A key challenge in successfully implementing Quality by Design (QbD) is achieving a thorough understanding of the product and the process. This knowledge base must include understanding the variability in raw materials, the relationship between the process and the critical quality attributes (CQAs) of the product, and finally the relationship between the CQAs and the clinical safety and efficacy of the product. Part 1 of this article presented a stepwise approach to defining a design space. This Part 2 explains how to validate, file, and monitor the design space. It also discusses how to implement QbD for existing products and how to integrate QbD with process analytical technology (PAT). 

 Quality by Design (QbD) is receiving significant attention in both the traditional pharmaceutical and the biopharmaceutical industry subsequent to the FDA's publication of the International Conference on Harmonization (ICH) Q8 guidance, 

  In the traditional approach to process validation, companies use process understanding from process characterization studies to define critical, key, and non-key process parameters. The critical process parameters are then controlled within a narrow range, and the process is validated to ensure it operates within the defined ranges for these process parameters. In the QbD paradigm, identifying critical process parameters and critical quality attributes (CQAs) will still be required in defining the design space for a process. However, companies will need to go further in developing their understanding of both the CQAs and how they relate to clinical performance, as well as in their understanding of how the process will ensure these identified properties are controlled.

  Online monitoring has been successfully demonstrated in some aspects of biopharmaceutical processes such as fermentation processes,

  and possibilities for future applications in raw materials,

  are currently under investigation. Once a design space has been defined it will be continually reassessed and changed, pending regulatory acceptability, based on process understanding.

  This is part of continuous improvement within the quality systems approach.

This article is the fourteenth in the "Elements of Biopharmaceutical Production" series. In this Part 2 of the article, we present a stepwise approach to validating, filing, and monitoring a design space. Industrial case studies from industry, both biotech and traditional small-molecule pharmaceutical manufacturing, are used to illustrate the key aspects. We also discuss how to implement QbD for existing products and how to integrate QbD with process analytical technology (PAT).  

Since a design space "assures quality" of the drug product, the limits defined in the design space could also provide the basis of the validation acceptance criteria.

  After the design space has been created, process validation becomes an exercise to demonstrate 1) that the process will deliver a product of acceptable quality if operated within the design space; and 2) that the small- or pilot-scale systems, scale-up parameters, or models used to establish the design space accurately model the performance of the manufacturing scale process. Thus, unanticipated manufacturing excursions that remain within the design space should not jeopardize the success of the validation exercise. After the design space has been established and validated, the regulatory filing would include all critical process parameters including material attributes (i.e., those included in the design space) and could also include key process parameters along with the corresponding acceptable and operating ranges.         

Monitoring a Design Space and Making Post-Approval Changes to Design Space

During commercial-scale manufacturing, the proactive trending of product performance on a continuous basis affords significant benefits through early detection of emerging issues and further optimization of the control strategy to ensure operation within the design space. By using tools such as design of experimentation and systematic problem solving approaches such as Six Sigma, manufacturing operations can resolve problems and continue to optimize processes. These tools allow for and encourage a systematic approach to resolving unknown sources of variability and improving manufacturing robustness. 

