Michelle Hoffman, editorial director of Pharmaceutical Technology.

Michelle Hoffman

Just when you thought the question of federal funding for embryonic-stem-cell (ESC) research had been settled, along comes a shocking decision by Royce Lamberth, chief judge of the Federal District Court for the District of Columbia, to remind you it's not. In August, Judge Lamberth made a decision that halted all federally funded ESC research. The decision was made in favor of the plaintiffs, Drs. James Sherley and Theresa Deisher, in their second attempt to sue the US Department of Health and Human Services (HHS), HHS Secretary Kathleen Sebelius, and the National Institutes of Health. The plaintiffs, who work exclusively with adult stem cells, allege that "obtaining NIH funding is necessary for their continued research," wrote Judge Lamberth in his decision. The judge goes on to say that, "allowing federal funding of ESC research ... increases competition for NIH's limited resources," and that such increased competition "is an actual, imminent injury." Later in the decision, Judge Lamberth writes, "the Guidelines [allowing federal funding for ESC research] threaten the very livelihood of plaintiffs, Drs. Sherley and Deisher." 

The plaintiffs filed a similar suit last year along with a list of other plaintiffs that included "embryos," and were denied standing. Acting as the only plaintiffs, Drs. Sherley and Deisher appealed that decision and were granted standing earlier this year.  Writing the opinion for that appeal, Circuit Judge Ginsburg of the United States District Court for the District of Columbia said that permitting federal funding for ESC research so intensified competition for grants that the plaintiffs "will have to invest more time and resources to craft a successful grant application. That is an actual, here-and-now injury." Judge Ginsburg continues with, "The Doctors will suffer an additional injury whenever a project involving ESCs receives funding that, but for the broadened eligibility in the [federal funding] Guidelines, would have gone to fund a project of theirs." 

In all likelihood, the plaintiffs are using the "competition" argument to put an end to a technology they oppose on moral and/or religious grounds. A flyer promoting an April presentation at the Massachusetts Institute of Technology by Dr. Sherley identifies him as an "outspoken critic of human embryonic stem cell research" because it promotes "the destruction of innocent human beings." And the website for AVM Biotechnology, for which Dr. Deisher is listed as "Managing Member and Research and Development Director," advertises its work on "adult and other morally acceptable stem cell therapies" as part of its program to deliver "effective and affordable prolife therapeutics." 

At the moment, the injunction has been temporally lifted pending further legal action. Nevertheless, the opinion itself, not to mention the on-again, off-again support for ESC research, will undoubtedly have a chilling effect on the future of ESC research in particular, but may also have implications for grant funding in general.  

By virtue of this decision, the courts seem to be setting a precedent for any researcher in any field to quash competition and improve their own chances of being funded.  

It is discouraging to think we will be perpetually stuck in an argument over ESC research, and it would behoove us to have a national discussion to decide once and for all whether we'll fund the research. It is disgraceful that a specious argument intended to stifle one field of scientific inquiry could potentially stymie any legitimate scientific pursuit, and it defies reason that our legal system could defend such an argument and fail to recognize the broader consequences. 

Science is a competition of ideas, with newer ones supplanting the old. Public funds to support research are limited, and our system—although not perfect—is meant to reward the best ideas with the most funding. Hopefully, the courts will permanently reverse this decision. Hopefully, too, we'll find a better way to negotiate the difficult moral issues inevitably raised by our scientific advancements without threatening the entire system that generates them.  

