Michelle Hoffman, editorial director of Pharmaceutical Technology.

Michelle Hoffman

Maybe with summer around the corner, corporations are getting spring fever and losing focus. But it seems that a lot of them are becoming distracted (again), and the quality of their products and operations are suffering. 

For example, as I write this, newspapers, TV, radio, the Internet, and the blogosphere are dominated by reports of BP's failed attempts to plug its catastrophic oil spill in the Gulf of Mexico (as well as BP executives' clumsy attempts to apologize for their mess). A few months ago, Toyota—a leader in quality control—issued massive recalls of its cars and trucks, stemming shockingly from lapses in quality control. 

And in a series of quality breaches that hit closer to home, we are learning more details about an ongoing succession of recalls by Johnson & Johnson of over-the-counter products, including a bizarre "phantom recall," in which the company contracted people to buy tainted Motrin off store shelves rather than formally recall the product. (In an article published on June 11, the 

quoted a company spokesperson as saying that the objective was "to remove the affected product from a unique distribution channel, mainly convenience stores and gas stations, with as little disruption and consumer confusion as possible." In that same article, the US Food and Drug Administration begged to differ. The article cited an email from one of FDA's recall coordinators as saying to J&J, "It seems that your company is doing a recall even though you are calling it a 'retrieval' ... your company should do a voluntary recall of the product since it appears to be that you are already doing a recall of the product." (The company did later institute a formal recall, according to the 

 article.) We are also learning that Pfizer dragged its heels in reporting adverse events associated with its cholesterol-lowering drug Lipitor and its antiseizure medication Lyrica, prompting FDA to issue a Warning Letter. 

In theory, the specters of legal liability and/or public disapproval (along with declines in sales and stock prices) are supposed to check corporate temptation to cut corners on quality or to be otherwise negligent. Nevertheless, recent events seem to indicate that neither liability nor public disapproval is adequate to ensure good corporate citizenship. 

So it should come as no surprise that after each of these incidents, the public looked to the government to increase its oversight of the affected industry. As a result of BP's fiasco in the Gulf of Mexico, there is strengthened public support for a moratorium on off-shore drilling and for greater government regulation of the petroleum industry. In response to the recent financial crisis, a bill is now wending its way through Congress that calls for greater regulation of the financial industry, banks, hedge funds, and mortgage lenders. And, in spite of the well publicized role of FDA in regulating drug safety, a recent poll indicates most people feel pharmaceuticals ought to be better regulated.  

Of the more than 2500 adults responding to a 

,  conducted in May 2010, 70% felt that the government should impose even stricter regulations on the pharmaceutical industry than it does now. Surprisingly, even a majority—61%—of respondents self-identified as Republican, who usually oppose government intervention in industry—felt that pharmaceuticals required more regulation than they now receive. (In contrast, 80% of self-identified Democrats supported stricter oversight of pharmaceuticals.) 

The American public is not alone in feeling that corporations—specifically their executives—need to be monitored a little more closely. Brian Hasselbalch in FDA's Division of Manufacturing and Product Quality, Office of Compliance, at the Center for Drug Evaluation and Research addressed the agency's enforcement role in promoting corporate responsibility at a recent meeting held jointly by FDA and Xavier University in Cincinnati, Ohio. The agency seeks to ensure that poor practices are not rewarded, and will take "swift, aggressive, and effective" enforcement action when needed, he said. 

Corporations are operating within a quality vacuum, and the public, as well as nature, abhors a vacuum. Ultimately, if corporations are unwilling or unable to regulate themselves, someone will do it for them. 

Articles

After a spate of industrial disasters, the public seeks greater oversight of corporations-so does FDA.

A Word to the Unwise

June is a big month for weddings, and it stands to reason that it would also be a big month for anniversaries. So it seems appropriate that this season also marks the anniversaries of two important events in the history of the pharmaceutical industry. The birth control pill was approved 50 years ago in May; and the International Conference on Harmonization (ICH) was born in April 1990. The two events are not unrelated, for each exerted an important impact on pharmaceutical regulations. 

Enovid, the first commercially available oral contraceptive first received FDA approval in 1957 to treat certain menstrual disorders. So G.D. Searle, the pill's manufacturer, anticipated the drug to breeze through FDA approvals when in October 1959, the company filed to market the drug as a contraceptive. They were wrong. 

