Michelle Hoffman, editorial director of Pharmaceutical Technology.

Michelle Hoffman

It's almost inevitable that when people speak of pharmaceutical innovation that someone doesn't ask how pharmaceutical companies can become more like Apple. It's a question that sprung up again with the death last month of Steve Jobs, Apple's iconic founder and innovator-in-chief. What was it about Jobs and the company he founded that nurtured so much innovation and creativity, and can it really be brought into pharmaceutical innovation? 

Jobs outlined his personal trajectory in a tale of passion and loss in his 2005 commencement address at Stanford University. His path to Apple started when he dropped out of Reed College in order to be free to take any course that interested him rather than follow a prescribed curriculum leading to a specific major. This in turn led him to a calligraphy course that, he says, informed his ethic of blending aesthetics and technology to create Apple products. But as with many great relationships, what started out with so much generative promise ended in heartbreak—Jobs's specifically, when at the age of 30 he was asked to leave the company he'd founded. 

 "I'd been rejected," he said, "but I was still in love." That first loss, painful as it may have been also relieved Jobs of the "heaviness of being successful," and replaced it "with the lightness of being a beginner again." Jobs the beginner embarked on yet another creative period that resulted in the formation of Next and Pixar, which ironically, brought him back to Apple and it to him for yet another creative period that yielded iPods, iPhones, and iPads and revolutionized both the computer and the communication industries. 

The other great focusing event in Jobs's life, as we all now know, was the imminence of his death from pancreatic cancer. In the face of death said Jobs, "we are already naked," and because of which, he admonished Stanford's class of 2005 not to be "trapped by dogma, which is living with the results of other people's thinking." Rather, Jobs urged the graduates to follow their individual passions. 

Jobs died the same week the winners of the 2011 Nobel Prizes were announced, and among those winners was Ralph Steinman, a Rockefeller University professor, who elucidated the biology of dendritic cells. Steinman died the same week as Jobs, just days before the Nobel announcement was made. But in an interview on National Public Radio on Oct. 3, 2011, Adam Steinman, the Nobelist's son talked about his father's passion for his work, and his desire to "instill a sense of excitement and discovery in the next generation." 

Reading these stories, one might suggest, as Jobs did in his Stanford address, that it's the threat of loss that should make one insist on following their passions to discovery. But I keep thinking of one my professor's observation that children are the true scholars, because they want to learn everything and are unfettered by dogma. Jobs and Steinman and other great innovators are the ones that,  in spite of prevailing dogma, never lose their childlike passion for learning and exploring. So the pharmaceutical industry may be misguided in looking for ways to inspire innovative thinking in its scientists. The real secret might be in not wringing it out of them.  

Articles

At a time when the industry is struggling with innovation, it might do well to learn a lesson from a few great innovators.

Passion, Innovation, and Loss

I have often gotten the impression that FDA's quality-by-design (QbD) initiative remains somewhat mysterious to pharmaceutical manufacturers, even though it's been about seven years since FDA first introduced the concept in its 2004 report, Pharmaceutical Quality for the 21st Century: A Risk-Based Approach. FDA must have had that impression as well, since the agency commissioned a study to gauge the industry's rate of adoption of the concept as well as its understanding of it, the results of which FDA officials present in this issue of 

 The study findings support anecdotal accounts of industry attitudes towards QbD. 

The report quantifies the degree of adoption among different industry sectors. Not surprisingly, innovator companies (called "New Drug" in the report) have embraced the program most fully. Twenty-two percent of new drug companies are categorized as "fully implemented" in the report, meaning that these companies incorporate QbD principles in almost all of their development programs. These companies also have a "systematic, comprehensive review and redesign of in-line products." In contrast, no generics or biologicals manufacturers fall under the fully implemented category.  

At the other end of the spectrum, generic-drug manufacturers appear to be most resistant to the program, with 40% of them being characterized as "novice," which is defined as a company "that is skeptical about the value of QbD," and uses "conventional development practices and has no QbD platforming." In other words, they're non-adopters. Biological manufacturers lie somewhere in the middle, with an impressive 67% venturing tentatively into "pilot" territory, defined as companies trying it out, but uncertainly. These results mirror responses PharmTech obtained in our 2011 Equipment and Machinery Survey (published in our March 2011 issue), where approximately 58% of innovator companies, and 55% of biotech companies, but only 35% of generic-drug manufacturers reported that QbD had a high or medium impact on their equipment-purchasing decisions.  