After reading your "From the Editor" article in the October 2010 issuetitled "This Again?" it's clear that the editor-in-chief of a majorpharmaceutical publication such as this has ventured off of science andinto the political world without knowing the facts.  To make thestatement that "in all likelihood" the plaintiffs are using thecompetition argument when they really have moral and/or religiousobjections to embryonic stem cell research is speculative at best andexposes your position.  It is very possible and likely that they dohave moral objections, but to say that their competition argument isunfounded shows that you don't understand how competitive it is forfunding.  Funding dollars are not unlimited and to blindly head down apath that has shown absolutely no success in any area of treatment isirresponsible and foolish.  Stem cell therapy has been tremendous fromsources that make sense, those that are not a risk of rejection andtumor growth.  To starve this area of funding and put it toward ESCslows down the rate at which we can legitimately help people who arehurting and dying while we play politics with an unfounded field. Don't you get it that ESC is being pushed not for real science but forpolitics and to devalue human life at all stages.  You cannot use ESC'swithout cloning someone and quite frankly, President Bush's originalfunding limit forced our scientists to find an ethical way to generateESC's which has been done by inducing skin cells into pluripotentcells.  These cells have not shown rejection issues like ESC's and haveshown promise in therapies.  Finally, your statements put women at riskin search of eggs that scientists will need for research.  Collegestudents, poor women, lured by dollars, will be put through anextremely dangerous procedure in the name of science when it isabsolutely unnecessary.  Please look into this topic closer and I thinkyou will recognize that we are fortunate so many people are objectingto this research for legitimate reasons.

Articles

The reopened debate over embryonic-stem-cell research could stifle many other scientific pursuits.

This Again?

 with Matthew Stober, global head of technical operations at Novartis.

Not so very long ago, vaccine development and manufacturing was something of a backwater in pharmaceutical R&D and manufacturing programs. Now, suddenly it's at the forefront. After all, Wyeth's (Madison, NJ) vaccine program was one of the attractions making it an acquisition target for Pfizer (New York). What's more, several analyst reports place vaccines as the highest growth sector of biopharmaceutical programs. What's happened lately to catapult vaccines into the spotlight?

(PHOTOS: PAUL TEARIE, STOCKBYTE, GETTY IMAGES SAM SARKIS, PHOTOGRAPHER'S CHOICE, GETTY IMAGES) 

A few things. The outbreak in recent years of two widespread and potentially fatal strains of flu elevated influenza from medical inconvenience to public-health emergency. Second, well-publicized delays in producing vaccine against the H1N1 pandemic strain in 2009 highlighted how ineffectual is the traditional manufacturing paradigm in responding to sudden large-scale outbreaks of influenza. Both events placed new pressures on manufacturers to find novel, more responsive, more scalable methods for vaccine production. 

Indeed just this past August, the President's Council of Advisors on Science and Technology (PCAST) issued a report to the president on ways to reengineer the entire influenza vaccine manufacturing enterprise to meet the challenges of a pandemic influenza outbreak. At the same time, the Department of Health and Human Services (HHS) issued a report describing how government and industry could work together to tackle pandemic influenza, and according to a recent press briefing by HHS Secretary Kathleen Sebelius, the Obama administration proposed a $2 billion strategy to create a more "nimble and flexible" system for responding to novel pathogens (see Washington Report). 

But switching to new manufacturing paradigms will not come easily or cheaply. For one thing, the traditional platform already has regulatory approval. But FDA released a guidance in February 2010 that paves the way for novel formulations and manufacturing approaches. Even if regulatory roadblocks were removed, however, there remains the stark economic reality that traditional influenza vaccine is a low-margin business, which leaves little incentive for innovation. Notes Rahul Singhvi, president and CEO of Novavax (Rockville, MD), "If you looked at the vaccine landscape today, it would be tough to say that influenza is a good area to go into given that five companies dominate the market and that the vaccine is basically a commodity." The trick for companies looking to move the technology forward is to find a solution as economical as it is effective.  

Influenza vaccine has traditionally been manufactured by a pretty dowdy process, one that has remained largely unchanged for the past 50 years. The process begins when the Centers for Disease Control and Prevention (CDC) identifies the specific strain of virus causing a particular outbreak and makes "seed" virus available to vaccine manufacturers. 

