everything will be different….for the moment, it’s pretty much all the same…."

Mr. Boneh outlined the main functions critical to the process: Warehousing, transport and staging, washing, in process control, tooling and size parts, and noted that conventional production concepts needed detailed planning and control and aimed for high utilization of equipment and other resources.

The result, he said, has been long cycle time and low flexibility. "Like a commander on the battlefield, each department manager would issue work orders but [didn't] know what’s going on in other departments….

To eliminate waste, the new plant was designed with a "pull" focus for production planning and manufacturing. Cycle time is now 1.5 days, where, for some of the company's older plants, it's typically three weeks.

Design for the new plant began late in 2002, by 2005 it was ready for inspection and FDA inspected it in 2006.

"Online quality assurance equipment is there but it is labor intensive," Boneh said, "and results depend on the quality of your staff. You need comprehensive quality systems in place, to prove to yourself and inspectors that you are really in control of what you’re doing.

The new facility uses a newer, crossfunctional approach to operations, he suggested. "We don’t need chief of staff to tell everyone what to do."

Since packaging has to work all the time, it determines requirements for other departments.

Teva has also created virtual production lines or "lean production" lines extending from weighing, granulation, fluid bed drying.  At this point, he says, only packaging is 80-100% utilized.

To use gravity fully, the company needed to build a high facility (several floors), but tall buildings are more expensive, and require more local permitting issues, so Teva eventually decided on a four-floor concept. 

To enhance GMP, a critical part of the facility design was the concept of closed material transfer between process steps, Boneh said. Manufacturing is carried on in production suites, each of which is separated from the others by corridors with airlocks.  Each suite produces one specific product.  Everything is washed inside each suite so that nothing dirty comes out.

Airlocks, meanwhile, enhance separation and ensure that no air is recirculated into the HVAC system. Only cleaned containers, parts and equipment leave the suites.

Production people didn’t like airlocks at first, Boneh said, but they improved overall hygiene.  Once staff pass airlocks they must wear extra protective gear.  Environmental and ergonomic considerations also drove design.  Special focus was given to exhaust air filtration, solvents and thermal oxidation, wastewater treatment and noise reduction.

Teva used simulation extensively to design the facility, which uses a multilevel concept model.  The plant is based in North Jerusalem, where the government offers investment incentives. Teva manufactures globally in 36 plants, Bohen says, and plans to double production by 2012.

It will be interesting to learn more of the specifics of this facility and its design. In the meantime, it was important to see representation from generics at this conference.

AMS

Installment 4

The Toyota Production System is guiding more pharma manufacturing managers today.  To ensure that attendees got the story from its source, ISPE invited a top Toyota executive, Gary Convis, senior executive advisor for Toyota Motor Engineering and Manufacturing, to speak about the system.  Mr. Convis is one of those charged with keeping Taichi Ohno's (shown, left, during a plant inspection in the 1950s) flame burning within the corporation.

Convis noted the company's phenomenal growth.  In 70 years, Toyota has become the world's leading automotive manufaacturer, making product in 64 companies and 27 countries with nearly 300,000 employees.  Toyota employs 40,000 people in the U.S. alone, creating "spinoff employment" of 400,000.

 However, he says, the auto industry shares the difficulties that pharma may face in attempting "right first time" production and in bringing human beings into the equation.  The struggle is to do R&D right, while meeting customer demands and reducing costs.

 He recalled coming to the U.S. in 1957, when Toyota sold its first vehicle, the Crown, in the U.S.  The model was an utter failure, lacking sufficient power to make it up the California hills and along the freeways.  Toyota pulled it out and bcame back three years later with an improved model.  The company has invested over $18 billion in its U.S. manufacturing operations and has two new plants under construction, one in Woodstock, Ontario, Canada, and the other in Mississippi.

When he first went to Japan, Convis says, he saw that operations ran like an orchestra. "Everyone seemed to know exactly what to do.  They all played their tunes in perfect harmony, as if under the influence of an invisible conductor.  I knew this could only happen in an environment characterized by teamwork, cooperation and continuous improvement."

Convis was hired to implement TPS in Fremond California, in a closed factory where management and operations relationship was terrible and product quality was poor.  The plant had been shut down for three years, and the company wound up rehiring 85% of the old workforce.

Convis likens Toyota engineers to physician/diagnosticians. "They observe the process, diagnose problems, and decide, together, how to solve problems and how to look for ways to improve."

One prerequisite is motivating people toward the ideal, by developing systems and tools that make it clear where to focus management attention.  These visual tools include production analysis boards, direct run, process diagnostics, stacked element charts and KPI charts.

He also advises, go and see what people on the floor are doing.  Convis says he parks his car about a quarter mile away from the production plant, and takes a different route to his office (which he moved, several years ago, from the building entrance to the plant floor area) each day, just to talk with, and watch, a different work group.