The reasons for skepticism reported in the FDA article also mirror what we've heard anecdotally. Quality professionals have a hard time getting management to buy into the concept—what the report referred to as a "disconnect between leadership and middle management." An additional misconception, which the report attempts to squelch—is that QbD is costly to apply.  

But there's also great uncertainty within industry, bordering on frustration, about what FDA wants. The report notes—and we've heard this ourselves—that industry perceives internal inconsistencies within FDA as to how the agency assesses a company's QbD efforts. Companies also express some degree of discomfort about talking with FDA at all. And again, I've heard individuals say that FDA might ask people to implement QbD in theory, but gives them a hard time when they try to put it into practice. FDA for its part intends to spend the next five years developing more internal consistency and clarifying expectations both within FDA and the industry. In other words, the agency will work to demystify QbD and nudge more companies towards implementation. 

At its core, the QbD initiative asks manufacturers to understand how variables—temperature, pressure, humidity, for example—govern the behavior of their reagents and their effects on product quality, principles we all learned in our high school science classes when we were first introduced to the experimental method. And that's the most mysterious thing of all.  How did a science-based industry manage to unlearn these concepts in the first place?  

A report commissioned by FDA evaluates the QbD program.

Retrospection and Introspection at FDA

Walking the exhibit floor of an industry trade show, one becomes accustomed to seeing certain incongruities. Scattered in with bioreactors and filling lines, you can expect to see various circus performers, putting greens, and the occasional motorcycle being raffled off. But at the June 2011 Biotechnology Industry Organization (BIO) annual convention in Washington, DC, one such incongruity was not a gimmick. It was the Samsung booth, smack in the middle of the exhibit floor. 

The electronics manufacturer has let its interest in the biopharmaceutical market be known for some time now. The company's $389-million investment in biosimilars was reported by 

 in July 2009, who also quoted Samsung Spokesman James Chung as saying, "Biosimilars is one the businesses [sic] we aim to grow strategically. We are planning to participate (in the business) aggressively."  

The initiative appears to dovetail with South Korea's plans to become a global leader in biosimilar research and development. Samsung, along with other South-Korean-based electronics firms, is contributing to a government initiative to develop the country's biosimilar industry. 

It may not be as odd as it seems that an electronics company is interested in biosimilars. After all, establishing bioequivalence between innovator and follow-on biologics will require a great deal of analytics, which might make use of electronic sensors and components. The oddity is that Samsung intends to actually manufacture biosimilars. 

Earlier this year, Samsung announced its partnership with Quintiles in a venture valued at $266 million, which, according to a February report by 

, is expected to start producing biosimilars by 2013, with most of these sales targeted at markets outside of the United States. 

US companies are also getting into the market. Pfizer publicly described its interest in the sector at the BIO convention. Diem Nguyen, Pfizer's general manager for the Biosimilars Business Unit, outlined the company's intention to enter the market with some small, well-defined biologicals, including insulin, before moving into larger more complex drugs. 

All of these entrants are spurred by optimistic projections of the market potential for these drugs. IMS Health released a report in July 2011 estimating that the biosimilar market will reach $2.5 billion globally by 2015. Other projections are even more enthusiastic. I thought I heard a McKinsey consultant project the biosimilar market to be $30 to $50 billion by 2020. Samsung, according to the 

 report, is projecting its revenues from biosimilar products to possibly exceed $1.8 billion by 2020 based on its estimated demand for these medicines. 

Yet, I find myself wondering: Why now? What's so compelling about this growth opportunity as opposed to, say, small-molecule generic drugs, branded monoclonal antibodies, gene therapies, or genomics-based drugs? At one time or another, each of these was deemed to be the next big thing in pharmaceuticals.  

Given the anticipated difficulty in manufacturing biosimilars and the almost-certain regulatory requirement for some limited clinical data on the follow-on drugs, how much profit is there really to be made in them?  