FDA sat on the application. Whereas the agency had previously required drug manufacturers to provide clinical evidence that a drug was safe, the agency now demanded that Searle provide evidence that Enovid was also effective for its intended use. Why had FDA changed its stance? Until that time, FDA had been asked to consider drugs to treat illnesses. Enovid presented the first case where a manufacturer proposed to give drugs to healthy people, and FDA, according to an account of the drug's approval history detailed in a PBS/American Experience documentary on the subject (

http://www.pbs.org/wgbh/amex/pill/peopleevnets/e_fda.html

), felt uncomfortable with the proposition. Thus was initiated the largest clinical drug trial ever run up to that point. During the trials, 897 women took 10,427 cycles of the drug with no side effects considered harmful at the time. In May 1960, Enovid finally received approval for contraceptive use with the proviso that it be used for a period of no more than two years at a time. The importance of this approval for women's social history are well documented. The other key consequence is that all drugs must now demonstrate evidence of both safety and therapeutic efficacy in clinical trials before they can receive FDA approval. 

Enovid's approval and the FDA's increased stringency were both obscured by the tragic consequences in Europe of the drug Thalidomide on children born to mothers who had taken the drug as a sedative. The Thalidomide debacle "revealed that the new generation of synthetic drugs, which were revolutionizing medicine at the time, had the potential to harm as well as heal," and so ushered in a period during the 1960s and 1970s of a rapid increase in "laws, regulations and guidelines for reporting and evaluating the data on safety, quality and efficacy of new medicinal products," according to an account of the history of ICH on the organization's website. During this time, the industry started becoming more international, but the registration of drugs remained a national responsibility. Technical details of drug manufacture had diverged to a point that, according to the ICH website, "industry found it necessary to duplicate many time-consuming and expensive test procedures," in order to market drugs internationally. 

Both trends—increasing regulation and increasing globalization—continue to this day. In fact, the pace of both is hastening. New chemistries and new classes of therapeutics bring new regulations. In addition, the potential for personalized medicine and comparative effectiveness research will likely drive drug companies to discover not only safer but more effective and more targeted drugs, which will in itself push regulatory bodies into new directions.  

The rise in globalization expands the number of markets into which manufacturers can sell drugs, and also expands the choice of suppliers from which manufacturers may buy equipment and ingredients. These twin conditions mean that drug companies may sell larger quantities of drugs—and therefore realize greater profits, all the while holding costs down by having more suppliers. But it also produces a situation where drugs could vary from one to the next geographic region and places greater importance on developing a global quality standard for finished products and for the ingredients that go into them.  

The birth of "the pill" and harmonization created a new paradigm for global standards.

Anniversary Season

Remember back in high school or even further back, maybe to junior high, to the kid who seemed cool and interesting—let's call her Marcia Brady. You really wanted to become friendly with her, but you held back. Maybe you were shy, uncertain about her response to you, and in your uncertainty, you decided that she probably didn't want to talk to you anyway. And then you decided she was really stuck up. And then you didn't want to talk to her all that much. And then you were more intimidated than ever.  			

But maybe years later, you run into Marcia. You're a grownup now with a life and a career and lot more confidence than you had back in the day. And you strike up a conversation with her and you find out that Marcia's really nice and that she did notice you in junior high. What's more, Marcia was really hoping you'd talk to her and never understood why you didn't.  

This nearly universal experience popped into my head recently when I sat in on an impromptu discussion with some industry insiders dissecting the industry's attitude about the US Food and Drug Administration. The discussion started where so many do: Why does pharma so often lag technologically behind other industries? The group offered that the classic answer has always been that pharmaceutical scientists must operate within the tight regulatory strictures of FDA. Pharmaceutical scientists are nervous about process innovation, the usual argument goes, because getting FDA to approve a novel manufacturing approach may delay the overall approval process. Better to stick with a tried-and- true, and previously approved, process. 

But that answer runs contrary to FDA's recent efforts at transparency as well as its now several-years'-old quality-by-design (QbD) inititative, both of which invite dialogue between industry scientists and regulators. Regulations are proffered in the form of "guidelines" and "guidances" and are left purposely vague precisely because the agency does not want to prescribe methodology. Rather, regulators stress that one size does not fit all. They want manufacturers to tailor their processes to the particular ingredients they're working with. To do that effectively, regulators also encourage manufacturers to understand as much as possible about the chemical and physical properties of the ingredients that make up their formulations. And most important, FDA officials want industrial scientists to share with them details about how the behavior of the ingredients informed their process design. 

