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BioPharmâ€™s 5th Annual Employment Survey

BioPharm International, January 2011 Issue (PDF)

Single-use bioreactors are commonly used for seeding stainless steel bioreactors or for producing material. The profitability of this equipment has been well demonstrated for more than a decade, but few data on their scalability are published. In May 2010, Merck Serono Biodevelopment began a study to evaluate the performances of disposable bioreactors. Because different technologies were available, this study compared performances of several types of mixing. The evaluation was performed both for seeding application and for clinical material production. This study featured 20–50 L disposable bioreactors with gas flow-rate scaled-down from seeding and production bioreactors. A fed-batch process producing a highly glycosylated molecule was performed twice in four types of disposable bioreactors. The quality of the molecule together with molecule concentration and cell growth were compared among the three single-use technologies. These process performances were also compared to 250 L and 1,250 L bioreactors and to a 3.6 L glass development bioreactor. These comparisons allowed Merck Serono Biodevelopment to conclude on their uses and on the scalability (up and down) of these disposable systems. This study was completed by a characterization of liquid–liquid and gas–liquid transfers inside each disposable bioreactor to estimate their potential in terms of cell culture. 

To decrease sterilization, cleaning workload, and reduce costs, the disposables market has been diversified to meet the needs of the biotechnology industry. At Merck Serono Biodevelopment (MSB), bags, tubing, and disposable cell culture containers commonly are used in production processes. Hybrid processes with stainless steel bioreactors, however, remain because a lot of factors have to be considered before implementing such technologies. Besides supplier support and quality, one critical point is the scalability of these bags. Of course it is easier when you design a new plant, but when you have existing stainless steel manufacturing bioreactors and you want to increase your capacity and produce material in disposable bioreactors, comparability and scalability between bioreactors could be a problem. From May to September 2010, MSB performed a study to evaluate and compare performances of different disposable bioreactors. Various equipment models are available on the market, so the options were sorted based on maximum working volume, mixing technology, current good manufacturing practice compliance, availability, data published, supplier experience, and internal requirements. To test different mixing principles, the following technologies were evaluated: ATMI-Pierre Guerin single-use bioreactors; orbital shaking and stirred mixing, both from Sartorius. Processes performed with this equipment began with a growth phase to evaluate bioreactor seeding performances, followed by a fed-batch process producing a high glycosylated antibody-like molecule, to evaluate the impact of culture in disposable bioreactors on molecule quality. Performances were compared to process development bioreactors and manufacturing bioreactors. The evaluation finished with a characterization of transfers by K

a, mixing time measurements, and temperature mapping. 

Cell culture was performed twice in each disposable bioreactor under the same conditions.  

A vial of Chinese hamster ovary (CHO) cells was thawed in commercial medium in a static container. Cells were expanded every two or three days in agitated containers until reaching 8.6.10

A sterility test was performed at 37 °C in each disposable bag two days before inoculation. The cells were then inoculated in parallel in all disposable bioreactors at the minimum working volume provided by the supplier. Growth was then observed for two days. Working volume was increased to the maximum working volume at the same cell density between bioreactors. Cell growth at maximum working volume lasted three days.  

Temperature was regulated at 37 °C. Stirring speed was fixed by the supplier. 

Oxygen was regulated at 50% only with oxygen at a flow rate scaled-down from MSB 250 L seeding bioreactor for paddle and stirred mixing bioreactors and at a flow rate fixed by the supplier and MSB according to its experiences with the orbital shaking bioreactor. 

In the same bag, cell suspension was partially removed and replaced by fresh medium to keep same seeding density between bioreactors. Cells were maintained at 37 °C for a few days, then a temperature switch was performed and production temperature was applied until production day 7.  

Oxygen was regulated at 50% with air and oxygen at a flow rate scaled-down from MSB 1,250 L production bioreactor for paddle and stirred mixing bioreactors and at a flow rate fixed by supplier and MSB according to their experiences with the orbital shaking bioreactor. The pH was maintained between 6.8 and 7.2 with sodium hydroxide 1N and CO

Agitation speed was fixed by the supplier for the paddle bioreactor. Agitation speed for stirred and orbital-shaking bioreactors was fixed by the supplier and increased by MSB to avoid large oxygen variations. 

Feed was added twice at the same amount per L, and sampling was performed every day at 1/200 of working volume. 

Every day, pH was checked with an external pH-meter and corrected if the difference was above 0.05 pH unit; cell density and viability were measured. During the production process, biochemistry analyses and molecule titration were performed in addition to previous in-process controls. At the end of the process, a capture was performed to check quality attributes (e.g., glycosylation, aggregates).  

a, was measured at maximum working volume in water at 37 °C by sparging air at the working flow rate applied during production process and at the maximum flow rate allowed by the equipment. 

Mixing time was measured at maximum working volume in phosphate saline buffer between pH 6.8 and 7.4 at 37 °C by injecting a small amount of sodium hydroxide 5N to increase the pH by 0.20–0.30 units. The pH was adjusted initial level with 8M acetic acid. 

Temperature mapping was performed at maximum working volume in water with six calibrated temperature probes at different places inside each disposable bag. Temperature increase was followed between room temperature up to 37 °C and temperature decrease to 37 and 29 °C. 

One of MSB's objectives is to provide grams of high quality recombinant proteins for preclinical and clinical studies. This production can be performed at different scales depending on needs. Thus, process performances in terms of cell growth, but especially protein concentration and quality, should be representative to MSB bioreactors.  

Cell Growth During Cell Amplification Phase

Cell growth at minimum and maximum working volume allowed MSB to evaluate seeding performances of disposable bioreactors.  

Cell growth was compared between disposable bioreactors and 250 L production seeding bioreactor in terms of doubling time or population doubling level (Figure 1). 

Figure 1. Population doubling level (PDL) from inoculation to production phase. For disposable bioreactors, it represents growth at minimum working volume (from working days 0 to 2) and at maximum working volume (from working days 3 to 5). Date for seeding bioreactors were from 1,250 L seeding bioreactors presented later. Data are the means from two bioreactors, with errors bars representing minimum and maximum levels.			