The case study presented in Figure 1A describes the impact of subtle changes in raw material variability on product performance and the importance of continuous monitoring throughout the product lifecycle to ensure product quality. During routine monitoring of product performance for an extended-release tablet, an incidence of high variability in dissolution results was observed. Although all of the lots produced during this period met specifications, the trend in variability raised concerns about the potential for product quality problems to arise in the future. Data analysis to evaluate process capability with respect to dissolution at 12 h was carried out and the results suggested that supplemental tier 2 or tier 3 testing would be required to ensure product quality. Since the root cause of the upward trend in dissolution was not understood, a project was initiated using Six Sigma methodology to identify the root cause, design an improvement plan, and verify the impact of the corrective action. Six Sigma is a well known, structured approach to solving technical problems that have no known solution, have a measurable defect or problem, and identifiable causes. The steps used in a Six Sigma approach are 1) define the problem, 2) evaluate the ability to measure the problem, 3) analyze the problem using the appropriate method, 4) improve the process, and 5) implement the derived controls. In this instance, the project team used production data and analytical methods to identify the root cause and develop and implement the corrective action in a few months. Further evaluation of various parameters through multivariate analysis showed the root cause of variability to be directly related to raw material properties. The raw material properties affecting the dissolution rate were identified and a new tighter specification was defined and implemented to control the quality attributes of the incoming raw material. The data and trend shown to the left of the vertical red line in Figure 1A were before the implementation of controls, while the data to the right of the vertical red line are from post-implementation. Following completion of the Six Sigma "Improve" phase, the process was found to be significantly more robust, as seen in Figure 1B. A statistical analysis showed that the process capability was 0.86 before the Six Sigma project, and 1.93 afterward. The histogram in Figure 1B of mean 12-h dissolution for before and after the Six Sigma project illustrates the improved robustness and a shifting of the dissolution mean towards the center of the allowable specification range. Further, a predictive model was developed using a JMP software-based analysis of historical production data. A multivariate dissolution model was created to predict the 12-h dissolution on an ongoing proactive basis. A Pareto analysis of the data versus the CQA ranked the variables by correlation. Five factors, all quality attributes of the formulation excipent and drug substance, were found to be statistically significant. Figure 1C shows the prediction profiler from the model. The steeper the slope, whether positive or negative, the more that factor contributes to variability in dissolution. The statistical model was validated using four different excipient lots, each converted to 10–13 lots of tablets. The data are presented in Table 1. The predicted dissolution from the model versus the average 12-h dissolution from the multiple tablets lots gave a prediction error of about 1.0%.    

Another case study illustrating the role of process monitoring in demonstrating process performance within a design space was recently published.

  Multivariate data analysis (MVDA) and modeling were performed using representative data from small-scale mammalian cell culture batches (2-L) and large-scale batches (2,000-L) manufactured with a cell-culture process. Several input parameters (pCO

, glucose, pH, lactate, ammonium ions) and output parameters (purity, viable cell density, viability, and osmolality) were evaluated in this analysis. An MVDA model was created using the 14 representative small-scale batches (2 L), and then used to predict performance at the 2,000-L scale. Results presented in Figure 2 show that the process at 2,000 L is indeed very representative of the 2-L process. All of the 11 large-scale batches lie within the control limits calculated from the 2-L scale data with the exception of two batches that deviated slightly from the control limits between time values 12 and 13. Further investigation indicated that one of these two lots had the highest viable cell density (VCD) and the other had the highest lactate levels compared to all of the runs. Thus, these two batches were somewhat "atypical," illustrating the usefulness of the batch control charts in fault diagnosis during manufacturing to diagnose events such as equipment failures and raw material issues.  

As highlighted in the case studies above, if the manufacturing process creeps outside the design space, process changes may be made and may require process characterization, validation, and filing of the changes to the approved design space.  

Process Analytical Technology (PAT) has been defined as "a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality." As such, the goal of PAT, as explained in the FDA's PAT guidance document,

  is to "enhance understanding and control the manufacturing process," which is consistent with the idea that quality cannot be tested into products, but rather should be built-in by design. Thus, PAT is an enabler of the concept of Quality by Design. The design space is defined by the critical process parameters, possibly including material attributes identified from process characterization studies and their acceptable ranges. These parameters and attributes are the primary focus of online, inline, or at-line PAT applications. Situationally dependent, "real time" PAT assessments could provide the basis for continuous feedback and result in improved process robustness. Yu et al. have reviewed the PAT concept and discussed its application to a crystallization process.

 analytical methods that could be combined with chemometric tools to analyze multivariate process information and provide a basis for future improvements in the modeling, simulation, and control of crystallization processes. The following case studies illustrate the integration between PAT and QbD. 