"The highest product quality, lowest costs and shortest lead times can only be gained by engaging and developing people," he said.  "Don't cheerlead.  Go and see what your people are doing, grasp actual conditions, observe carefully, humbly benchmark against others and listen carefully to what others are saying."

He recalls a technique of Taichi Ohno (father of the Toyota Production System):   "When he was training people, he'd draw a circle around them on the plant floor and say, "Look, stay here and observe what's going on."  It's amazing what you can learn by doing this."

Convis emphasized the importance of using standard tools and standardized work processes to solve problems.  He also says that "customer" needs to be understood, not only as the final distributor or consumer of the product, but the next person in the product value chain---the person dependent on whatever work you have been assigned.

It would take some transformation to get pharma facilities to resemble car factories in their use of 5-S and standardized work processes, as well as continuous flow, pull systems, kanbans and visual management.   Convis visited some plants and noted the huge inventories of incoming material, works in progress and finished goods.  "There's great opportunity for continuous improvement," he noted. "IN particular, reducing the inventories of incoming materials."

Convis also gave listeners a brief Japanese lesson, discussing Jidoka, and the need to build quality into the manufacturing process, mentioning error proofing (poka yoke) and Andon, the process by which management, maintenance and other workers are notified of any quality or manufacturing problem.

Heijunka, or leveling the work, is also the key to reducing quality fluctuations, he said.

Convis emphasized the importance of the individual and the "help chain," in which employees expose and attack problems, seek out their root causes, then move to fix them and avoid future occurrences, one by one.

Toyota views people as its most important asset, and, typically goes through 100 people to hire just three or four, he said, summarizing some of the key aspects of any successful manufacturing program as:.  

• Kaizen

• Genchi genbutsu - going back to the source, discovering the facts and building consensus about how to solve the problem

• Teamwork

• Respect

• Involvement

AMS

A recent survey by the Lean Enterprise Institute (LEI) finds that most middle managers are still selling Lean programs as a way to cut costs.  When those cost savings don't magically appear in short order, senior management often pulls the plug on the programs, a state of affairs familiar to many pharma companies. 

Bill Swichtenberg analyzed the report and chatted with LEI Director Chet Marchwinski recently. For more, read on.

The key may lie in handling performance reviews for these middle managers quite differently.

Average OEE in pharma is still in the 30's.  At the Pack Expo last week, Heidi Parsons interviewed technical experts from Bosch and Parsec Automation for their insights. Among other topics, Europe's EN 954 was discussed in connection with downtime and safety problems. To watch, click here.

Greetings from Las Vegas, all, where PackExpo is in full swing.  I haven't been able to see many booths yet, but I've heard presentations from David Ray at Parsec Automation and Bob Naegle at Videojet, each of which was exciting in its own way.

Ray gave a thorough explanation of how Parsec's real-time process management software can help manufacturers determine Overall Equipment Effectiveness (OEE). He provided enlightening examples of how seemingly minor problems in efficiency or availability can quickly lead to significant production losses, and conversely, how much extra money a small gain in OEE can generate over a one-year period. Ray is a Six Sigma Black Belt, so he isn't just selling a product.

Naegle detailed Videojet's new line of track-and-trace solutions, developed through the company's recent acquisition of Prism, a data management software provider. The Prism software leverages Videojet's marking and coding capabilities to create sets of unique codes with parent-child relationships between codes used at the package, case and pallet level for ultimate traceability. The flexible system allows pharma manufacturers to specify their preferences for alphanumeric code, serial 2-D codes or complex 2-D codes, to upload the software to their own or Videojet-provided computers, and to use internet-based programs to track when and where those codes are scanned. This system seems promising both for anti-counterfeiting and anti-diversion as well as for product recalls.

More to come; time to head to another meeting. 

-HP

At the very least, let's rename QbD "Intelligent Design." That way, columnist Emil Ciurczak quips, we can get faith-based government funding to teach it in U.S. public schools. 

For more on Quality by Design and the disconnect with some Pharma H.R. departments read Emil's latest column (posted below for the link-averse):

-AMS

The Perfect Storm*

I was perusing the “Positions Available� section of Chemical & Engineering News (just looking, I enjoy not showing up five days a week at the same place) and, as usual, grumbling about the descriptions. One that always gets me is the desire to place an Organic Chemist in charge of an Analytical department. I often see someone in charge of something and comment that I could easily DO the job, but that I could never GET the job. There is a tendency to advertise for the person currently holding a position, not for someone to do a better job. That might prompt a “You’re overqualified for the position,� from the HR department.