Linear regressions of these curves gave cell doubling time (see Table 1). 

Table 1. Regression coefficients and slopes of Figure 1 curves			

Regression coefficients of all curves were above 0.99; therefore, cells exhibited a regular growth either at minimum working volume or at maximum working volume, whichever bioreactors were used.  

These results indicate that flexibility of disposable bioreactors as the minimum working volumes was between half and 1/5 of maximum working volumes. Doubling times were similar between stainless steel and disposable bioreactors. They are all compatible with production bioreactor seeding application. 

The production process includes a temperature switch to compare cell growth between bioreactors; therefore, an integral of viable cells (IVC) was plotted instead of cell density (Figure 2). 

Figure 2. Integral of viable cells (IVC) in production phase at maximum working volume for disposable bioreactors, a 1,250 L MSB production bioreactor, and a 3.6 L process development bioreactor. Data are the means from two bioreactors, with errors bars representing minimum and maximum levels.			

Cell growth in disposable bioreactors using a paddle and stirred mixing system was similar to cell growth in traditional bioreactors; however, cell growth in the orbital shaking bioreactor was lower.  

The variability between runs was quite low, even when runs were carried out with different cell bank vials and cell amplifications. Nevertheless, it is not relevant to conclude on robustness of disposable bioreactors as only two runs were performed. 

Viability Profile During Production Phase 

Cell viability profile (Figure 3) could be linked to shear stress inside the bioreactor. This parameter could reflect the impact of the mixing type. 

Figure 3. Viability in production phase at the maximum working volume for disposable bioreactors, a 1,250  MSB production bioreactor, and a 3.6 L process development bioreactor. Data are the means from two bioreactors, with errors bars representing minimum and maximum levels.			

Viability drop started at production day 6 for all bioreactors except the orbital shaking bioreactor. This particular bioreactor has a completely different mixing profile compared with the others because nothing except the bag comes into contact with cells. The agitation is external, while in other bioreactors mixing is generated by an internal element inside the bag. The higher viability observed in orbital shaking could also be linked to the lower IVC presented in Figure 2. 

In a same way as IVC, viability profiles with paddle and stirred mixing bioreactors were similar to traditional bioreactors. 

Disposable bioreactors with internal agitation seemed to reproduce cell growth and viability profiles better than traditional bioreactors. 

Glucose Metabolism During Production Phase 

Glucose is a key nutrient of cell metabolism and was followed (Figure 4) with a semi-automatic biochemistry analyzer. 

Figure 4. Glucose concentration in production phase at the maximum working volume for disposable bioreactors, a 1,250 L MSB production bioreactor, and a 3.6 L process development bioreactor. Data are the means from two bioreactors, with errors bars representing minimum and maximum levels.			

Despite different cell densities especially in the orbital shaking bioreactor, glucose concentrations were similar between all bioreactors throughout runs. 

Features

A case study to compare the performances of several types of mixing in disposable bags with stainless steel bioreactors.

Comparing Fed-Batch Cell Culture Performances of Stainless Steel and Disposable Bioreactors

The beginning of the new year is the time when many of us take stock of where we are and where we are headed. So, we will do the same and look at some of the key forces that we see driving and shaping the contract services industry, particularly those companies offering contract development and manufacturing services (CDMOs and CMOs). 

Like the broader economy, the pharmaceutical services industry will continue to recover at a slow, steady pace, but a return to the halcyon days of the last decade is extremely unlikely. The good news is that many of the indicators are improving. Research and development (R&D) spending is growing, and financing from public equity markets and venture capitalists has improved. The large mergers and consequent integration efforts have been largely completed, and the global bio/pharmaceutical companies are again focused on pursuing compounds through their pipelines. 

Still, there is a great deal of uncertainty clouding the picture. The big restructuring efforts may be over for now, but bio/pharmaceutical companies continue to cull their pipelines to focus their efforts on the most promising therapeutic areas and candidates. Mid-size bio/pharmaceutical companies are doing the same thing, as witnessed by Biogen Idec's (Weston, MA) decision late last year to exit all therapeutic areas except neurology. Further, although external financing has improved, much of that is going to late-stage candidates, so the efforts of early-stage bio/pharmaceutical companies are still hampered. 

Other complicating factors include government efforts in all Western countries to reduce spending. These potential cuts could hurt bio/pharmaceutical profits and potentially hit heretofore sacred cows such as the National Institutes of Health, which underwrites a great deal of bio/pharmaceutical research in the US. 

The best news for the CDMO and CMO industry is that most major bio/pharmaceutical companies appear committed to outsourcing more of their development and manufacturing requirements. All of the companies have recognized the need to reduce fixed overhead costs and match spending to what is actually happening in their pipelines. So, although total R&D spending may grow at low single-digit rates, total outsourced spend should grow at a faster rate. 

Although the outsourcing pie will increase in size, it certainly won't be divided up evenly. As the pharmaceutical industry restructures, so will the contract services industry that supports it, and industry consolidation will be a principal result. That restructuring is well underway in the clinical and preclinical development arenas, where the five largest firms already command nearly 50% of the market and are picking up share at a rapid pace. As discussed in past columns, the market leaders have succeeded by building a track record of dependable performance for their clients and broadening their offerings to meet the needs of their increasingly global clients. 

The same dynamic is taking place in the CDMO and CMO world, but at a slower pace. Outsourcing in this arena is slowed down by the considerable investment in manufacturing and laboratory assets that the global bio/pharmaceutical companies already have in place. Given the high costs of operating those facilities, companies are under pressure to keep them as highly utilized as possible. A growing number of global bio/pharmaceutical companies have even resorted to selling their excess capacity on the open market. Until the global companies are ready to face the considerable costs of closing down those underutilized facilities, the pace of outsourcing development and manufacturing activities other than packaging and laboratory services will be slow.  