In the most basic manufacturing scenario, seed virus is introduced into fertilized chicken eggs, where it reproduces in large numbers and is secreted into the allantoic fluid—essentially the white of the egg. The fluid is collected after a few days and purified, and this purified fluid forms the basis of the vaccine. (Because some egg-related matter remains in this formulation, people with egg allergies often experience adverse effects with this vaccine, an additional motivation to move away from egg-based manufacturing.) 

The traditional vaccine contains either live, attenuated, or killed virus particles. Live, attenuated virus can replicate in the vaccine recipient, and can confer immunity without causing disease (at most, it may cause some limited respiratory symptoms). In contrast, killed virus cannot replicate in the recipient, but still confers immunity.  

For the most part, this process with few innovations has reliably produced influenza vaccine for decades—as long as the demand for vaccine is predictable. Most experts estimate that it takes one to two eggs to manufacture each dose of vaccine, so producing some 100,000 doses of vaccine requires a lot of eggs and a lot of advanced planning. Amassing that number eggs can be difficult, to say the least. "It's a scramble every year," says James Gombold, director of testing services for Charles River Biopharmaceutical Services (Wilmington, MA). 

The difficulties don't stop there. The seed virus is replicated many times in the course of manufacturing. But viruses are notoriously sloppy in their replicative fidelity, so the virus in the vaccine can potentially differ from the infective strain—which can result in a less protective vaccine than required 

 "It's a dirty little secret," says Alan Shaw, chief scientific officer and chairman of the board of VaxInnate (Cranbury, NJ) "that you get mutants during passage." 

To circumvent this problem, stringent analytical testing is required—DNA and protein analysis, primarily—to demonstrate homology between the virus in the vaccine and the infective strain, says Gombold, who directs the testing program for Charles River. Additional testing is required to ensure that avian pathogens lurking in the eggs do not end up in the vaccine, although Gombold says that this is probably more a precautionary measure than a response to any known incidence of contamination. Nevertheless, the additional testing adds time and costs to egg-based manufacturing.  

Eggs have been the preferred system for vaccine manufacturing because in general, the virus grows well in them—but not always. H1N1, for example, did not, in spite of what Shaw calls manufacturers' "heroic effort...to make vaccine quickly and appropriately."  

But even if the virus does grow well, says, Shaw, egg-based manufacturing can take longer than expected. "It's an egg-by-egg process," he says. "There's not much of a surge capacity for egg-based business. You can't ramp up by a factor of 20, which you essentially need to do [in a public health emergency]. The point is, the egg system has its days numbered." Many people think cell-based systems may take its place. 

Cells are the natural targets for viruses, so it makes sense to exploit that relationship to manufacture them. Viruses cannot reproduce on their own. They contain the requisite genetic information, but not the replicative machinery. Cells, on the other hand, do. In order to reproduce, viruses penetrate and co-opt the replicative machinery of dividing cells. Fertilized eggs contain dividing cells, but in limited numbers. Dividing cells don't occupy in the entire volume of the egg, so space isn't optimized, in contrast to cells in a bioreactor.  

A bioreactor containing enough cells to produce 50,000 doses of vaccines occupies far less space than do the number of eggs required to produce a comparable batch. Notes George Kemble, senior vice-president and head of research for MedImmune (Gaithersburg, MD), whose FluMist vaccine is currently manufactured in eggs, "Try to make 2000 L of cell culture fluid versus 2000 L of egg fluid. Not to mention the personnel needed."  

Furthermore, the cells used—most frequently an immortalized canine kidney cell line—can be characterized in advance and stored frozen until large quantities of vaccine are needed, where they can be quickly thawed and amplified. Rapid amplification is the most compelling advantage of cells, say most vaccine makers. The first dose of vaccine can be produced within a week of infection with seed virus in both cells and eggs. "It's the time to produce the 100,000th dose that differs," says Kemble. 