Besides the obvious usefulness of PAT in ensuring that the process operates within the approved design space, PAT can also be useful in broadening the design space based on enhanced knowledge and understanding. The case study involved an ion exchange (IEX) chromatography step that removes an impurity (Impurity 1) from the product to levels below the drug substance specifications.

  A typical chromatographic profile is illustrated in Figure 3 with the earliest fractions (A) showing pure product, middle fractions (F) a mix of product and impurity and latter fractions (Y) primarily impurities. In the traditional approach, pooling of such a column is performed by UV absorbance at 280 nm. The key advantage of such pooling is the simplicity of implementing UV-based pooling criteria in a manufacturing environment. This approach works well for bind-and-elute applications in which the entire peak is collected from baseline to baseline and the protein concentration is linearly correlated to the absorbance signal for the range under consideration. However, in the case of a high-resolution separation where a part of the peak is being collected to pool the product and reduce one or multiple impurities, this approach is not optimal because absorbance-based methods are not able to differentiate between product and other proteins or other species that have a similar absorbance profile. Thus, if the impurity levels in the feed material vary from lot to lot, pool purity will also vary. This could result in lot rejection if the load material had a higher level of Impurity 1 than the IEX column is capable of clearing. To prevent such an event, the process parameters for the process column would need to be maintained within tight ranges, resulting in a narrow design space for the IEX column. On the other hand, in a PAT based approach, an online high performance liquid chromatography (HPLC) system could be used to design a dynamic control scheme that would allow testing of the IEX column eluate as it elutes in real time. Thus, irrespective of the concentration of Impurity 1 in the feed material, the IEX column pooling procedure can be adjusted such that the pool quality is consistent and meets the drug substance specifications.

Case Study 4:   Monitoring the Dryer Bowl

A second case study involving use of PAT sensor technology to monitor a drying end point is shown in Figure 4. Traditional approaches to drying might minimally utilize time and temperature to control the drying process. At the end of a defined drying period, the operator is generally required to sample the powder bed to obtain the loss-on-drying values and compare the results against approved specifications. If the results are satisfactory, drying is complete and material is transferred to the next manufacturing step. Alternatively, if results are above the in-process specification limit, the material can be re-dried.  

If instead, near-infrared (NIR) sensors are used, the fluid bed drying process can be monitored continuously and moisture content end point determined in real time for each drying cycle. Risks from sampling errors and from raw material and environmental variability that contribute to process variability are reduced if not eliminated. Process development studies based on time, temperature, airflow and dew point were carried out to evaluate their effect on the dried material's physical properties, including particle size and residual solvent content. The commercial process was simulated at laboratory, pilot, and commercial scale. Because of equipment design differences (e.g., the bowl, agitation, and bag design) at different scales of manufacturing, specific and some redundant trials at each step were deemed necessary. Figure 4A shows a schematic of an NIR detector attached through the wall of the dryer bowl. Figure 4B shows several examples of real time data generated throughout the drying cycle. NIR sensors monitored and enabled control of the drying cycle through a control algorithm. As the results were obtained during each run, it was possible for the process parameters to be adjusted to produce dried material with consistent quality attributes. Applying PAT in this manner led to a process with lower variability.  

Case Study 5: Detecting Raw Material Variability

Figure 5 illustrates another case study involving a potential PAT application that is currently under study. In this application, raw materials are identified by NIR to gain the tangible benefits of speed, accuracy, and cost savings that NIR offers over traditional wet chemistries. NIR analysis allows for trending of raw material lot quality in real time and early detection of any shifts in quality. A subsequent manufacturing step involves an extrusion unit operation which can be monitored continuously inline for temperature and active ingredient concentration. An ultra-performance liquid chromatography test is performed offline to test the material for presence of a degradation product. Particle size distribution is continuously monitored during milling for process consistency and controlled by feedback or feed-forward control for manufacturability or compression performance as a function of particle size. Finally, the tablet's weight, thickness, potency, and hardness are tested at line at the tablet press for continuous quality verification and feedback control of compression. These additional data sources reduce quality risk and variability while increasing process understanding.  