We see the formulations development and manufacturing segment engaging in a technology arms race in which competitors seek to broaden their formulation and processing "toolbox." The goal is to build a service offering that is comprehensive enough to serve a large share of a major client's needs and address the requirements of a broad swath of the industry's development pipeline. CMOs are rushing to add such capabilities as dry granulation, solubility enhancement, and handling of high-potency compounds, as well as bolstering their preformulation capabilities. In addition, CMOs are building their analytical capabilities for large molecules, reflecting the nature of the candidates in the pipeline. This drive to acquire drug-delivery, processing and analytical technologies is crucial to the effort to fain "preferred supplier" status with the global bio/pharmaceutical companies, which favor suppliers with broad capabilities in their drive to reduce the number of supplier relationships they maintain. 

CMOs specializing in APIs went through a similar technology arms race 10 years ago. They learned that a broad technology offering was a necessary but not sufficient dimension for competitive success. Technology capabilities often can be duplicated, making it difficult for CMOs to differentiate themselves on that dimension alone. Although CMOs expand their technical capabilities, they will need to maintain their focus on performance and serve a client base with increasingly global aspirations. 

It looks to us that the biggest challenge facing the CMO and CDMO industry is globalizing its offerings. Clinical research organizations (CROs) have moved aggressively to create a global footprint, and their ability to support international clinical trials is a big reason why the largest CROs such as Quintiles (Research Triangle Park, NC) and Icon Clinical Research (Dublin) have come to dominate the CRO industry. 

CMOs and CDMOs have been slow to attack the global development and manufacturing opportunity. Only a few Western API development and manufacturing companies, including Lonza (Basel), Aptuit (Greenwich, CT), and AMRI (Albany, NY), have made a major effort to establish their presence in emerging markets. In part, this slow pace reflects the relatively recent nature of the opportunity: demand within emerging markets for services such as formulation manufacturing and clinical packaging is following the growth of clinical trial activity in those countries. The slow response only reflects the fact that establishing a presence in the emerging markets requires significant investment in key business assets, including facilities, senior management and technical staff, and knowledge about how to do business in those countries. 

Interestingly, the CDMOs and CMOs that have been most aggressive in growing their global network of operations have been those companies founded and headquartered in the emerging markets themselves, companies such as Piramal Pharma Solutions (Mumbai), WuXi AppTech (Shanghai), and Jubilant Life Sciences (Noida, Uttar Pradesh, India.) Understanding the next steps these companies will take to become truly large global players in the CMO and CDMO market is central to knowing where the industry is headed next.

Jim Miller is president of PharmSource Information Services, Inc. , Springfield, VA, 703.383.4903, 

Outsourcing Insights

CDMOs and CMOs face weak economic recovery, consolidation, and globalization.

What to Watch For in 2011

Rewind to five years ago: A start-up biotech on the block with an innovative drug in Phase 3 clinical trials is hiring. If a recruiter approached you for the job, you might have at least given it a shot, considering that even if the start-up fails, you would be able to find another job quickly. Fast forward to the present: A new biotech company in your town is hiring. Your company has had two rounds of layoffs, and even though your workload has doubled, you aren't interested in moving. "We are doing more with less but people are either taking no risk or taking longer to keep the risk the same," says a Boston-based biopharmaceutical manufacturing professional from a big biotech.  

These sentiments are reflected in the responses to 

fifth annual salary survey, which shows that biopharmaceutical professionals are working harder than they did last year with fewer resources, which has resulted in increased workload and higher stress levels. 

The economic crisis had a big impact on the biopharmaceutical job market by tightening up the availability of capital, eliminating jobs, and eroding companies completely. More than 50,000 pharmaceutical jobs were lost in 2010. In addition to the economic forces that affected all industries, the pharmaceutical industry faced additional challenges from drug recalls, patent expirations, and dwindling pipelines, which have resulted in more mergers and acquisitions (M&As). 

A California-based CMC professional says that M&As accentuate the reduced activity of research. "Lack of products reduces revenues and sales, and therefore, investment in R&D and that leads to reduction in resources," he says. He adds that the number of people per project has decreased in his company, there are hiring controls, and the company is replacing personnel selectively.  

More than half (63%) of our respondents have been through a merger, acquisition, or downsizing within the last two years (Figure 1), although over half of them (61%) said it had no significant effect on them. The rest said their job responsibilities changed (30%) as a result of a merger or downsizing activity, while the remainder chose to leave their companies voluntarily (9%). 

Figure 1. If your company merged, was acquired, or downsized, was it tied to the economic downturn? 

There are fewer people to work on projects, agrees the biopharmaceutical professional from Boston. "Our revenue was lower than expected this year, therefore the company would not have hired enough people dedicated to certain projects." His company recently eliminated a couple layers of management, so there are now fewer people to manage more people. He has seen a similar trend in other companies. "Companies are trying to get rid of redundancies so managerial levels are being skipped. For example, earlier, a senior manager had 2–3 reports but now those middle managers have been removed, and the same person now has 7–8 reports," he adds. 

Similarly, a QA professional at a big pharma company in New Jersey says that there has been an internal reorganization at her company. "Our San Diego facility has been closed, and we are in the process of consolidating a few others," she says. Her company also has cut a number of its internal programs.  

"We have to do everything extremely lean—not only lean manufacturing but also lean development," says the biopharmaceutical professional from Boston. "Last year, we looked at how to work smarter and leverage new technology to do the same or more work with less people." This lean approach has become a new baseline because there are now additional cost pressures that lead to downsizing, he adds. 

For those who survived the economic crisis and M&As, the resulting environment has created the challenges of increased workload and high stress levels, according to the survey. As shown in Figure 2, a majority of respondents (67%) said their workload has increased within the past year. "Business increase without staff increase," was the topmost possible cause for the increased workload, followed by "staffing cuts" and "merger and acquisition." 

Figure 2. Within the past year, has your workload increased or decreased? 

Similarly, more than half of our respondents (58%) said their stress level has increased in the last year (Figure 3). Some of the reasons cited for this include "business uncertainty," "management uncertainty," "inter-departmental conflicts," "negative workplace attitudes," "more stringent procedures," and "lack of training and continuing education." 