Among manufacturers, Novartis was the first to use this cell-based system. The company already produces two vaccines in cells in its Marburg, Germany, facility. Recently, Novartis opened a cell-based facility in Holly Springs, North Carolina, in which says Matthew Stober, Novartis's global head of technical operations, the company hopes to be able to produce up to 150 million doses of pandemic influenza vaccine as early as 2013.  

"The regulatory pathway to achieve FDA licensure for vaccines is a long and complex one, particularly if clinical studies are involved. However, because Novartis accelerated the investment of this facility under the current pandemic threat, bulk prepandemic vaccine [against H5N1] could be produced from the site as early as late 2011 under an emergency use authorization," says Stober. Other drug manufacturers, including GlaxoSmithKline (GSK, London) and MedImmune are exploring cell-based programs.  

So why aren't all manufacturers embracing cell-based facilities? For one thing, manufacturers with facilities geared toward egg-based manufacture can't retrofit them to produce vaccine in cells, says Gombold. But the real hesitation is economic. A dose of vaccine currently sells for under $10 says Shaw, and that's "not good for a producer that has to stay in business." Nor does it provide the kind of revenue that justifies the investment required to build a cell-based facility. "Only an external subsidy makes it feasible," he says. 

Indeed, the US government provided approximately 40% of the $1 billion for Novartis's Holly Springs facility. MedImmune can consider the move because it already has bioreactors. "It would be different if we had to build the factory anew," says Kemble. Like Novartis, MedImmune has also received government funds that Kemble says, "help enormously." Once a facility is built, cell-based production should cost much less on a per unit basis than egg-based manufacturing, he adds.  

 GSK currently produces its vaccine in eggs and will for the foreseeable future, says Martine Wettendorff, vice-president, Influenza Vaccines Development Leader. But the company is not insensitive to the problem of scale up for a pandemic. GSK's answer is to make the existing vaccine more potent through the use of adjuvants, thereby reducing the amount of antigen required for each dose.  

The company markets pandemic influenza vaccines in Europe and Canada that contain its proprietary ASO3 adjuvant and plans to seek FDA approval to supply an adjuvanated H5N1 vaccine in the US. Nevertheless, the company is researching cell-based technologies, which Wettendorff describes as "not yet a fully mature technology. The cost of goods remains a challenge," she says, but GSK is "always looking around at what's happening to lower that cost as well as at recombinant technologies." She reflects the attitudes of many who feel the cell-based technology is not yet an economically viable proposition. 

"This is where we come in," says VaxInnate's Shaw. "We can ramp up very quickly and cost effectively." The possibility of bringing new ideas to an old product has produced what Björn Lundgren, vaccine marketing manager for GE Healthcare Bio-Sciences (Uppsala, Sweden), a producer of equipment and reagents for vaccine manufacturing, calls an "R&D playground." Several biotech firms are banking on recombinant technologies as the future for influenza vaccine production. 

Rather than reproduce entire virus particles, recombinant technologies like VaxInnate's produce selected viral proteins from the infectious strain, the sequence for which can be obtained from CDC. VaxInnate produces the viral surface protein hemagglutinin (HA) in the bacterium 

, which Shaw calls "a prodigious producer of protein." Prodigious enough, in fact, that at the current selling price, the company can realize a profit, he says. However, until recently, 

seemed an odd choice in which to express the highly glycosylated HA protein, because the bacterium does not glycosylate its proteins.  

As it turns out, says, Shaw "[HA] doesn't have to be glycosylated." VaxInnate harvests its protein and refolds it in urea, he says. When combined with an adjuvant, the protein seems effective in the company's early-stage clinical trials. 

Medicago (Quebec, Canada) produces virus-like particles—including recombinant HA—in plant cells, which do glycosylate their proteins but in a manner different from mammalian cells. That hasn't seemed a problem, though, says Nathalie Charland, the company's product portfolio director, who says that initial clinical studies uncovered no deleterious immune responses to the plant-glycosylated protein. Both companies believe they can produce pandemic-scale quantities of their vaccine within three weeks of receiving the seed-virus sequence from CDC. 