It seemed to our insiders that rather than embrace flexibility, many in industry are afraid of it and crave more explicit direction from regulators. Some in the industry may feel that flexibility involves too much risk and responsibility. Others may continue to perceive FDA as an enforcement agency, an industrial police force ready to trap and punish innovators. Clearly, that mindset has to change before QbD becomes widely adopted. Our insiders predicted that it may take a full 10 years before industry "dinosaurs" become extinct, which will pave the way for QbD to become a nearly universal modus operandi.   

If anything brought home FDA's genuine interest in reaching out to industrial scientists, it was a panel discussion organized by 

at Interphex 2010 in which three FDA staffers made suggestions for new and abbreviated drug applications. The unmistakable message in that and the subsequent Q&A session was that agency officials want manufacturers to know and understand their ingredients as they pass through the manufacturing process.  

And FDA wants you to share your rationale with them—before filing an application, while the application is undergoing regulatory assessment, and afterward if you make changes in the process, ingredients, formulation, suppliers, or delivery devices. FDA wants you to talk to them. They really, really do.  

FDA wants industry to talk to them about the science underlying process innovations-really.

A Very Brady FDA

"You can never be too rich or too thin," Wallis Simpson, the late Duchess of Windsor once famously said. But the new healthcare reform bill may well be both. Largely thought to be a dead issue since Republican Scott Brown was elected to fill the Senate seat left vacant by the death of Massachusetts's Senator Edward Kennedy, the bill is expected to be a pared down version that includes provisions acceptable to partisans on both sides of the aisle. This so-called "skinny" bill could contain the following provisions, according to a Jan. 21, 2010 

Insurers could not deny coverage to children under the age of 19 on account of pre-existing medical conditions. 

Insurers would have to offer policyholders an opportunity to continue coverage for children through age 25 or 26. 

The federal government would offer financial incentives to states to expand Medicaid to cover childless adults and parents. 

The federal government would offer grants to states to establish regulated markets known as insurance exchanges, where consumers and small businesses could buy coverage. 

The federal government would offer tax credits to small businesses to help them defray the cost of providing health benefits to workers. 

If a health plan provides care through a network of doctors and hospitals, it could not charge patients more for going outside the network in an emergency. Co-payments for emergency care would have to be the same, regardless of whether a hospital was in the insurer's network of preferred providers.     

In its slimmed-down version, the legislation would likely cover fewer than half of the estimated 30 to 40 million uninsured individuals in the United States. Nevertheless, the bill may face funding hurdles—especially in this economic climate. "While both parties might agree on what should be in the bill," said Steven Usdin, senior editor at BioCentury Publications during a roundtable on the subject at the Biotechnology Industry Organizations' annual CEO and Investor Conference in early February, "they disagree on how to fund it." In other words, the reform measures may still be too rich for lawmakers' blood. 

Ironically, healthy people continue to opt out of insurance plans, causing insurers to raise their rates even more. If this continues, health insurance will cover only the sickest, wealthiest Americans—a scenario that can't be good for anyone, including the pharmaceutical industry.  

Not to be deterred, the White House made one more push in early February to bring all the parties back to the table. The president issued an invitation to Democrats and Republicans to participate in a televised summit in which representatives will attempt to reach a consensus about the contents—and maybe the financial support—of a healthcare bill. Fortunately, representatives from both parties have accepted the invitation. 

The meeting may well represent the last chance for lawmakers to craft a plan with some meat on its bones at a price that does not require a king's ransom.  

http://www.nytimes.com/2010/01/22/health/policy/22health.html?scp=1&sq=A%20New%20Search%20for%20Consensus%20on%20Health%20Care%20Bill&st=cse

If both sides of the aisle don't agree on even mild healthcare reform soon, the bill could die out.

Skinny or Dead

 "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, 

 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. 

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). 

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. 

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). 

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). 

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). 

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).

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.  

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.   

The second annual Pharmaceutical Technology Bioprocessing Survey offers a snapshot of the industry following 2009's megamergers.