Case Study 6: Monitoring Multiple Unit Operations

It is possible to combine and coordinate process knowledge from multiple unit operations to achieve a holistic picture of the entire manufacturing process for a given product. Consider the process train for manufacturing a solid oral dosage form illustrated in Figure 5. Several unit operations are required to combine the right quantity of active pharmaceutical ingredient (API) and excipients under appropriate processing conditions and in a controlled environment to produce a drug product that consistently meets quality attributes. Through the use of appropriate sensor technology, the real time profile for the manufacturing process at each step or unit operation could be generated. During commercial manufacturing, material is moved through each manufacturing step only if the real-time profile is consistent with expected historical data. At the end of a manufacturing cycle, a review of the real-time profiles for all unit operations throughout the process could determine conformance and verify that the product meets quality attributes. If the reported profile is consistent with historical data, based on population analysis, real time release of product can be considered. Fundamentally, only those lots that fall outside the known population of data would require additional off-line testing or be rejected. 

Successful implementation of QbD in the pharmaceutical industry requires a concerted effort between the regulators and the industry. Case studies such as those presented here will serve as useful tools in gaining the common ground and defining best practices in the various functions: Research and Development, Quality, Manufacturing and Regulatory. Ultimately, the implementation of QbD is likely to result in increased efficiencies both for regulatory reviews and for pharmaceutical manufacturing. 

This article summarizes the presentations and discussions that occurred in the plenary session titled "How do you sell Quality by Design (QbD)?" at the PDA–FDA Joint Regulatory Conference held on September 24–28, 2007, in Washington, DC. The objective of the session was to discuss the challenges that are encountered when implementing the QbD paradigm. 

, is a director of process development at Amgen, 805.447.4491, 

, is a law clerk at McDonnell Boehnen Hulbert and Berghoff, LLP, 

, is division vice-president for quality at Abbott, North Chicago, IL, and 

 is director of strategic quality and technical operations at Abbott. 

 1. US Food and Drug Administration. Guidance for industry. Q8 pharmaceutical development. Rockville, MD: 2006 May.  

 2. US FDA. PAT Guidance for industry. A framework for innovative pharmaceutical development, manufacturing and quality assurance. Rockville, MD: 2004 Sept. 

 3. Gnoth S, Jenzsch M, Simutis R, Lübbert A. Process analytical technology (PAT): batch-to-batch reproducibility of fermentation processes by robust process operational design and control. J Biotechnol. 2007;132:180–6. 

 4. Kirdar AO, Conner JS, Baclaski J, Rathore AS. Application of multivariate analysis towards biotech processes: Case study of a cell-culture unit operation. Biotech Prog. 2007;23:61–7. 

 5. Johnson R, Yu O, Kirdar AO, Annamalai A, Ahuja S, Ram K, Rathore, AS. Applications of multivariate data analysis (MVDA) for biotech processing. BioPharm Int. 2007 Oct;20(10):130–44. 

 6. Kirdar AO, Green KD, Rathore AS. Application of multivariate analysis for identification and resolution of a root cause for a bioprocessing application. Biotech Prog. 2008;24:720–6. 

 7. Rathore AS, Sharma A, Chillin D. Applying process analytical technology to biotech unit operations. BioPharm Int. 2006 Aug; 19(8):48–57. 

 8. Rathore AS, Yu M, Yeboah S, Sharma A. Case study and application of process analytical technology (PAT) towards bioprocessing: use of on-line high performance liquid chromatography (HPLC) for making real time pooling decisions for process chromatography. Biotechnol Bioeng. 2008;100:306–16. 