Recombinant proteins do have one drawback, however. They tend to be less immunogenic than are whole viruses, and therefore require some kind of adjuvant to boost potency. Says Mark Tomai, head of vaccine business development for 3M (St. Paul, MN), "The type of vaccine dictates whether and what type of adjuvant is required."  

Both the Medicago and VaxInnate formulations include adjuvants. The Medicago adjuvant is part of the plant-cell membrane that envelopes the virus as it buds off from the plant cell. VaxInnate uses flagellin, a bacterial protein that binds to toll-like receptors on immune cells and activates them. There has been some concern, notes Tomai, that toll-like-receptor ligands distribute throughout the body causing nonspecific and unwanted immunological effects. VaxInnate circumvents that by coupling adjuvant and antigen, which, says Shaw, prevents adjuvant molecules from "swimming around on their own," and instead directs the immune response specifically against the antigen. 

Novavax manufactures a trio of viral proteins inside insect cells, producing a virus-like particle, which Singhvi says closely resembles the actual virus in electron micrographs. He adds that without  adjuvant, the preparation has elicited a strong immune response in Phase II clinical trials. Like the others, Novavax's production costs are competitive with traditional vaccine manufacturing, says Singhvi. "That's why we believe we can enter the market without being pushed out based on cost," he says. 

Beyond recombinant proteins there are DNA vaccines, such as the one under development by San Diego-based biotech company Vical. Plasmid DNA containing a viral gene sequence and formulated with Vaxfectin, the company's proprietary lipid-based adjuvant, is injected, and the recipient's own cells manufacture the immunogenic proteins. The vaccine, says, Vijay Samant, Vical's president and CEO, provided a lasting immune response to H5N1 in Phase I clinical trials. 

"It's hard to predict which technology will be the winner," says Lundgren. Choosing one and standardizing it, he thinks will be the real key to manufacturing an effective, scalable, and low-cost influenza vaccine.  

 with Novartis's Matthew Stober, global head of technical operations.

Drugmakers hatch new manufacturing paradigms in the wake of the 2009 H1N1 influenza pandemic.

Vaccine Manufacturing Reborn


 This article is an online exclusive bonus to the 

 Novartis recently built a plant for cell-based manufacture of influenza vaccine in Holly Springs, North Carolina. What will be produced at the facility? 
 

 Novartis opened its Holly Springs, North Carolina facility in November 2009 in collaboration with the US Department of Health and Human Services (HHS). The opening of the Holly Springs manufacturing facility is part of our continued commitment to address urgent healthcare needs for our patients. 

The facility has been designed and constructed with the support of the US government to produce seasonal flu cell-culture vaccine, pre-pandemic [H5N1] and pandemic [H1N1] influenza vaccine. The facility will be ready to respond to an influenza pandemic as early as 2011 if licensed in an emergency. The plant is expected to be running at full scale and approved for commercial production in 2013. Additionally, the site will have a fill/finish facility capable of producing both flu and non-flu products. 

  Does Novartis also have an egg-based manufacturing program? If not, why not? If so, what are the challenges/limitations of producing vaccine in eggs? Are those challenges/limitations alleviated in cell-based systems? Are there challenges inherent in cell-based manufacture that are not challenges in egg-based systems? 
 

 Yes, Novartis uses both egg and cell-culture technology to produce vaccines in order to provide the greatest amount of vaccine. While egg-based technology is still the most widely used, cell-culture manufacturing offers several advantages over traditional egg-based manufacturing, such as the ability to more rapidly respond to time-critical situations, since there is no need for chicken eggs. Other advantages include more rapid and scalable manufacturing, enhanced consistency and reliability, and cell-culture-derived vaccines can be administered to patients who are allergic to eggs.

 Please give me a sense of the relative yields of egg- versus cell-based systems.
 

