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Michelle Hoffman, editorial director of Pharmaceutical Technology.
Results from our annual survey. This article contains online bonus material and is part of a special issue on Bioprocessing and Sterile Manufacturing.
This article is part of a special issue on Bioprocessing and Sterile Manufacturing
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 Pharmaceutical Technology 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.
QbD and PAT
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.