Figure 3. Within the past year, has your stress level at work increased?  

For small companies, this stress is added by diminished financial support. "Venture investors, often the umbilical cord of food/fuel for the industry, long provided the lifeblood for young biotechnology companies, but the model is more challenged today," writes Steven G. Burrill, the CEO of Burrill and Company, in his column, 

, in this issue. "In addition, because biotech companies are competing in an investment-constrained environment, they often only have sufficient funds to complete one phase of a project successfully before building the capabilities required to move their project through the next phase," writes Burrill. 

"We have always been asked to do more with the same number of resources," says Rob Gronke, a principal investigator at Biogen Idec. "In terms of stress, it depends on how you can handle change. Those who can't are stressed out more than others," he adds.  

Despite the economic turmoil, our survey shows that the salaries of biopharmaceutical professionals increased in 2010. "Bonuses and benefits might have been cut based on revenues, but salaries haven't changed," says the QA professional from New Jersey. "The salaries for top talent remain competitive," she says. 

As shown in Figure 4, the mean industry salary this year was $121,243 in the United States, significantly higher than the $96,742 figure for 2009. Interestingly, the mean income in Europe has gone down. In 2010, the average salary in Europe was €63,022, compared with €68,711 in 2009. 

Like last year, our US and European responses reflect a salary gap between men and women. Earning a mean salary of $93,788 (€45,624 in Europe), women lag behind their male counterparts, who earn on average $133,855 (€69,103 in Europe). 

This year's survey showed that the US biotech jobs with the highest salaries included corporate management, consulting, and process development 

Although pharmaceutical companies have been fairly conservative in hiring, the CMC professional from California, who is going to begin a new job in 2011, says finding a job was easier than he thought because he has a unique skill set. "Companies are still downsizing. It is easier for an associate level scientist to find a job than at a VP level." 

According to ZRG Partners' 2010 Global Life Science Hiring Index, regulatory and quality roles were the most in demand globally for the second quarter of 2010. ZRG's index, which was launched in January 2010, uses confidential hiring numbers from selected benchmark companies in medical devices, pharmaceutical, and outsourcing/contract services. 

One would imagine that the frustration stemming from work conditions would result in low job satisfaction, but our survey showed by and large, most biopharmaceutical professionals are satisfied in their jobs. The sense of security hasn't changed much compared with last year. In 2010, 70% of respondents said they feel "secure," "very secure," or "extremely secure" in their current jobs (Figure 6), a tad higher than last year's figure of 68%. 

Our survey shows that a lot of people are sitting tight. The majority of respondents (62%) said they are not likely to leave their jobs in the next 12 months, compared with 60% last year. For those who expect to change jobs, the reasons are split: About a third (27%) cited involuntary departure, but 28% said they would make a move for a better salary or more satisfying work (16%). 

Figure 6. How secure do you feel in your current job? 

The job satisfaction levels of biopharmaceutical professionals are similar to those of last year. The vast majority of our respondents (88%) are extremely satisfied, very satisfied, or satisfied with their jobs; only 11% are not satisfied, as shown in Figure 7. 

Figure 7. Please rate your overall job satisfaction   

Job satisfaction seems to be relative and depends on the extent to which the individual is enjoying his/her work. "I have been in my job for 20 years and I have been part of an important program in the company so I haven't considered changing jobs whether the market was hot or cold," says Gronke.  

Clearly the economy has taken a toll, and the year 2010 has been tough for the biopharmaceutical industry. Still, people voice cautious optimism. "The economy is coming back slowly, and I think a majority of the people who were laid off will be hired," says the CMC professional from California. The majority of our survey respondents (68%) also think employment opportunities will rise in the next 12 months (Figure 8). 

Figure 8. Do you think employment opportunities will rise in the next 12 months? 

"It is hard to say how it will pan out, as with biosimilars coming into the market, competition will increase, but the outlook for biopharmaceutical industry looks promising in both the short- and long-term," says the CMC professional from California. "There will be shake out and consolidation but it will drive innovation in the industry," he adds. 

The QA professional from New Jersey agrees, "In general my view for the long-term is that we will have more competition in biologics, less blockbusters." According to her, there is potential to increase overall revenue, "The size of the cake is not going to increase but the slices will increase. The fields like upstream and downstream might be saturated but the drug substance market will still benefit from having qualified professionals in regulatory and analytical." 

The biopharmaceutical professional from Boston has an interesting view, "We might not see great increase in salaries or bonuses, but the economic crisis might strengthen employees' loyalty to companies, and we will see fewer employees changing jobs. Biopharmaceutical companies will concentrate development on innovative products and focus on optimizing workflow," he adds.  

 fifth annual international salary survey shows that despite increased workload and stress levels, biopharmaceutical professionals are satisfied and feel secure in their current jobs. Perhaps Burrill summed it up best: "Going forward we will see a much stronger industry evolve as companies implement their business strategies in response to the new economic realities."

Some biopharmaceutical professionals we interviewed for this story spoke on condition of anonymity.

How did biopharmaceutical professionals fare during a year of hiring freezes, high anxiety, and increased workload? Our survey finds out.

BioPharm International's 5th Annual Empolyment Survey

Over the past two years, the face of the workforce has changed drastically. Companies eliminated bonuses, froze salaries, and downsized staff. Those employees who remained worked harder and longer. Now, with an economic recovery seemingly in motion, companies are developing new, creative ways to repair the damage. 

Today's workforce, and the one we can expect to see for at least the imminent future, is more creative than ever before. It's a melting pot of employee types—permanent hires, temporary and contingent staff, 1099 contractors, and now—the newest addition to the mix—insourced labor. 

Although insourced employees work onsite, they are employed by a third-party staffing supplier or a contract research organization, and supervised by a project manager from that organization. 

For pharmaceutical companies hesitant to rebuild their full-time workforces, but in need of a way to meet increasing demand, insourcing presents a viable solution. Here's why:  

 Insourcing gives companies elasticity to staff up quickly if workloads escalate. Similarly, if projects dissipate or clinical trials end, staff can be scaled back without a round of layoffs. 