And finally, there is the disturbing variability in those market projections themselves. Is it really possible that the market will grow from $2.5 billion to $50 billion in just the five years between 2015 and 2020? Or are analysts using wildly different starting assumptions? And if they are, can we trust that anyone's model is robust? 

I know we'll all be watching and reading with interest as the biosimilar story unfolds. And only time will tell whether biosimilars are the next big growth area, or just the latest high-tech bubble. 

Are biosimilars the next big thing or just the next big bubble?

Biosimilars or Bust

In the course of every relationship, there arise moments for the "difficult conversation." Usually it's of the "where are we headed with this?" variety. But that's really just part of a larger question: Do we have a shared philosophy, and what is it? 

Whether we think of it that way, nations ask themselves this question routinely. Should our nation be guided by a religious philosophy, or not? Should we elect our leader as a group, or should a person ascend to leadership through inheritance? If the times require us to alter our viewpoint, do we decide as a group, or does someone decide for us, and if so, who? 

Sometimes the answer is explosive: Whoever we are, it's not working, and we need to change now. 

That's the kind of answer that can lead to revolutions. In the US, we've mostly dealt with the question of our national ethic more quietly, starting with the first national conversation, which lay out a basic philosophy in the form of a constitution. Nevertheless, there have been many difficult conversations we've failed to have as a nation. To whom do we accord full citizenship, for example? Not even the Founding Fathers could agree on this one, thereby establishing the alternative to a national conversation: the local conversation. Instead of making a national decision about which people could own land, vote, or intermarry, those questions were left to local governments. 

In these cases, challenging and sometimes overturning local philosophies (and sometimes overturning them again) has been, not through legislation, but through the courts, through litigation. That's how we've handled teaching evolution in schools, gay marriage, and abortion—locally and through litigation. 

Some conversations, it seems, are just too difficult to have nationwide. I expected the conversation about stem-cell therapies to be one of those too-difficult conversations as well, one that would also be handled case by case and concession by concession—through litigation rather than legislation. 

So it came as a surprise to learn that in mid-May, US Representatives Brian Bilbray (R-CA) and Diana DeGett (D-CO) introduced the Regenerative Medicine Act of 2011 (H.R. 1862). The Act notes that, "Regenerative medicine products have already successfully treated numerous health conditions, and have the potential to provide cures, treatments, and diagnostics for a range of diseases and disabilities including diabetes, spinal cord injury, heart disease, stroke, and various forms of cancer." 

				The proposed legislation goes on to say, "A United States national strategy on regenerative medicine is critical to ensure that this technology fulfills its potential to cure and treat diseases and disabilities, reduce overall health spending, and promote economic growth."			

Not once does the Act mention stem cells, embryonic or otherwise, which are among the therapeutic agents used in regenerative medicine. It is the potential use of embryonic stem cells that makes a national conversation difficult, because, like the still-unresolved abortion debate, it pits technology against notions of personhood. Indeed, the stem-cell debate has already been the object of some well-publicized litigation. And it seemed likely that the entire debate would continue that way. 

Whatever the fate of the Regenerative Medicine Act of 2011, I hope it sets a precedent for the way we discuss novel, but potentially ethically thorny issues of technology in the future. After living together as a nation for 235 years, shouldn't we at least know how to broach difficult conversations? 

Which route will we take to arrive at a national stem-cell policy?

Legislation v. Litigation

If you, like me, were a science student as an undergraduate who had friends in the humanities, you had the inevitable discussion about the objectivity of fact versus the subjectivity of faith. 

The scientist would cite the rigor and reliability of the scientific method and the "truth" of reproducible results. The humanities student would argue that the so-called axiomatic truth of the sun rising tomorrow, for example, was just another form of faith. The scientist, argued the humanities student, was operating under the assumption that past behavior was a predictor of future behavior and so believed the sun would rise tomorrow merely because it had every day in the past for eons. 

The arguments are not very original, nor are they decisive, and yet they remain with me. Every so often during introspective moments, I subject myself to a sort of epistemological grilling: How do I really know what I think to be true? What data set am I using to reach my conclusions, and how was it generated? And finally, do I believe this to be true because I want it to be, because it's an act of faith or will, or is there really substantial, objective support for this? 

