Trends in Bioprocessing

This article is part of PharmTech's supplement "Bioprocessing and Sterile Manufacturing 2010."

It is hard to ignore the asendancy of biopharmaceuticals within the pharmaceutical industry. First, there were the megamerg-ers: Pfizer-Wyeth, Merck-Schering-Plough, and Roche-Genentech, motivated in part by Pfizer, Merck, and Roche s desire to improve their biopharmaceutical positions. Then there was the defection of Roche from the Pharmaceutical Research and Manufacturers of America (PhRMA) to the Biotechnology Industry Organization (BIO) to better brand itself as a biopharmaceutical manufacturer. Finally, we have the results from our 2010 Bioprocessing Survey: Practically a quarter of respondents say their companies just entered the biopharmaceutical manufacturing space in 2009, and over 50% of respondents report that their companies added biopharmaceutical manufacturing capacity in 2009. We reached out to the readers of Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International to take the pulse of the biopharmaceutical sector. More than 380 industry insiders, representing small biotechs and large pharmaceutical companies with revenues ranging from under $50 million to over $50 billion, in the US and abroad, completed the survey in January. What follows is a snapshot of the current biopharmaceutical industry—its products, challenges, triumphs, and innovations.

Figure 1: Companies producing small molecules and biopharmaceuticals versus biopharmaceuticals only.

Products and processes

Almost 48% of respondents work for companies that produce biopharmaceuticals exclusively; the remaining 52% work for companies that produce both small-molecule drugs and biopharmaceuticals (see Figure 1). Twenty-five percent of respondents just entered the biopharmaceutical space in 2009, and 56% of all respondents report that their companies increased their biomanufacturing capacity within the past year.

There was a clear pattern, in terms of the revenue levels of companies adding biopharmaceutical capacity. About a quarter of those adding capacity work for companies with annual revenues under $250 million, suggesting that these small-cap companies are late-stage biotech startups installing capacity for their first few products. The percentages dip down among the mid-cap companies and then rises again, to about 27% of respondents from large-cap companies with annual revenues in excess of $10 billion adding capacity. These numbers may well reflect capacity acquired through this year s megamergers.

Among those adding capacity this year, 51% increased production of an existing product (versus 59% last year); 53% added new products to their line. Twenty-one percent added capacity through the acquisition of a new company with a biomanufacturing program (down from 28% last year), and 20% in-licensed drug products (down from 24% last year) (see Figure 2)

Figure 2: Reasons for adding biopharmaceutical manufacturing capacity (multiple answers allowed).

Respondents produce the same product classes as last year and in approximately the same relative proportions (see Figure 3). Nevertheless, some product classes have seen small declines over last year's levels, possibly reflecting the fact that companies are shelving some riskier product lines. At 54%, the highest product class remains protein-based drugs other than monoclonal antibodies (mAbs). mAbs came in second, with 40%, followed closely by vaccine production, at 36%. This year, only 12% of respondents say their companies produce nucleic-acid based products, down from 18% last year, and 10% say their companies are involved in the production of cells for tissue- and/or cell-based therapies, a drop of 7% from last year's level. Forty-one percent of respondents anticipate that their companies will manufacture follow-on biologics, while 22% say their companies will not. The remainder do not know.

Figure 3: Classes of compounds produced by respondents (multiple answers allowed).

Production challenges

Protein producers continue to grapple with problems producing high-enough yields (49% of respondents who produce protein-based products), purifying the high yields they do produce (47%), and stabilizing the product (43%). Formulation (29%) and regulatory issues (29%) are also problems for respondents (see Figure 4). For those working with nucleic-acid-based drugs, delivery and purification top the list of challenges, with each of those troubling about 40% of respondents. And nearly 40% of respondents also had problems with regulatory issues, stability, or formulation. In fact, for producers of nucleic-acid-based drugs, the only thing that seemed not to be a challenge was expression levels, with only 20% reporting some difficulty.

Figure 4: Current technical challenges confronting manufacturers of protein-based drugs (multiple answers allowed).

Process development and scale-up were the two largest challenges confronting manufacturers of cells-for-tissue and cell-based therapies, with about 45% reporting difficulty with each of these two aspects. Other challenges included formulation (confronting a little over 40% of respondents), followed by stability, regulatory, and cost issues for about 30% of respondents each.

Vaccine manufacturers prefer cell-to egg-based production systems about 2 to 1, and 30% of those using egg-based systems plan on changing to cell-based systems. Those who don't plan to switch cite higher product yields and lower costs as reasons. However, almost 70% say they'd consider moving to an egg-based system if the costs of retrofitting an egg-based operation to accommodate a cell-based process were sufficiently low.