 The human resources department might not have approved an increase in permanent staff yet, but there is still work that needs to be done. Insourcing solves this problem. Because insourced employees aren't managed by anyone in-house, and typically are allocated through an outsourcing budget, they aren't added to the headcount.  

 Insourced engagements often support functions that had been outsourced previously, but that yielded better results when completed internally. By insourcing, companies keep control over the process, improve communication, and eliminate data-transfer issues.  

 Because the pharmaceutical company is only paying for the talent and management of these employees, costs are significantly less than traditional outsourced services.  

Layoffs performed during the recession likely left open laboratory and desk space. These resources can be used by insourced employees, who can complete processes crucial to the organization in-house. With processes and standard operating procedures already in place, all pharmaceutical companies need is the necessary talent to drive a function or project. 

 Risk is the key differentiator between using temporary labor versus an insourced team. With temporary labor, the sponsor company's manager supervises the staff, and the temp has limited benefits. Because of potential legal problems involved with this type of employment, companies typically limit the amount of time they employ a temp, thus creating constant turnover and increasing training costs. With insourcing, the resources are clearly under the direction and control of the service provider, and employees typically have access to a comprehensive benefits plan. This eases legal concerns and allows resources to be deployed for the life of the engagement.   

In the scientific arena, tasks that are crucial to the outcome of the project, but that are repetitive in nature and can have metrics developed around them, are ideal for insourcing. These include positions in quality control testing, clinical testing, environmental monitoring, validation, and manufacturing. By insourcing these functions, the sponsor's employees can focus instead on development work and process-improvement issues.  

Pharmaceutical companies aren't the only benefactors of insourcing arrangements. Insourced employees can benefit, too, by earning varying levels of responsibility and the opportunity to switch projects during their tenure. 

 is the vice president of Life Science Talent Solutions at Yoh, Philadelphia, PA, 

Final Word

Why this workforce trend is well-suited for pharmaceutical companies.

The Case for Insourcing

US is almost always at the cutting edge. When it comes to scientific innovation, the arts, and popular culture, the US often sets the pace. Not so when it comes to developing regulations for follow-on biologics or biosimilars. There, the US is uncharacteristically the follower, lagging behind Europe. The European Medicines Agency (EMA) developed a regulatory framework for follow-ons in 2003 and issued its first guidelines in 2005. In contrast, the US just began to tackle these regulations in earnest in the fall of 2010, when it held its first hearing on the subject. 

To be accurate, the medicines actually manufactured under EMA guidelines are small, very well characterized molecules, such as recombinant human insulin. The more strenuous debate on both sides of the Atlantic centers on what constitutes proof of similarity for larger, complex biomolecules like monoclonal antibodies.  

With the November 2010 release of two draft guidelines, one on similar biological medicinal products containing monoclonal antibodies, and the other on immunogenicity assessment of monoclonal antibodies intended for 

 clinical use, EMA once again leads the way. The focus of the "biosimilarity exercise," notes the guideline on similar biological medicinal products, "is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been established by the reference product." And the tests EMA asks for—both 

are aimed at determining "all functional aspects of the MAb even though some may not be considered necessary for the mode of action in the clinic." Taken together the two guidelines ask manufacturers to evaluate differences between innovator and follow-on MAbs in process-related impurities due to differences in expression systems used by different manufacturers as well as "less well characterized" impurities, differences in formulation, unusual excipients, in addition to consideration of post-translational modifications that can affect the conformation, aggregation and ultimately the immunogenicity of the follow-on product. The guidelines go on to outline tests for pharmacodynamics,  immunogenicity, and suggest an overall risk-based approach to follow-on MAb manufacturing.  

In releasing their draft guidelines before the FDA does, EMA anchors the discussion in terms of tools, technologies, and tests required to approve follow-on MAbs and puts FDA in a position where it can only be reactive. Furthermore, in light of movements to harmonize regulations, any move by FDA to implement different regulations could appear uncooperative (and possibly economically protectionist).   

Should EMA also enact these regulations before FDA, which seems likely, EU manufacturers will get a head start over their US counterparts in producing, testing, and marketing the follow-ons, which experience could put firms seeking to do business in the US at a competitive disadvantage in what promises to be a tight and competitive market. At a time when US manufacturers are already operating in a competitive global market, can they really afford to be followers on follow-ons? 

Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies (Draft)

http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500099361&murl=menus/news_and_events/news_and_events.jsp&mid=0b01ac058009a3dc

Guideline on Immunogenicity Assessment of Monoclonal Antibodies Intended for in vivo Clinical Use (Draft

http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500099362&murl=menus/news_and_events/news_and_events.jsp&mid=0b01ac058009a3dc

Michelle Hoffman is the editorial director of 

From the Editor

So often a leader on the world stage, the US is a laggard when it comes to regulating follow-on biologics.

Following on Follow-Ons

Glycosylation can significantly influence the safety and efficacy profiles of biopharmaceuticals. Changes in product glycosylation during scale-up can lead to serious regulatory and commercial problems because of the risk of altered clinical performance. This article presents an approach to biopharmaceutical development and manufacturing that reduces these scale-up risks. It combines a Quality by Design (QbD) framework and a suite of visual informatics tools designed to aid the implementation of QbD for therapeutics with complex glycosylation. 

Biopharmaceutical glycosylation is highly complex and a major source of within-batch heterogeneity and between-batch variability. Designers and manufacturers of biologics, therefore, must effectively measure and control glycosylation throughout the drug lifecycle, particularly during scale-up and after significant manufacturing changes.

TRADITIONAL APPROACH TO GLYCOSYLATION AND SCALE-UP

The possibility of nonuniform glycosylation during scale-up is inherent in the traditional approach to biopharmaceutical development, which typically is:  

produce a drug product for early-stage development in a small-scale bioreactor (this becomes the reference material for subsequent comparability studies) 

characterize the glycosylation of the reference material, invoking ICH Q6B and other relevant guidelines to direct the analyses  

scale up in stages, optimizing cell -culture conditions and downstream processing to keep the scaled-up material similar to the reference material. 

invoke ICH Q5E to compare the glycosylation material from large- and small-scale bioreactors. During this exercise, focus on the overall shape of oligosaccharide patterns by comparing the relative amounts of major glycan species.