 9. Rathore AS, Branning R, Cecchini D. Design space for biotech products. BioPharm Intl. 2007 April;20(4):36–40.  

Articles

Features

Understanding the relationship between the process and CQAs.

Quality by Design: Industrial Case Studies on Defining and Implementing Design Space for Pharmaceutical Processes (Part 2)

The US Food and Drug Administration has struggled with a depleted work force, obsolete information technology, and a weak science base, according to its advisory Science Board. A new administration and new FDA leadership provide an opportunity for change. This is "a watershed time" for the FDA, says Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER). The public is concerned about drug quality and imports, industry is caught in a productivity crisis, and the global financial meltdown may dry up investment for biomedical innovation, she observes. Her goal is to restore public confidence in the drug regulatory process, capitalize on advances in science and technology, improve postmarket oversight, and make the FDA "the recognized leader in drug regulation."          

Such a turnaround will not be easy. Rep. Rosa DeLauro (D-CT), who chairs the House Appropriations subcommittee that oversees the FDA's budget, asserted at a meeting sponsored by the Institute of Medicine in April, that the FDA needs "urgent and dramatic reform." The agency cannot perform basic functions, she said, such as keeping track of clinical trials, conducting required inspections, and following up on commitments for postmarket studies. "FDA is barely hanging on by its fingertips," attorney Peter Barton Hutt told the House Energy & Commerce Committee a year ago, joining the chorus seeking increased resources for the beleaguered agency.  

Fixing the FDA may require a major overhaul to better fit the global world of pharmaceutical and food production. Because the regulatory model for food is very different from that for drugs and biologics, DeLauro and others propose to transfer the FDA's responsibility for food regulation to a new federal agency that would assume responsibility for multiple programs now spread around dozens of government offices.  

To avoid such a disruptive change, agency officials are taking steps to demonstrate their ability to prevent and deal with food contamination problems. They also propose a less radical reorganization that would split the FDA into two "directorates," one for food and another for medical products. There is support for such a move from food operators, who feel they play second fiddle to drugs at the FDA, and also from some medical product companies that fear being hit by more restrictive food import policies.  

Taking the "food" out of FDA is not likely to happen any time soon, as the new Obama administration has much more crucial tasks at hand in the economic and health arenas. But if Congress follows through on proposals to authorize the FDA to regulate tobacco, that could provide an opportunity for broader organizational changes.  

Improvements in FDA operations, resources, and infrastructure will be shaped considerably by the next FDA commissioner. Lots of names have been circulating in the last month, a sign of the agency's high visibility and importance to the new administration and to Congress. There is considerable hope that the FDA's new leader will be named and confirmed by the Senate in a few months.  

One priority for the new commissioner is to push for continued growth in appropriated funds in the agency's 2010 budget. The Alliance for a Stronger FDA has called for a 20% increase in the FDA appropriations to $2.25 billion for next year. That's less than $400 million in new money—a drop in the bucket for most federal agencies.  

A prime goal for biotech and pharmaceutical manufacturers is for the FDA to approve new therapies for market and oversee product development, manufacturing, and marketing in a fair and efficient manner. All the attention on drug safety has raised concerns about a more risk-averse atmosphere at the agency that may slow authorization of new products.  

But there's light on the horizon with an increase in the number of innovative therapies approved by the FDA in 2008. The agency experienced a new low in approvals of new molecular entities (NMEs) in 2007, and it looked like this past year would be just as bad or worse. But in November, the FDA passed the 2007 approval total of 18 NMEs and appeared on track to act on several more before year-end. Although it's always easier to show gains from a very low starting point, both industry and the FDA are happy to consider this a sign of hope for the new year. 

Another priority for a new commissioner is to revive the FDA's depleted field inspection force. The Office of Regulatory Affairs (ORA) is in disarray because of years of under-funding. Most of its top officials have retired or moved to other jobs, leaving the organization without the leadership needed to make necessary operational changes. District laboratories require new equipment for efficient product analysis, and scientists need infrastructure to conduct risk assessments and analysis. The explosion in global manufacturing and increased complexity of supply chains, moreover, have increased the potential for counterfeiting and terrorism. Heparin was "a wake-up call," says Woodcock. It "brought home the need for vigilance throughout the supply chain" and highlighted the importance of manufacturing controls.  