These are questions I revisit every year when we conduct our annual Bioprocessing Survey, which you can read in this month's special issue on Bioprocessing and Sterile Manufacturing. (Thank you, by the way, to those who took the survey; and for those who did not, there's always next year.) The biopharmaceutical manufacturing sector has over the years been exploring the benefits of single-use, disposable components in its operations versus those of traditional stainless-steel components. Opinions about the relative merits of one kind of equipment over the other abound. And they diverge, depending on whether one actually uses disposables. 

In many cases, users of all-stainless equipment underestimate the advantages of single-use and overestimate the challenges. For example, only 35% of all-stainless users (and 31% of those using hybrid systems-systems that combine stainless and single-use components) perceive a cost advantage to all-disposable systems as opposed to 54% of those who actually use all-disposable systems. In another example: only 18% of respondents who use all-stainless equipment think that process reproducibility is an advantage to all-disposable equipment. In contrast, 31% who use all-disposable cite reproducibility as an advantage. Users of all-stainless may also overestimate challenges to all-disposable manufacturing lines. Twenty percent of respondents who use all-stainless equipment think that all-disposable equipment increases the risks of contamination. No one—0%—of those who actually use all-disposable equipment does. 

The survey cannot determine how firmly held are these beliefs or what it would take to dispel them. But it's an interesting object lesson to me and perhaps to others who see science and scientists as purely objective. 

I had another reason to consider attitudes toward disposables in particular. During the INTERPHEX 2011 conference, I hosted a panel discussion around continuous manufacturing. The discussion focused on traditional small-molecule, solid dosage forms. I learned that one of the hurdles is finding an automated method for moving powders from one unit operation to another—the answer to which for some products may be to keep all the chemistry in solution. It then occurred to me that a completely soluble process would start to look a lot like the process for biopharmaceuticals and could therefore benefit from the use of disposable components. If that's the case, then the "objective truths" of a whole new group of process developers and engineers will have to be overcome.I wonder how our survey results will look then.  

Those who doubt there's faith in science, should check out our annual Bioprocessing Survey.

Perception and Reality

This article is part of a special issue on 

Biopharmaceuticals continue to be the hot growth sector, and most revenue projections suggest that biopharmaceuticals will occupy an increasing number of spots in the top 10 highest revenue generators in coming years. Nevertheless, the results from the third annual 

Bioprocessing survey indicate a slowdown in new entrants to the market. In 2009, more than 50% of respondents said they were entering the biopharmaceutical manufacturing arena for the first time. In 2010, only 23% did. But new entrants and veterans alike all face significant challenges and opportunities, and 249 respondents, representing firms large and small told us about them throughout March 2011. 

Just as in years past, slightly under half of respondents (48%) produce biopharmaceuticals only, with the remainder working for companies that produce both traditional small-molecule pharmaceuticals as well as biopharmaceuticals. As in the past, there is a dramatic division in company revenues—the majority of respondents producing biopharmaceuticals only work at companies with revenues under $10 billion; the majority of respondents producing both biopharmaceuticals and traditional small-molecule drugs work for companies with revenues above $10 billion. Half of all respondents added biopharmaceutical manufacturing capacity this year, but they come from companies of all revenue classes, with 86% of respondents from companies with revenues up to $1 billion and 88% of respondents from companies with revenues more than $50 billion saying their companies increased capacity. Fifty-seven percent of respondents increased capacity because they added new products to their line (about 72% of those were products developed internally), and 52% increased production of an existing product. Approximately 18% of respondents acquired a company with a biomanufacturing program, and an equal number in-licensed a biopharmaceutical product that necessitated a capacity increase. Among those who decreased their capacity, 31% decreased production of an existing product, and an equal number outsourced production of a product that had previously been manufactured in house.  