There are three main risks of this approach. First, the cells of the expression system could behave differently in the scaled-up process, thus resulting in altered glycosylation—so the comparability exercise fails. The risk is the possible modification of safety or efficacy profiles. Second, the overall 

 pattern might look the same after scale-up but the safety or efficacy profiles do change significantly because of alterations in relative quantities of minor glycoforms with high bioactivity that were not considered significant in the glycan structure analyses (glycoforms are forms of the drug that share the same protein backbone but have different oligosaccharides). Third, the glycosylation could alter after scale-up, leading to modified clinical performance of the drug, but the structural changes may not have been picked up during glycoprofiling.  

This article outlines a five-step approach to the realization of glycoprotein therapeutics that reduces scale-up risks. It combines a Quality by Design (QbD) framework for the development and manufacture of the drug and a suite of visual informatics tools designed to aid the implementation of QbD for drugs with complex glycosylation. 

STEP 1: ESTABLISH THE GLYCOSYLATION COMPARABILITY SYSTEM 

The first step in this approach is to establish a comparability system for glycosylation that takes into account the clinical performance of the drug's component glycoforms rather than just glycan primary structures. This is the heart of the QbD framework and is achieved by basing the measurement and control of glycosylation on glycosylation critical quality attributes (GCQAs), i.e., glycosylation parameters that affect patient safety and clinical efficacy. Table 1 shows potential GCQAs for a typical monoclonal antibody (MAb). 

Table 1. Candidate glycosylation critical quality attributes (GCQAs) for a typical monoclonal antibody 

Determining critical quality attributes (CQAs) is a crucial part of implementing QbD. ICH Q8 describes failure mode and effects analysis (FMEA) as a tool for determining the criticality of a drug's attributes. However, as discovered in the A-MAb project,

  there are two significant problems with applying FMEA to drug glycosylation. First, the traditional FMEA equation (risk priority number = severity × occurrence × detection) applies to the detection and occurrence of faults during the manufacturing process. However, the criticality of a therapeutic's structural attributes should depend on its effect on clinical performance, but neither on the influence of the manufacturing process on that attribute nor on the effectiveness of the analytical tools. Second, drug developers using FMEA generally recognize the problems with the standard RPN equation and will modify it, but there is no consensus on what factors should be in the new version and how those factors should be scored. In the case of A-MAb, a MAb for the treatment of non-Hodgkin's Lymphoma, the therapeutic effects of B cell killing occur primarily by antibody-dependent cell-mediated cytotoxicity (ADCC) and are influenced by the drug's Fc glycans. The A-MAb report details the use of two FMEA variants for assessing the criticality of various glycosylation parameters (galactose, afucosylation, sialylation, high mannose, and nonglycosylated heavy chain). The two tools scored criticality in different ways and gave roughly similar results for the risk ranking of the A-MAb glycosylation parameters but showed dissimilar risk levels. For example, tool #1 (where criticality = impact × uncertainty) categorized sialylation as high risk while tool #2 (criticality = severity × likelihood) scored it as moderate risk. 

At Ludger, rather than using FMEA, we use two informatics tools developed for reliable GCQA determination and ranking: safety and efficacy (SE) profiling and impact maps. These tools are used iteratively to build up and refine GCQAs throughout the product lifecycle. They address factors embedded in the A-Mab FMEA tools described above, but deal with them in a different way. 

SE profiling is a tool for discovering potential GCQAs. It involves classifying the component glycoforms of a drug into different safety and efficacy (SE) categories and analyzing the structural relationships between glycoforms in those categories. For a simple classification, there are three safety categories: S (safe), N (not safe), and U (unknown safety level) and four efficacy categories: L (low efficacy), M (medium efficacy), H (high efficacy), and V (unknown efficacy). There are 12 combined SE categories for glycoforms. These include SL, SM, SH, and so forth. The glycoforms that we put into a SE profile could be produced by our candidate expression system. The parameters considered include all those mentioned in relevant regulatory guidelines such as ICH Q6B and the latest EMA guideline for MAbs.

  Figure 1 shows an example of an SE profile for glycosylation of a therapeutic MAb.  

Figure 1. The annotations above and to the right of the matrix indicate the key glycosylation features of drug glycoforms occupying the corresponding matrix squares. Each square represents a safetyâefficacy category. Potential safety and efficacy glycosylation critical quality attributes (GCQAs) are shown in the rows and columns respectively. A drug with optimized glycosylation is composed of glycoforms from the SM and SH categories (indicated by the squares with thickened borders). 

The SE profile is like a chessboard where the position of the pieces (the glycoforms) denotes their therapeutic power. The GCQAs relate to transformations of structural form and the power found when moving from one square to another. The greater the increase or decrease in power for a move, the greater the effect of that GCQA on the clinical performance of the drug.  

An SE profile reveals two distinct classes of GCQA: Type I GCQAs connect glycoforms in different SE categories (i.e., information indicates that they alter a drug's clinical performance) and Type U GCQAs are glycosylation parameters that place glycoforms into the U and V categories (i.e. whether or not they alter a drug's clinical performance is uncertain).  

The GCQAs identified in SE profiles are further analyzed and prioritized using impact maps. These are mathematical graphs showing (a) the effects (i.e., the degree and type of influence) of a drug's glycosylation attributes on its biological behaviors, (b) the effects of those behaviors on the clinical safety and efficacy profiles, and (c) evidence for those effects. The effects are represented by lines linking attributes to behaviors and then to safety or efficacy, the degree of impact being denoted by line thickness. Figure 2 shows an impact map. The maps are annotated with references to evidence for the effects. These references are weighted with knowledge strength. This is an index composed of a veracity index (v1 = idea with no experimental evidence, v2 = expert opinion, v3 = peer reviewed data, v4 = data on the drug) and a relevance index (r1 = data for another molecule, r2 = data for a related molecule, r3 = data for your drug). The 12 combinations of v and r can be classified into five groups of knowledge strength from very weak (v1–r1) through weak, medium, strong, to very strong (v4–r3). The knowledge strength can be denoted by the color of impact lines to allow focus on the most reliable data. Interactions between glycosylation attributes or behaviors also can be denoted on impact maps as can evidence for lack of effects.  