The FDA's field force operates on a 70-year-old model that relies on generalists who inspect a vast range of operations, from vegetable growers to antibiotic producers. With the emergence of complex production methods for biologics, the FDA established an elite Team Biologics with expertise in biotech manufacturing to inspect those sites. CDER has sought to replicate that model by developing a highly trained pharmaceutical inspectorate to evaluate drug manufacturers. 

The surge in food and drug contamination incidents in the last two years has generated support for the FDA's Beyond Our Borders initiative that is establishing overseas branches to better monitor the growing number of foreign manufacturers of products destined for the US. The agency opened offices in China in November and plans additional outposts in India, Europe, Latin America, and the Middle East to track local political and economic developments and be on the spot if problems arise.  

But even with more resources and foreign offices, the FDA will never be able to inspect every manufacturer on a timely basis. Other approaches may be needed to support field operations, including certification programs for foreign manufacturers, increased reliance on inspections by foreign regulatory authorities, improved risk management of inspection programs, and more efficient technology assay procedures validated by the agency.  

Any improvement in field operations will require significant investment in new interoperable information systems. The FDA's IT infrastructure is "obsolete, unstable, and lacks sufficient controls to ensure continuity of operations," according to the Science Board. Most agency records are on paper and stored in document rooms that are difficult to access. Research laboratories lack the computing infrastructure necessary to conduct appropriate analyses and studies. Many of the agency's network servers have exceeded their recommended service life, and the system lacks security and normal backup capability.  

A reliable, modern IT system could bring considerable efficiencies to the FDA operations. Instead of sending inspectors to check manufacturing operations and product quality, cutting-edge technology could allow the agency to position remote sensing devices at plants able to detect product contamination or diversion in real time. Information from large health-system databases could uncover signals of adverse events more quickly and effectively. And access to clinical trial data on marketed products could assist reviewers and monitors in evaluating new safety and efficacy issues. The latest prescription drug user fee program, PDUFA IV, has mapped out a plan for establishing an all-electronic submission platform for drugs based on format and data standards. The FDA expects to spend approximately $2.5 billion over the next 10 years for new IT systems. Ensuring that such information systems fit the agency's complex organization and legal structure will require skilled oversight of vendors, which is another challenge for the new commissioner. 

Washington editor, Chevy Chase, MD, 301.656.4634, 

Columns and Departments

FDA aims to regain public confidence in 2009.

Revitalization, Reform Ahead for The FDA

 It is a time of change, not only for the finance and automobile markets, but also for the pharmaceutical and biopharmaceutical industries. Even before the downturn in the world economy, drug makers were already facing big challenges, including drug safety, patent expirations, and dwindling pipelines, and had started restructuring and conserving costs. The year 2008 witnessed a constant stream of job cuts in the pharmaceutical sector, including layoffs at Merck (8,400 jobs), Schering-Plough (5,500 jobs), Wyeth (5,000 jobs), UCB Pharma (2,000 jobs), and Abbott (1,000 jobs). There has been a slew of job cuts at small- and medium-sized biotechs as well. 

During such times of change, almost everyone, at every level of the biopharmaceutical industry, is asking questions such as, "What is the general outlook for the industry?" or "Will employment opportunities decrease in the future?" and "How will the economic downturn affect me?" Besides charting the current trends in salaries—including the gender gap—in the biopharmaceutical sector, 

 third annual salary survey explores these questions and more generally, finds out how secure biopharmaceutical professionals are feeling in their jobs.   

 corporate research department in the fall of 2008. The survey was emailed to 24,417 readers around the globe and generated 593 responses. To encourage participation, all subscribers who responded to the survey were entered into a drawing to win one of five $100 gift cards. The maximum statistical error of the survey, at a 95% confidence level, is +4.2%. (Some percentages may not add up to 100% because of rounding.)  