Figure 1: What class(es) of biopharmaceutical does your company manufacture? (multiple responses allowed) 

Therapeutic proteins other than monoclonal antibodies (mAbs) continue to constitute the largest product class, produced by 51% of respondents, followed by monoclonal antibodies (45%), and vaccines (29%). These percentages reflect some interesting changes from last year's product mix. The percentage of respondents involved in monoclonal antibody production is up slightly, about five percent over last year, while vaccine manufacturing is down about seven percent. The percentage of respondents involved in nucleic acid products remained virtually unchanged—14% this year, versus  12% last year, while there was a slight uptick in the number of respondents producing cells for cell and tissue therapies, 14% this year compared with 10% last year. Forty-five percent of respondents say their companies plan to produce follow-on biologics, up slightly from last year's 41%. The remainder either will not (21%) or don't know (34%). Eleven percent of respondents say their companies produce only follow-on biologics right now, while 23% say they  produce both follow-on and branded products.  

Among those who manufacture proteins, producing adequate yields and purifying them remain the two most vexing problems, with an equal number—41%—of respondents identifying these as challenges. However, if we look closer, we find that 47% of those producing non-mAb proteins saying that purifying product is a challenge (versus 40% who produce mAbs). About equal numbers (45% of mAb producers; 43% of non-mAb producers) say producing high enough yields is a challenge. In general, the challenges in protein production are similar regardless of the type of protein produced, with about 44% of respondents of both classes of proteins saying they have problems with protein aggregates, and a slightly lower percentage expressing concern over protein stability.  

Figure 2: What kind of equipment do yo uhave in  your biopharmaceutical manufacturing facility right now? 

Purification and stability are also issues for manufacturers of nucleic acids, with 47% of respondents identifying each of these as key challenges. At 33%, scale up is also a challenge for nucleic acid manufacturers. Process development is the major challenge for 43% of producers of cells for cell and tissue therapies, followed by cell stability (36%) and process scale up (34%). 

The debate continues over the use of disposables in biopharmaceutical manufacturing, with firms considering the convenience, cost, and the environmental impact of single-use, largely plastic, components. Anecdotally, it seems the industry is increasingly embracing disposable components. Yet our survey indicates an insignificant increase in the number of respondents using all-disposable systems—9% this year versus 8% last. Hybrid systems, which combine stainless and disposable components, remains the most popular choice, but the 66% of respondents using hybrid systems represents a notable decline from last year's 72%, which was down from the previous year's 74%. The use of stainless components continues to rise—26% of respondents this year report using all stainless equipment, an increase over last year's 20%. Interestingly, 11% of respondents who now use hybrid systems say they plan to convert to fully disposable equipment in the coming year, while no respondents anticipate moving to an all-stainless system. No companies with revenues above $5 billion use completely disposable systems; 88% of respondents from companies with revenues in excess of $50 billion use hybrid systems.  

Table I: What is (are) the greatest advantages to disposable equipment? (Multiple answers allowed) 

As in years past, we detected some marked differences in perceived advantages and challenges with disposable equipment among users of that equipment versus non-users. The first discrepancy arises over the question of cost savings. Thirty-five percent of all-stainless users (and 31% of hybrid users) believe there's a cost advantage to all-disposable systems. In contrast, 54% of all-disposable users say cost is an advantage to all-disposable systems, suggesting users of the other two systems underestimate the savings to be gained by an all-disposable system. Those who use all-disposable systems also perceive disposables to be more environmentally friendly (23%) than do all-stainless users (15%) and hybrid users (10%). All-stainless users also underestimate process consistency that can be achieved with all-disposable equipment, as only 18% of stainless users cite this as an advantage, contrasted with 31%, who actually use all-disposable systems. Additional responses suggest it may be easier to incorporate automation and may have greater regulatory acceptance than all stainless users might think. 

These same discrepancies arise when respondents were asked about the challenges inherent in single-use technologies. Users of all-stainless equipment overestimated the cost, risk of contamination, and process inconsistency, compared with respondents who use all-disposable equipment. On the other hand, all-stainless users underestimated the difficulty of incorporating process analytical technologies, implementing QbD principles, and the risk posed by extractables and leachables. In addition, users of hybrid technologies reported having greater challenges gaining regulatory acceptance (12.4%) than did users of all-disposable equipment, none of whom (0%) reported this as a challenge.  