Equipment

The push in biopharmaceutical manufacturing equipment has been toward disposable, single- or limited-use components. The advertised advantages include reduced risk of contamination and a lower cost relative to the high capital outlays required to purchase the more traditional stainless-steel equipment. In addition, disposable equipment is supposed to eliminate cleaning and cleaning validation steps, which may also indirectly make them an economical choice for some manufacturers.

Table I. Compound class versus equipment used.

We have been interested to see how quickly disposable equipment is being adopted by biopharmaceutical firms. We've also been curious about the attitudes of pharmaceutical scientists who actually use disposable equipment versus the attitudes of those who don't. In some cases, we've noted marked disparities, both positive and negative, in assumptions about disposables between those who have experience with them and those who don't.

We were interested to discover, for example, that there has been no statistically significant migration from one to another type of equipment since last year. Hybrid systems—composed of both disposable and stainless-steel components—remain the most popular, with 72% of respondents using them (a slight decline from last year's 74%). At 20%, the second most popular equipment class is stainless steel (up from 19% last year). Disposables remain the choice of only 8% of respondents, about the same as last year. Nevertheless, some respondents indicated an intention to move to a different type of equipment. Nineteen percent of respondents who currently use all stainless equipment are considering moving to a hybrid system, and another 5% are considering going to all disposable. No one currently using all disposable systems is thinking of moving back to completely stainless systems, but 8% are planning on incorporating some stainless equipment when they move into hybrid systems. About 3% of respondents currently using hybrid systems are thinking of moving to all stainless systems, and 7% are planning on moving to all disposable systems.

Table II. Perceived advantages of disposable equipment versus equipment actually used (multiple answers allowed).

We also saw planned migrations between equipment types when we broke down the usage statistics according to compound class (see Table I). Four percent more manufacturers of therapeutic m Abs use all disposable equipment this year versus last, brining the total to 8%. There was a corresponding decline of 4% relative to last year in the number who report using hybrid equipment, down to 77%. As they did last year, 15% of m Ab manufacturers use stainless-steel equipment.

We noted no significant shifts in equipment use for manufacturers of protein-based drugs other than mAbs, nor for those producing nucleic-acid-based products. The largest movement took place among manufacturers of cells for tissue- and/or cell-based therapies. Disposable use for these manufacturers is up 5%, to 13%, and hybrid use is up 4% to 81%. Only 6% of nucleic-acid drugs use stainless equipment, reflecting a 9% decline over last year..

Table III. Perceived disadvantages of disposable equipment versus equipment actually used (multiple answers allowed).

We were also curious about the attitudes toward disposables among users of the various equipment classes. One of the bigger surprises was that 20% of users of stainless equipment and an equal number who use hybrid systems think an advantage of disposable equipment is the ease with which automation can be introduced (see Table II). In contrast, no one—0% of respondents—who actually uses disposables thinks the equipment is easy to automate. On the other hand, those who use all stainless or hybrid systems grossly underestimate the overall ease of use of disposables. Fifty-one percent who use stainless, and 65% of hybrid users think disposables are generally easy to use. In contrast, 82% who actually use disposables report them to be easy to use.

Thirty-one percent of respondents who currently use stainless fear that processes are not reliably reducible with disposable equipment (see Table III). Only 18% who use disposable equipment and 18% who use hybrid equipment report that. Those who use disposables find that process analytics are more difficult to incorporate: 27% versus 17% stainless users who think that. Those who use stainless equipment and hybrid equipment also seem to overestimate the challenge of assembling a disposable production train consistently: 22% of stainless and 21% of hybrid users believe that consistency of assembly would be a challenge, versus 0% who actually use disposable equipment.

Figure 5: Functions outsourced (multiple answers allowed).

Outsourcing

With announced layoffs and restructuring, we'd expect increased plans to use outside contract manufacturing and development services, but there seems to be no appreciable increase over last year. Thirty-three percent (versus 30% last year) say their companies intend to outsource some aspect of their biotherapeutic manufacturing program, whereas 51% do not (versus 50% last year). Interestingly, the reasons for outsourcing have changed somewhat.

Figure 6: Process analytical technologies used (multiple answers allowed).

This year, fewer respondents—45%, compared with 59% last year—say their companies lack biomanufacturing capacity, and 41% versus 45% last year, cite cost effectiveness. More respondents, 30% this year as opposed to 25% last year, say their companies outsource because they've increased manufacturing output—by increasing the number of products they manufacture, or by increasing the volume output of existing products. Fewer respondents say their companies lack the expertise in house, with only 13% citing that as a reason this year compared with 19% last year.

Among those who do outsource, 49% outsource the manufacture of both drug substances and finished products, down 14% from 63% last year (see Figure 5). Forty-two percent outsource API manufacture, and 31% outsource finished products. Thirty-nine percent outsource the manufacture of materials for clinical trials, and 34% outsource their full-scale commercial manufacturing. Twenty-six percent outsource process development activities, and 19% outsource formulation development.