The vast majority (64%) of survey respondents are from the US. Another 19% are from Europe, 8% are from India, and 5% are from Canada. About half work in publicly traded companies, 37% in privately held firms, 5% in academic institutions, 5% in government, and 2% in nonprofit organizations. About 1% of respondents are self-employed. 

A little more than a third (37%) of respondents work in biopharmaceutical manufacturing companies, 15% in small-molecule pharmaceutical companies with a biotech focus, 7% in contract manufacturing, and 7% in research institutes (Figure 1). Most of our respondents work in fairly large companies: 50% work in companies with 1,000 employees or more, and another 10% work in companies employing between 500 and 1,000 people.  

Despite the current economic scenario, biopharmceutical professionals continue to earn good salaries. "The pay is excellent in the biopharmaceutical sector when you get into specialized skills," says Stephan Krause, director of quality at MPex Pharmaceuticals and a member of 

Editorial Advisory Board, who started this new job only a month ago after leaving a small biotech that went under. "With the number of unemployed people in the job market, your negotiating power during a job interview might be less, but the salaries haven't gone down," he says. 

As shown in Figure 2, the mean industry salary is $89,760 in the United States, and €62,721 (approximately $85,927, converted at an average exchange rate over 2008 of €1=$1.37) in Europe. In the US, 37% of respondents earn more than $100,000 and 23% earn between $75,000 and $100,000. The salary breakdown among European respondents was similar: 39% earn more than €70,000 ($95,900) and 23% earn between €50,000 and €70,000 ($68,500 to $95,900).  

Like last year, this year's survey showed that the US biotech jobs with the highest salaries included corporate management, information technology, legal, and plant engineering (Figure 3). And job opportunities are relatively good in the biopharmaceutical sector, especially at the higher levels, says Krause. In particular, he sees a lot of opportunity in the areas of quality and regulatory affairs. "Those two areas are going to be in great demand because regulations are becoming more complex with lot of outsourcing now being done in development," he says.  

With the monoclonal antibodies market projected to grow to $12 billion by 2010, industry experts think that job opportunities will continue to rise in the coming years even if opportunities in the traditional pharmaceutical sector don't keep pace. "The biopharmaceutical sector has more opportunities compared to small-molecule companies," says a senior professional employed at a large pharmaceutical company. "It is simple mathematics—just compare the number of small-molecule drugs to large-molecule drugs in the pipeline." 

A closer look at the list of job cuts by big companies this year shows that it's mainly Big Pharma, not the big biotech companies, that have downsized this year. Most experts, however, believe this is unrelated to the slow economy, seeing the causes in the industry itself, in such as drug failures, drug safety concerns, and dwindling pipelines. With many blockbuster drugs lined up to come off patent in 2010, Big Pharma is stepping up efforts to save costs and invest in large-molecule drugs. 

Of course, the biotechnology industry is not immune to the economic downturn. Small biotech companies, which depend on investors for cash, are struggling to get funding amid the credit crisis. These companies are rapidly restructuring as a result of the negative capital markets, says Steven Burrill in his column ("Burrill on Biotech" p. 26). "Staff is being reduced and many R&D programs have been put in the refrigerator until better times prevail."  

For the most part, however, large biotechs have been able to withstand the financial market's meltdown so far. "It could be because the big biotechs' financial strength is tied more to their product portfolio than the stock market," says a senior process development manager, who has worked with small and large biotech companies during his 15-year career. 

Recruiters have also seen fairly consistent activity in the biotech sector. "The larger biotech companies that we work with are still hiring," confirms Pete Ferguson, president of health and life sciences for Yoh, a recruitment company that provides contract employees to the pharmaceutical sector. 