Table II: What is (are) the greatest challenges to disposable equipment? (Multiple answers allowed) 

The percentage of respondents who say their companies outsource the manufacture of biologics rose again slightly this year over last year (36% this year versus 33% last), which represented a small rise over the previous year (30%). The reasons for outsourcing seemed to have changed slightly from last year's reasons. This year, 51% of respondents say their companies outsource to compensate for no or limited manufacturing capacity, whereas only 45% gave this reason last year. The percentage citing cost effectiveness climbed this year, to 49%, up from 41% last year. Companies with revenues under $10 billion are most likely to outsource, and their reasons for doing so differ, as well. A greater percentage of respondents from companies with revenues under $5 billion outsource because they have no or limited manufacturing capacity (for example, 71% of respondents from companies with revenues between $1 billion and $5 billion give this as the reason). Companies with revenues greater than $5 billion outsource to realize cost savings. Smaller companies—those with revenues under $500 million also say they lack the expertise internally (up to 75% of respondents from companies with revenues under $250 million, as opposed to 33% from companies with revenues between $5 billion and $10 billion). 

Overall, 61% of respondents say they outsource the manufacture of clinical-trial materials, and 49% said they outsource the manufacture of both drug substance (APIs) and finished drug product. Thirty-three percent outsource the manufacture of drug substance only, and an equal percentage (31%) said they outsource process development and full commercial-scale manufacture. The functions least likely to be outsourced were drug product only, and formulation development (29% each). There were no clear-cut patterns when it came to the size of companies and the functions they outsourced. In general, companies with revenues under $500 million were more likely to outsource process and formulation development, than were companies with larger revenues. Whereas companies with revenues above $500 million were more likely to outsource the manufacture of both drug substance and drug product than were smaller companies.  

Table III: Challenges according to protein class. 

There was no appreciable change over last year in the number of respondents reporting that their companies incorporate quality-by-design (QbD) principles into their operations—65% this year versus 67% last. Nor is there a significant difference over last year in the percentages of respondents who say QbD helps to improve their process understanding (69%), manufacturing efficiency (50%), and improved product quality (49%), while reducing variability (47%). Among those who do not incorporate QbD into their processes, 42% say they lack sufficient guidance from regulatory agencies, 25% say they don't understand the initiative, and 23% don't see any advantages to be gained. Finally, 21% say QbD is too costly. Companies with revenues above $1 billion are more likely to incorporate QbD than are smaller companies—with 92% of respondents in companies with revenues between $10 billion and $50 billion, and 100% of respondents in companies with revenues above $50 billion saying they incorporate QbD. In contrast, only 50% of respondents in companies with revenues under $500 million say they do. Respondents in smaller companies are less likely to understand the initiative and more likely to find it too costly than are their counterparts in companies with larger revenues. 

While 65% of respondents say they incorporate QbD into their manufacturing operations, only 44% say they incorporate process analytical technology (PAT), although here there is a dramatic difference between larger and smaller companies. Fewer than 60% of respondents from companies with revenues below $5 billion say they incorporate PAT, whereas more than 70% of respondents from companies with revenues higher than $5 billion say they do.  High performance liquid chromatography (HPLC) is far and away the most frequently employed analytical technology, with 69% of respondents saying they use it. That's followed by 31%  each who say they use disposable sensors and Fourier-transform infrared spectroscopy (FT-IR).  

As the economy comes out of the recession, the hope among equipment manufacturers is that customers will increase their spending in 2011, compared with 2010. Will they? Interestingly, only 26% say they plan on increasing their equipment purchases this year over last (down from 31% who made that prediction last year—a very accurate prediction, since exactly that percentage report that they did in fact increase their spending levels in 2010 over 2009 levels). Another 36% say they expect spending levels in 2011 to remain the same as 2010, and 13% (down from last year's 15%) say they expect to decrease their spending levels. 

Finally, we asked respondents to tell us what innovations would improve their process efficiency and/or product quality. This year, respondents hoped for better automation, better control of post-translational modifications and analytics that can discern small variations in protein composition (in real time) and in cell metabolism. Others hoped for more streamlined purification processes and an alternative to Protein A. 

Results from our annual survey. This article contains online bonus material and is part of a special issue on Bioprocessing and Sterile Manufacturing.