Think about that statement for a second. Were you to need an operation, would you tell a doctor, “No, you’ve performed too many heart transplants - you’re overqualified?� Somehow, I doubt it; but we seem to think chemists, pharmacists and process engineers become worthless when they have experience. Perhaps the quote should be, “No. I think we can find someone to work for less money.�

That got me to thinking about our narrow-minded industry. Years ago, while I was at Sandoz, the Colors and Chemicals division moved to South Carolina, leaving a number of employees to seek other positions. Since internal hiring was our practice, I suggested that a woman I knew to be a super chemist submit an application for our section. At the time, I was in the QC department doing my original NIR work (early 1980s). After several weeks, her application had not appeared. When I enquired as to its status, I was told by HR that she didn’t have the buzz words, “USP and routine tests� on her resume, so they ignored it.

She eventually got the job. She and I worked together and presented several NIR papers…but, not because of any help from the HR people. She was to be doing method development and those words don’t appear on any QC job description!  She was perfect for the job, but couldn’t get it.

Makes me wonder how we expect QbD and PAT to succeed. Since they are new, there are very, very few job descriptions with those “buzz words� included. Fewer still are resumes with QbD or PAT as accomplishments or goals. As a horse will run back into his burning stall when he panics, so, I fear, will management and HR fall back on “tried and true�  (or is that “tired�) descriptions and position-filling procedures. One problem with filling a position with someone who has dome nothing but that job is that there is no cross pollination. Since the paradigm has changed with QbD, doing the job the same way with the same personnel…well, refer back a few columns to the definition of insanity.

I fondly recall the cross-training I received at Ciba in 1970: one week making tablets, one week in sterile products, one week in clinical packaging, etc. When I started my “real� job I had an understanding of where my position fit into the overall scheme of things. While I was tasked with measuring package/product interactions, I had sampled a full-sized V-blender, made my own chewable vitamin C tablets, made pre-formulation compatibility samples for stability testing, and worked with the consumer products (like Binaca breath spray). Do companies take the time to do this cross training anymore? Whence cometh then QbD personnel, prithee?

Once more, with my firm grasp of the painfully obvious, I would like to make a simple suggestion. Would it be all that hard to do some cross-pollination within departments? On a larger scale, The Swiss giants (at the time still independent) Ciba, Sandoz, etc. had continuous exchange programs for US and Swiss scientists so that they could familiarize themselves with the other groups within the company. It was much easier to work from another continent when you knew the faces and job skills or your overseas colleagues.

Now, extrapolate this to QbD; wouldn’t it behoove a Physical Pharmacist, setting parameters for new APIs, to actually work on a compression line and see the potential problems? How about pre-formulation people actually being concerned with real stability issues? One immediate benefit of the cross-training program at Ciba was when a formulator (Glenn van Buskirk, by name) was reformulating a chewable Ritalin tablet. Before he proceeded to stability trials, he asked if the new ingredients might interfere with the current assay. In fact, the red dye (they were cherry-flavored, if I recall) interfered with the colorimetric assay, which developed a red color for spectrometric quantification. His awareness of another department’s potential dilemma allowed Analytical R&D to develop a new assay before it was needed.

How much better would a QbD program be run if all the members of the committee had a smattering of knowledge of each step in the production of a solid dosage form?  Unless we start to work as an organic unit, we may as well break out the slickers and life vests; it’s gonna get ugly before the weather breaks.

References:*From the book and movie of the same name: implying all (weather, in that case) conditions coming together to wreak more havoc than any one by itself.

As we found in developing articles for our August issue, pharma is embracing the Toyota Production System (TPS), but mainly one pillar of that system: Kan ban, or Just in Time.  Waiting to be developed is Jidoka, the other pillar of TPS.  People can't always agree on what it means says U.K. based ABB Robotics pharma industry segment manager, Bengt Stom.   We'd asked Bengt for his views on Jidoka and for pharma's readiness to embrace robotics.  Here's some of what he had to say.

PM Why isn't use of robotics gaining traction faster in pharma?

B.S. That pharmaceuticals companies have been reticent in addressing the use of robotics stems largely from the recent history of producing very large volumes of similar product 24/7 with no need for flexibility. Such production often lends itself to fixed automation whereby recipes never change.

However, as pharma companies [move away from the blockbuster drug model], the need for  flexibility in both volumes and packaging types will pressure manufacturers to [look for new ways to] introduce ever greater flexibility.This is where robotics technology always beats fixed automation systems.Of course, there is also the perfectly normal human prejudice of ignoring the unusual or unfamiliar because it challenges conventional thinking and experience.

PM How is Jidoka being incorporated into robotics products for pharma today?

B.S. There is widespread confusion over how to define Jidoka.Some interpret this as simply the ability to automatically stop a system if things go wrong. I prefer the more holistic concept that the automation system is intelligent enough to assess what is going on and act accordingly – rather as a human might.
What is needed is a combination of software and hardware.  By incorporating vision systems, weighing transducers and proximity sensors, the robots can be instructed to act in accordance with the performance of the overall system.  In other words, if a line slows, or product flow falters, the robots simply adjust their actions accordingly.  The key to the integration of this proven hardware lies in the ability of the software to integrate the robot controls with the senor data provided.  This software is also made simple to use in order to open up the possibility for increased machine intelligence to everybody.