Figure 2. A partial impact map for monoclonal glycosylation. The diagram shows part of the impact map for core FucÎ±1,6 and bisecting GIcNAc residues of an antibody relying on ADCC activity for its therapeutic effect. The map shows the degree of effects of glycosylation features on ADCC activity and key evidence for the effects. For this drug, core FucÎ±1,6 is an efficacy GCQA as there is a critical path (high effects) from Fuc to ADCC to efficacy, but bisecting GIcNAc is not. Note that biGIcNAc could still be a GCQA if it had an impact on another biological behavior of the drug that affected safety or efficacy. 

GCQAs are identified in the maps by critical paths with high effects linking glycosylation parameters by biological behavior to safety or efficacy. GCQAs are prioritized by ranking all behaviors affecting safety in descending order of the degree of impact, doing the same for behaviors affecting efficacy, and then ranking the GCQAs alongside those behaviors.  

Impact maps are simple but powerful visual tools to reveal the evidence for assigning criticality to any glycosylation parameter. They should be updated as knowledge is acquired throughout the drug's lifecycle. Note that in this system, the criticality of a glycosylation attribute is independent of both its measurement and control during biomanufacturing. A critical attribute remains critical even when it is well controlled and detected, which are the goals of the next steps.  

STEP 2: DEVELOP A TUNED GLYCOPROFILING SYSTEM TO MEASURE GCQAS 

A flexible glycoprofiling system should be developed that is tuned to the drug's GCQAs (so they are measured reliably) and tunable to different stages of your drug's lifecycle. This tuning can be aided by measurement maps. These are extensions of impact maps and are obtained by listing all the glycoprofiling methods available and drawing measurement lines from each method to each GCQA that it could measure. Figure 3 shows an example of a measurement map. 

Figure 3. A measurement map for nonhuman GalÎ±1,3Gal in a monoclonal antibody. GalÎ±1,3Gal has been identified as a GCQA from the drug safetyâefficacy profile and impact maps. This measurement map shows the relative merits of various glycoprofiling methods for GalÎ±1,3Gal for this drug. The thickness of each measurement line is proportional to the suitability of the method. The stars indicate the key methods chosen to measure GalÎ±1,3Gal at different stages of the drug lifecycle.  

The glycoprofiling methods considered should include your inhouse glycoanalyses, methods commonly used in the industry, and those outlined in the new 

 on glycoprotein and glycan analysis and improved variants. In general, one needs analyses that separate and identify glycan or glycoform species. This is typically achieved using a combination of high-performance liquid chromatography (HPLC) or capillary electrophoresis (CE) and mass spectrometry (MS) plus sequencing grade exoglycosidases to analyze released oligosaccharides, glycopeptides, and intact glycoproteins.

The reliability of measurements is denoted on the measurement map by the thickness of the measurement lines, and the ease of measurement for different stages of the drug lifecycle can be denoted by coloring or annotating the lines. Measurement reliability should be assessed according ICH Q2(R1) or similar guidelines, for analyses performed on a particular drug. Measurement maps to aid the selection of a set of glycoprofiling methods that provide either relative or absolute quantitation of the full range of GCQAs.  

It is usually not feasible to measure all GCQAs at every step in a product's lifecycle. However, they should all be measured before and after product scale-up. Also, for effective comparability studies, companies should aim to identify all the major peaks in HPLC, CE, and MS glycoprofiles early on in drug development.  

STEP 3: DESIGN A QTPP WITH OPTIMIZED GLYCOSYLATION  

The next step in the QbD framework is to define the drug's quality target product profile (QTPP). For novel biopharmaceuticals, this should include optimized glycosylation to maximize the drug's clinical performance.  

In terms of SE profiles, a completely optimized drug will have only SH (safe, high activity) and SM (safe, medium activity) glycoforms. Compared to the unoptimized therapeutic, such a drug would tend to be:  

less sensitive to changes in its clinical performance following glycosylation changes typically found during scale-up

more potent, so requiring a smaller level of scale-up

less heterogeneous, being composed of fewer glycoforms 

To illustrate the importance of glycan optimization, consider a drug composed of two types of glycoforms, H and L (e.g., afucosyl and fucosylated MAb with ADCC as mode of action or highly sialylated and low sialylated gonadotropin), where the H form has 10-fold greater activity than the L. In an unoptimized drug with 88% of L form, 12% of H forms would contribute over 57% of the total drug activity. If the specification for the H forms was 12% ± 3% the drug activity could vary from 1.81 to 2.35 (~30% variation in total activity from low to high limits). In an optimized drug with 88% of H forms, those would contribute over 98% of the total drug activity. If the specification for the H forms was 88% ± 3%, the total drug activity could vary from 8.65 to 9.19 (~6% variation in total activity from low to high limits).  

Glycan optimization starts with picking an expression system with the appropriate glycosylation machinery.

  For example, MAbs expressed in NS0 cells can contain glycosylation with potentially immunogenic nonhuman epitopes (Gala1,3Gal and NeuGc) as well as high levels of core fucosylation (so the dominant glycoforms fall into the undesirable N and L categories). Switching to Chinese hamster ovary (CHO) cells reduces the N and L category glycoforms at a stroke, thus resulting in a safer, more potent product. Further improvements could be made by using one of the growing number of alternative expression systems with improved or tunable glycosylation.    

The glycosylation of biopharmaceuticals produced in mammalian expression systems is profoundly affected by the physicochemical, nutritional, and mechanical environment in the cell culture. This environment changes as bioreactors of different size and configuration are used during drug scale-up. A major cause of altered glycosylation in traditional scale-up schemes is that the large-scale tanks cannot be forced to behave like the small ones used to produce reference material. Scale-down systems overcome this problem by reversing the direction of mimicry and forcing small reactors to behave like the large bioreactors.