Figure 7: Current technical challenges faced by manufacturers of cells for tissue or cell-based therapies (multiple answers allowed).

Quality by design

It's been a few years since FDA rolled out its quality-by-design (QbD) initiative, and we would have anticipated that more companies would have incorporated QbD principles into their manufacturing paradigm. So it came as something of a surprise to see a slight decline in respondents reporting the use of QbD in their biopharmaceutical manufacturing operations—67% this year, versus 70% last year. Nevertheless, 13% more respondents say they understand the initiative this year, bringing the percentage up to 62%. Furthermore, only 38% say they lack guidance and direction from regulatory agencies, as compared with 46% last year, and 23% more respondents than last year see the process and quality advantages to the QbD program. In spite of the fact that more respondents understand and appreciate the benefits of QbD, 17% cite cost as an impediment to implementation.

Among those who do incorporate QbD, 71% say it has improved process understanding, 51% say they've seen improvements in product quality, 49% say they've realized greater manufacturing efficiencies, and 45% say QbD has reduced variability in product quality. Twenty-eight percent say the initiative has reduced costs, but this is down from 38% who said the same thing last year. Finally, 23% credit QbD with speeding regulatory approvals.

Figure 8: Current technical challenges faced by manufacturers of nucleic-acid based drugs (multiple answers allowed).

Fifty-three percent of respondents incorporate process analytic technologies (PAT) into their manufacturing operations, about the same as last year. Among those who do use PAT, the most widely used technology is high-performance liquid chromatography (HPLC) (73%), followed by 46% who use spectroscopy (other than near infrared spectroscopy [NIR] or Fourier transform infrared spectroscopy [FT-IR]), 43% who use chromatography (other than HPLC or ultra-performance liquid chromatography), 31% who use NIR, and 28% who use FT-IR (see Figure 6).

Spending

This year, as we hopefully recover from the recession, one might expect spending to increase over last year. This year, 31% of respondents anticipate their companies to increase spending on biopharmaceutical manufacturing activities. But if history is any predictor, respondents tend to underestimate spend. Last year, 29% anticipated spending increases in 2009, compared with 41% percent of respondents who report that their companies actually did increase spending.

Figure 9: Purification technologies used by respondents for manufacturing proteins (multiple answers allowed).

Innovation

We asked respondents to tell us about the innovations that have most improved their processes in the past year, and what they hope to see in the future. Respondents said that disposables in various forms had improved their processes. Single-use sensors, bioreactors, chromatography columns, and filters were mentioned repeatedly. Respondents look forward to more improvements and innovations in single-use technologies to enhance product quality and process efficiencies. In addition, they are looking for manufacturers to create analytics that can discern the disposition of glycans on proteins and processes that allow better control of protein glycosylation, better contamination identification and detection methods, improvements in affinity resins for protein purification, improvements in cell-based expression systems, and improved analytics for determining protein structural information.

Figure 10: Vaccine production systems used by respondents.

Survey Participants

Three-hundred-and-eighty-four respondents completed the survey this year. About 79% were male, aged 45 on average, and represented an average number of 17 years professional experience. At 48%, the largest number come from the United States (including Puerto Rico), followed by 26% from Western Europe, 7% from India, 6% from Asia other than India or China, and 2% from Canada. Thirty-one percent indicated their companies were innovator pharmaceutical companies producing branded drugs, 28% were from biotech companies, 10% were from contract manufacturers, and 7% were from generic companies. The rest represent consultants, consumer healthcare companies and suppliers of raw materials, equipment and machinery. About 20% are in research, and another 19% are in process development. Sixteen percent are in production management, 14% are in quality assurance and control and 5% are concerned with regulatory affairs. The remainder are consultants or perform some other job function. Their companies' average revenue is $10 billion.

Figure 11: Biopharmaceutical manufacturing focus of respondents (multiple answers allowed).

Figure 12: Quality-by-design advantages realized by respondents (multiple answers allowed).

Figure 13: Type of manufacturing equipment currently used by respondents.

Figure 14: Respondents answer whether their companies are likely to manufacture follow-on biologics once a regulatory pathway is established in the US.

Survey Participants

Figure 15: Percentage of biomanufacturing capacity increased by respondents' companies in 2009.

Figure 16: Percentage of respondents' companies that outsource biotherapeutics manufacturing.

Figure 16a: Reasons for outsourcing biotherapeutics manufacturing (multiple answers allowed).

Figure 17: Percentage of respondents' companies that are incorporating QbD into biopharmaceutical manufacturing activities.

Figure 17a: Reasons for not incorporating QbD into biopharmaceutical manufacturing activities.

Figure 18: Reasons for decreasing biopharmaceutical manufacturing capacity in 2009.