PM How far is the industry from embracing the concept of artificial intelligence

BS Again, the question begged is “what constitutes artificial intelligence?�. If this simply infers the ability of a machine to make rudimentary “human like� assumptions and decisions, then many automation systems already have artificial intelligence.  However, if what is meant is the ability of machines to learn, then I think this is some way off yet.  The solution to true artificial intelligence lies with computer scientists, ancillary sensor designers and software developers

In a recent Bloomberg interview (watch a clip here), consumer advocate Ralph Nader commented on the U.S. automotive industry and whether or not it can meet proposed fuel efficiency standards (he believes requirements will ultimately be watered down). 

He says that U.S. automotive companies have all the technical expertise required but have been focusing more on engine development for bigger and better SUVs than on fuel efficiency, he says.  In the meantime, he suggests that Detroit's suppliers are harnessing innovation far more effectively than the automakers themselves.  GM's motto, he says, should be "going backwards into the future."

Is there a parallel here for Big Pharma?  Columnist Girish Malhotra thinks so. 

(On the subject of Chinese imports, Nader believes that the U.S. and China should establish a consumer protection treaty.  For Part 1 of his Bloomberg interview, click here. )

Here's Mr. Malhotra's essay.

Generic drug manufacturers must grapple with the tightest of all pharmaceutical profit margins. This is especially true of generic manufacturers in developing countries. Branded drug makers had not suffered from such constraints in the past, but this situation is about to change.

As key drug patents expire over the next five years, manufacturers of name-brand pharmaceuticals will lose about $100 billion in revenue and associated profit to generics manufacturers, at a time when there are fewer blockbuster drug candidates in the pipeline and costs for drug discovery, development and commercialization have escalated.

Branded pharma is also seeing increased competition from generic manufacturers in developing nations. Despite cost and other pressures, Indian and Chinese generic manufacturers have challenged existing business models, and are realizing the benefits of intellectual property (IP) protection by developing patents of their own, channeling increased profits into developing branded drugs.

Big Pharma could learn a few lessons in manufacturing efficiency and agility from some of its generic competitors in Asia. History is full of examples like this: 60 years ago, an obscure company in Japan began to pursue manufacturing innovation. Toyota soon surprised Detroit and the world with what it had learned.

Today, name-brand drug companies are attempting to improve margins by consolidating or outsourcing manufacturing, repositioning their R&D and realigning their sales forces. But have enough of these companies looked at how they are designing their processes for API manufacturing? So far, unlike generics manufacturers, especially those operating in the developing world, branded drug makers have had little incentive to reduce drug prices to consumers, or to reduce their own costs.

Efforts to cut manufacturing costs must be escalated. Today, most drugs are still produced by inherently inefficient and costly batch processes. Very little has been done to advance improved batch and continuous processes in pharmaceutical manufacturing. This is a real shame because the benefits of better manufacturing methods and technologies can be realized quickly.

FDA is encouraging implementation of process improvements in the manufacture of active pharmaceutical ingredients (API) and dosage formulations. Conversion yields of most existing commercial API processes are poor, resulting in wasted raw materials, inefficient manufacturing and unnecessarily high costs to the consumer. A quick and concerted effort is needed to improve API manufacturing, involving a thorough understanding of process chemistry, reaction kinetics, physical chemistry, unit processes and their incorporation into the simplest unit operations. The results will not only be high conversion yield but “greener� manufacturing processes.

As to the naysayers, let history be their guide. In the early 1970s, when the global environmental movement arose, many believed that effluent regulations would bring manufacturing to a stop. They didn’t. Instead they improved efficiency, as those who complied with the new regulations improved their processes, which led to greater profitability.

Pharmaceutical manufacturing has been meeting environmental standards and FDA guidelines. But FDA and EPA cannot force manufacturers to improve their operations or reduce cost. Change must come from within.

Will that change ever come? Recently, I saw a reaction process that took about 60 hours to carry out. The same reaction step could be done in a different way without altering the basic process, reducing the cycle time by 75% and increasing the process capacity by the same percentage. ROI for this project could be realized in about three months.

There are many other examples of different API chemistries where improving cycle times and conversion yield will improve margins, reduce waste and environmental emissions, and reduce the cost to the customer — a win-win for all.

Toyota transformed automaking, not only with its business process management system but also with the engineering and improved fuel efficiency of its engines. If Big Pharma does not begin to innovate in its manufacturing and use of process control, it, too, may meet the fate of automakers who were slow to respond to market forces.