 Novartis sets high standards for all its products and aims to achieve the highest yield possible using both egg-based and cell-based technologies.  As demonstrated from last year’s A(H1N1) pandemic, yields are a biological process and cannot always be guaranteed. Producing high enough yields was one of the main challenges in developing the H1N1 vaccine because the volume of vaccine produced depends on how well the virus can replicate. However, cultivating viruses using a cell line offers the possibility of a more robust virus production and seed-strain development that more closely matches circulating viruses, which could potentially translate into a more immunogenic and effective response.

 Please give me a sense of the start-up times for egg- versus cell-based paradigms. Scale-up?
 

A major advantage of using next-generation influenza manufacturing where eggs are no longer used is that the lead time to order and take delivery of eggs is eliminated. The Novartis proprietary cell line also allows for manufacturing flexibility. Because the lead time is eliminated, cell-culture-derived influenza vaccine can be produced more quickly and efficiently in emergency situations such as pandemics. For example, Novartis was able to produce the first monobulk vaccine for the A(H1N1) pandemic in only 60 days.


 How do you purify your cell-based vaccines? How does this compare with egg-based purification paradigms?
 

The Novartis cell-derived influenza vaccines are purified in a way that is similar to that used for egg- based vaccines, though there are additional purification steps.  For example, host-cell proteins are removed during purification. In egg-based vaccines, some egg proteins remain in the vaccine.


Many people have said the cost of manufacturing vaccines in cells is prohibitive without government subsidies. The Holly Springs plant was built with a $485 million grant from the government. If the government had not bestowed this grant, would Novartis have built a cell-based manufacturing facility on its own?
 

New technologies are initially more expensive due to preliminary investment. Cell-based technology is an example of an innovation that required this type of investment. Once the technology is further developed and put into effect, the increased productivity makes the overall cost savings more apparent, which is why the partnership with the government was so important when building the facility. Additionally, cell-culture technology is beneficial because it provides a foundation for future biotechnology innovations.


 If vaccine production is seasonal, how will the plant be used in the off season? 
 

The facility in Holly Springs, NC, was designed to be capable of producing seasonal flu cell-culture vaccine, pre-pandemic vaccine, and 150 million doses of pandemic vaccine within 6 months of an influenza pandemic declaration.  Additionally, the site will have a fill/finish facility capable of producing both flu and non-flu products. 


 Many companies are exploring the use of recombinant technologies for influenza vaccines. Does Novartis have such a program? If yes, please describe. If no, why not?
 

As a leader in innovative science and technology for vaccine development, Novartis Vaccines is not using only cell culture technology, but is also applying additional scientific breakthroughs such as adjuvants and reverse vaccinology to develop the most efficacious vaccines possible.

Reverse vaccinology is a method by which viruses such as influenza are generated from segments of DNA. For prospective pandemic influenza vaccines, reverse vaccinology can be a useful technology because the process does not require manufacturers to work directly with potentially highly infectious pandemic strains, rather only segments of the virus's genome. 


 I understand that Novartis has a proprietary adjuvant. Could you describe what this adjuvant is and how it stimulates the immune system?
 

 Novartis’s proprietary adjuvant MF59 has an established safety profile. It is the only oil-in-water adjuvant supported by more than 12 years of post-marketing clinical safety data and more than 45 million doses of commercial use. The adjuvant has also been studied in randomized clinical trials and observational studies involving 124,000 individuals including children, adults, and elderly, and has been licensed for use in individuals 65 years of age and over in the seasonal influenza vaccine, FLUAD, since 1997 in the European Union.

Benefits of vaccines produced with the MF59 adjuvant include established safety, immunogenicity, cross-reactivity, long-term boost-ability, T-cell immune memory, and antigen-sparing properties.

Novartis' Matthew Stober discusses vaccine manufacturing, including egg- and cell-based systems.