Trends in Bioprocessing

Well established as an analytical tool for biomolecular interaction analysis, surface plasmon resonance (SPR) is a spectroscopic method that has entered the biopharmaceutical toolkit as a technology for supporting process-development and quality-control operations. Among its virtues, the technology offers real-time, label-free detection, which may prove useful in the future as a process analytical technology (PAT). 

spoke with Fredrik Sundberg, director of Strategic Market Development at GE Healthcare, which produces an SPR system under the name Biacore, to learn how this analytical tool can be incorporated into biopharmaceutical manufacturing. 

SPR exploits the binding between two molecules to measure the interaction between an analyte and ligand. In the case of Biacore, the interaction takes place on a chip surface, where the ligand is immobilized. SPR provides more comprehensive information about binding events than any other technology on the market today such as affinity, kinetics, specificity, and active concentration of a particular protein in solution. For example, you can detect protein concentrations in a purified sample or in a crude sample. 

What do you mean by active concentration? 

You get real-time binding data about how much of your protein of interest is actually actively binding to the target. In fact, you can see the binding taking place as it happens in the processing unit by looking at the system-controller computer. This allows you to characterize the product and detect certain impurities during purification and process development. Due to the sensitivity of the SPR detection principle, it is possible to very effectively assess comparability of products by looking at binding kinetics and conducting epitope mapping. For example, you may be able to detect various protein modifications by looking at changes in binding patterns. SPR detection not only measures total protein content in an unknown sample, like you would do with A280 (optical absorbance at a wavelength of 280 nm). In fact, with SPR, it is possible to very accurately measure the active concentration without using a calibration curve. This allows companies to improve their assays in general by using SPR for raw material control of  critical reagents used in, for example, ELISA-based immunoassays. 

Where do you see SPR being useful in a bioprocessing setting? 

It is very useful during process development. Because you can detect concentrations of your product in real time, you can determine how various processing variables are affecting your product yield and product integrity. It could also be used during commercial bioprocessing for quality control to detect product and product changes. In process development, it has been used for detection of protein aggregates, for example, or host-cell-proteins during product purification. SPR is often used in combination with other biophysical methods such as microcalorimetry, size-exclusion chromatography (SEC), and liquid chromatography/mass spectometry. And as companies move into follow-on biologics, they will find they can configure the system to determine the immunogenicity of product variants. It's even possible to design experiments to identify parts of a molecule that may trigger immunogenicity so a company can go back and re-engineer the product and process to reduce that product's immunogenicity. 

The sample analysis is fully automated and supports both 96-well and 384-well plates. First, the ligand is injected by an autosampler through the microfluidics system in the processing unit over a chip onto which it is immobilized. After the chip is coated with the desired density of ligand, the analyte is injected, and binding is measured by an optical unit. Accurate concentrations of the unknown samples can be calculated based on the amount bound, which corresponds to the signal measured from changes in refractive index. For example, coating the chip with Protein A would allow you to measure the concentration of antibodies (since Protein A would attract the constant fragment [Fc] of the antibody). To achieve greater specificity, or to combine measurements using the multiple flow cells in the system, one might also use a specific antigen as ligand to measure the concentration of only those antibodies in the sample with the antigen-binding (Fab) region specifically capable of recognizing the ligand. 

What are the advantages of SPR over existing analytic technologies? 

Because SPR detects binding in real time, and sample prep is minimal, there's a tremendous time-saving over, say, ELISA or high-performance liquid chromatograhy. Variability is low, and the coefficient of variability often falls in the range of 1–5%, even for very crude samples (e.g., cell-culture supernatants). Apart from the improved productivity, SPR also resolves affinity into its kinetic parameters (on-and off-rates) which enables scientists to assess more clinically relevant parameters such as recognition and stability of binding to target-binding site. 

Could you give us an idea of what sort of time saving you're talking about? 

You would get an answer from an ELISA assay in a matter of hours, but SPR could give you an answer within a few minutes (3–10 minutes). For process engineers, this can shave considerable time off process development. Also, unlike HPLC, SPR does not require you to produce a standard curve, so that  essentially SPR enables calibration-free concentration analysis. This is of great advantage when you have an unstable standard, or if a standard is not available. 

What is the future potential of SPR as a PAT tool?  

The real-time capability and critical information from SPR would provide a great advantage in PAT applications in the future. On-line or in-line detection of product with SPR would provide critical information of quality attributes and how these are affected by process modifications. For example, there have been some academic initiatives that have proven the possibility of connecting Biacore to bioreactors for continuous monitoring of expression levels over time under various conditions.  