In this step, scale-down bioreactors are used within the QbD framework to select a suitable clone, define the design and control spaces for drug manufacturing, and define and reproduce the cell culture conditions that will be used in the full-scale system and all intermediate-scale bioreactors.  

There are some important things to note: 

1.  Clone selection should be performed with the glycoform pattern of the QTPP in mind. In particular, the selection criteria should include both drug titer and the quality of the GCQAs. 

An approach to biopharmaceutical development that combines Quality by Design with a suite of visual informatics tools to reduce scale-up risks.

High-Throughput Multi-Product Liquid Chromatography for Characterization of Monoclonal Antibodies

The global financial crisis and subsequent slow economic recovery during the past two years has created an unprecedented time for the biopharmaceutical industry. After enjoying more than 40 years of easy access to capital, the rules of the game have changed forever. The capital markets have permanently restructured, making capital more difficult and expensive to secure.  

The rules under which the industry has operated and the way it has evolved since its inception have largely been obliterated. A confluence of powerful forces including global economic trends, policy changes, healthcare reform, and technological advances have transformed the way in which companies need to operate to be successful. 

Biotech executives are currently writing their new "play book" in response. It is clear that the business models that were used to create current value are no longer going to be effective going forward. Companies have to adapt to a risk-averse environment where capital, while still available, has become much more difficult to access.  

During the past two years, we have seen investment banks fail, hedge funds and private equity investors closing their doors, and the public equity markets spiral down, out of control. Venture investors, often the umbilical cord of food for the industry, long provided the lifeblood for young biotechnology companies, but the model is more challenged today.  

Companies have taken a variety of alternative approaches to access capital, such as turning to registered direct offerings, selling future product royalty streams, and selling options to promising compounds. In addition, because biotech companies are competing in an investment-constrained environment they often only have sufficient funds to complete one phase of a project successfully before building the capabilities required to move their project through the next phase. This is why companies are beginning to adapt their business models to a more virtually integrated one. This involves developing a network of third parties that provide services such as contract development, manufacturing and sales, all supported and managed by lean, in-house "coordinating" departments.  

The successful companies of tomorrow will be virtually oriented and globally focused. The evolution of a more "virtual" business model means that companies can piece together the resources they need as they go. As a result, venture investors are now looking for alternative structures with which to build value (virtual companies, proof-of-concept (POC) financing of projects, building companies post-POC, etc.).  

With capital in short supply, many biotech companies have been showcasing their best assets and shelving others. We have seen a huge surge in partnering deals during the past 12 months and product partnerships will continue, but in a buyer's market, only those opportunities that are particularly strategic will be considered. The leverage recently gained by biotech firms in negotiating advantageous deal terms will decline; Meanwhile option-based approaches that keep much of the program risk with the originator will increase in popularity.  

Although financial markets and potential partners at home may be lukewarm about the potential value of technologies and products, emerging markets could place on them a much greater value. Smart companies will look outside their borders. They also will think strategically about the value their products may hold in different markets. 

We predicted at the beginning of  2010 that the general markets would be choppy and that biotech companies would begin to perform well in the second half of the year.It appears that this scenario has played out now that 2010 is over. 

After surging 6% in October, the biotech industry came down to earth in November with the Burrill Biotech Select Index dropping 1.5%. The capital markets faired no better with Dow Jones Industrial Average closing the month down 1% and the Nasdaq Composite Index down 0.37% (Table 1). Dragging on the markets was a concern that Europe's debt crisis will continue to spread and much of the world's economy continues to sputter. 

Table 1. The Burrill Biotech Select index almost 11% gain in 2010 has come mainly in the second half of the year. 

The Burrill Biotech Select index's almost 11% gain in 2010 has come mainly in the second half of the year. The biotech industry has certainly benefited from a return of investor confidence. However, that confidence has not been distributed evenly across the board. It has been linked to the stellar stock performances of companies such as Genzyme, Dendreon, Illumina, and Pharmasset. Many of biotech's blue-chip companies, in fact, have had sub-par years with Amgen, for example, down 7% year-to-date and Vertex Pharmaceuticals down almost 23% for the same period. 

The unevenness in the capital markets also can be seen in biotech's newly minted public companies. This year, 16 new biotech issues have debuted on the US market, but most of them have been plagued by lackluster receptions (selling fewer shares well below the pricing range) and their average market performance at the end of November was down 13.2%. 

shows that the US biotech industry was on track to raise more than $20 billion by the end of 2010, not bad in a year that had its ups and downs. Follow-on financing and IPOs were down quarter-over-quarter and venture capital financing continued to flow with $1.3 billion raised from about 90 deals announced in the third quarter. 

Of the partnership deals that disclosed their financial terms, a whopping $9.6 billion was collectively raised in the third quarter of 2010 by U.S. biotech companies–up 8% on the $8.9 billion raised through partnership deals in Q2 of 2010.  

We are on pace to equal last year's record-setting total for partnership dollars, an incredible amount given the uncertain economic environment. Big Pharma's appetite for biotech innovation continues unabated. 

Going forward, we will see a much stronger industry evolve as companies implement their business strategies in response to the new economic realities. 

 is chief executive officer at Burrill & Company, San Francisco, CA, 415.591.5400, 

Burrill on Biotech

Business models that were used to create current value are no longer going to be effective going forward.

Biotech Writes its New "Play Book"

The political tensions wrought by last November's mid-term elections will affect pharmaceutical manufacturers in many ways in the coming year. Congressional Republicans will seek to cut the federal deficit by squeezing resources to government agencies, including the US Food and Drug Administration. New House leaders may also seek opportunities to criticize lax regulatory oversight and drug quality failures that compromise product safety. Pressure on federal agencies to appear as tough regulators and to obtain additional revenues will intensify government efforts to fine violative companies and to ratchet up industry user fees. 

Top priorities for manufacturers include user fees, new health initiatives, and regulatory compliance.

BioPharm International-01-01-2011