Novartis's Influenza Vaccine Program: A conversation with Matthew Stober, global head of technical operations for Novartis

 Michelle Hoffman You've probably been getting a lot of requests to fill out surveys lately, including requests from us (but more on that later). You do know why, don't you? These are the months that journals set their editorial calendars, that trade-show organizers craft their programs, and that vendors design their advertising campaigns. They all want to know about you. The only people who probably don't get to know about your interests and careers are, well, you. So, I'll fill you in.  

Recently, we obtained results from an independent survey of industry professionals who belong to some of the professional organizations and attend the large industry trade shows. The survey, conducted in July, was sent out to 34,247 people, 353 of which completed the entire survey. The following results reflect their responses. 

More than half (53%) of the respondents come from conventional bio/pharmaceutical manufacturing companies. An additional 13% are consultants; 10.4% perform research and/or analytical services; 9.3% are in drug-delivery technology manufacturing; 5.4% work with ingredients, excipients, active pharmaceutical ingredients, and/or specialty chemicals; and the remainder are in education, government, architecture, engineering, or construction (see Figure 1). Twenty-one percent describe their job function as scientist, 20% as manager, 18% as director, and 13% as CEO or vice-president. 

Twenty-seven percent are engaged in research and development (R&D), 22% in quality control/assurance or validation, 11% in technical or analytical services and support, 9% in marketing sales and management, 8% in production and manufacturing, and 6.5% are engaged in project management. The remaining respondents fall into engineering (5.4%), corporate management (4.3%), education, regulatory affairs, materials management/purchasing/procurement, and packaging. 

On average, your companies earn revenues of $10 billion a year and spend $196 million on R&D. Thirty-six percent of you report that your companies are planning to expand and/or build new facilities in the coming year, and 48% of those say that expansions are planned in the United States; 19% say Western Europe, 8% say China; and 3% say India. Forty-three percent of respondents report that their company plans to sell products into the BRIC (Brazil, Russia, India, and China) countries, and 35% say their companies plan to source materials from BRIC countries. 

Of the 73% of you that are interested in receiving additional professional training, 37% are interested in learning more about topics related to quality assurance and control. Approximately the same percentage of respondents want to learn more about regulatory affairs. Thirty-four percent are interested in validation, and the same percentage want to increase their knowledge of process development.  

This particular survey did not ask about your sex, but anyone who's attended a conference or trade show in this industry knows that it's overwhelmingly male. Other surveys indicate that about 75–80% of bio/pharmaceutical industry employees are male. 

As for what you like to read and how, we are collecting those data now through the PharmTech reader-assessment survey. To get you the information you need when and how you need it, please take some time to fill us in. You can access the survey online at 

. We look forward to learning even more about you.  

 is editor-in-chief of Pharmaceutical Technology. Send your thoughts and story ideas to  

New data provide insight into pharma-industry professionals' daily lives.

Survey Says...

An industry insider shared with me recently that he perceived a "crisis in training." In his opinion, industry-wide cost cutting has laid waste over the past 10 years to training programs and personnel. Not only have formal training programs gone by the wayside, he said, but layoffs have eliminated many of the skilled and knowledgeable practitioners who would typically act as mentors to less seasoned operators. He was blunt in his assessment of the situation: "We've gotten dumber as we've become leaner." 

He remarked that the decline in the quality of process and procedural understanding among pharmaceutical manufacturing professionals is global. In his experience, even department managers don't understand the core technologies they deal with, including what they're doing or why. Companies, he said, are cutting back on funds to send their employees to outside training programs as well. As a result, mid- and upper-level managers are far less well versed in even basic knowledge than they've been in the past, and this, he said, may account for several of the recent well-publicized product recalls, contaminations, and plant closings. 

Sadly, he does not think that companies perceive the problem as a training issue, and at the same time, registers his disbelief that corporations are not more concerned that department heads seem to demonstrate a basic lack of understanding of the policies and procedures they implement and enforce.  

To find out whether this insider's opinion was just an isolated view, I talked to a second industry veteran whose indictment of the training programs within pharmaceutical companies was equally harsh. Abysmal. Woefully inadequate, he said. He described a system commonly known as "read and sign." That is, new hires are given documents describing some 200 or so procedures and policies that they are expected to read over the course of a week. They are then asked to sign a statement indicating that they've read and understood the documents before they are considered sufficiently "trained" to enter the plant floor, where they encounter for the first time the very equipment they're supposedly trained to operate.  

A few times, he confided in me, he's entered those training rooms to find people asleep. He also related the recent product recalls to poor training programs.  

"What training programs?" asked another industry veteran. "Companies are in the business of making product, not in training people. Every hour spent on training someone is an hour less that they're making tablets." This particular calculus does not account for the catastrophic effects of plant shutdowns and lost business following product recalls, which in the end seems to be the more accurate cost of inadequately training personnel. 

In these cost-conscious times, the pharmaceutical industry is certainly not the only sector cutting corners on quality in order to improve cash flow. Publishers, for example, have reduced paper quality, turned to stock photos over custom graphics, or have replaced seasoned staff with interns. As a result, readers may notice more spelling errors or less engaging images in their publications. But unless the publication is a medical or professional journal, the quality gaps are not likely to endanger the public. The pharmaceutical industry does not have that luxury. 

In the final analysis, some cost cutting is just too expensive, and it's tragic to think that massive recalls are required before companies reconsider their commitment to training personnel. The pharmaceutical industry shouldn't have to be reminded of the value of an ounce of prevention.  

Industry's focus on cost cutting has led to a dangerous gap in training and knowledge.

An Ounce of Prevention

Until just a few years ago, most people working in the United States operated under the default assumption that the US economy was sound, would always be sound, was growing, and would continue to grow. Such is the nature of bubbles. 

Economic indicators tell us that the worst is over, but we emerge from the crisis a little bit chastened and somewhat less sure of ourselves. We also discover that the world isn't quite the way it used to be. The great recession has shifted the tectonic plates of commerce and altered the geography of business. As a result, economic isolationism is no longer an option.   

This change is glaringly apparent throughout the pharmaceutical industry. In most cases, products that once were made entirely within the confines of a single factory are no longer even manufactured by a single company. A drug discovered by one company might be formulated by another, manufactured by a third, and marketed by a fourth. Service providers now reside in different countries and more often these days, on different continents. If it takes a village to raise a child, it seems to take a world to manufacture a drug. 

So what does all of this mean? On one hand, it means that companies now enjoy many options for sourcing ingredients and can get the best services at the best price. And indeed, our annual PharmSource-

Outsourcing survey indicates that this year, more companies than in years past are actively sourcing materials from India and China or are planning to do so. On the other hand, the global availability of ingredients and services creates additional competition for domestic firms—also evident in this year's survey results. 

It also means that adept project managers become crucial to the success of the enterprise. With more pieces of the project in pieces, competent project management is absolutely required to make sure that the project equals the sum of its parts. The difficulty of coordinating services across many different vendors has prompted many service providers to expand their service offerings horizontally and become "one- stop shops."  

Naturally, increasing the number of parties involved in a project increases the associated risk and complexity. The logistics of communication and transportation become exponentially complicated as geographic distances and the number of vendors increase. And the greater the distance between supplier and purchaser, the greater are the opportunities for adulteration, contamination, and counterfeiting.  

Add to this complexity the potential for natural disasters, as well as economic and political disasters, and the opportunities for disrupted service are indeed large. Client companies need to be certain of the solidity of their outsourcing plans; they also need to put in place contingency plans. In the end, making safe cost-effective drugs effectively may be as much a matter of good project management and solid risk mitigation as it is good science. 

With more hands in the manufacturing pot, a good contingency plan is crucial to success.