In this time of threats and opportunities, are biopharmaceutical professionals feeling secure in their jobs? Overall, our respondents feel secure in their jobs. Seventy-one percent (71%) of respondents said they feel "secure," "very secure," or "extremely secure" in their current jobs (Figure 4).  

This sense of security continues despite the fact that, like last year, 54% have been through a merger, acquisition, or downsizing within the last two years. Perhaps the secure feeling remains because only 7% were laid off as a result of such corporate upheaval, and 48% said they were unaffected by the process (Figure 5). The rest either said their job responsibilities changed (38%) as a result of a merger or downsizing activity or that they chose to leave their companies voluntarily (8%).  

A global quality control manager with 20 years of experience, currently employed at a leading Big Pharma company, feels more secure now because his company is trying to transition from small-molecule drugs to biologics. "There is a new initiative to become the next-generation biopharma, so I feel secure," he says.  

Most respondents also feel their academic background has served them in their current job functions: 50% say their education prepared them extremely well or well, and 38% say it prepared them adequately. Job experience has proven more valuable: 74% of respondents say their employment experience prepared them extremely well or well for their current role; another 22% say it prepared them adequately. 

Most respondents also work for companies that support their continued professional development: 75% say their organizations pay for them to attend conferences; 74% say the same for in-house training; and 73% attend outside courses or workshops. 

The above are perhaps some of the reasons why biopharmcaeutical professionals are feeling secure even in these times of economic insecurity. A broad portfolio of products is keeping the big biotechs financially strong and in a position to recruit people. Bill Bennett, senior director of science and policy assessment at Genentech says, "Our business is actually doing pretty well and the economy isn't threatening it very much at the moment." 

"The economy has made the market more robust for a big biotech because of good molecules being available," says John K. Towns, director of global CMC regulatory affairs at Eli Lilly and Company. The big companies are benefiting from this economy, Towns says, because they have the money to buy small biotechs with new compounds at low prices and move these forward in the pipeline.  

Although the big biotechs are generally sheltered from the current economic crisis, the same can't be said about the small biotechs that are struggling to survive as the venture capital funds that drive these companies are drying up. Job security is therefore down at cash-hungry small biotechs as they continue to make wholesale layoffs in a desperate attempt to stay afloat. 

In fact, as we went to press, representatives from the US biotech industry, supported by the Biotechnology Industry Organization (BIO), were planning to meet with the members of Congress to ask for a temporary change in the tax law that would let money-losing companies get cash from the government now, in exchange for tax credits they would pledge not to take if they eventually became profitable. The change, if approved, could enable the industry to receive potentially hundreds of millions or even billions of dollars. 

Bader, who has worked for three large pharmaceutical and three small biotech companies, says the insecurity at small companies is balanced by a greater sense of personal control. "In a small biotech, the security equation is rather simple. You look at how much cash the company has, what the burn rate is, and you can calculate how many months it can survive before the next financing period," he says. "The small biotechs carry more risk, but you feel more empowered as you understand the risks and how you can affect them."  

So are biotech professionals still confident enough to risk job changes in this turbulent economic climate? The majority of respondents (60%) said they are not likely to leave their jobs in the next 12 months, compared to 40% who said they are likely to leave their jobs. As shown in Figure 6, for those who expect to change jobs, the most common reasons would be a job offer with better salary (29%), a job offer with more satisfying work (16%), or a geographic move to a more desirable location or for family reasons (10%). About a quarter (27%) cited involuntary reasons.  

From the recruitment point of view, Ferguson, the recruiter, thinks biopharma remains a good career choice. "Typically, the life sciences industry has been a little more recession-proof than other industries. I think it is going to continue to be a very strong industry," he says. "As far as anyone coming out of college, I would certainly recommend it for a career as the demand is still there," he adds.  

Levine echoes Ferguson's words. "The industry has been through lots of ups and downs, but overall it is a strong industry with a lot of prospects, he says. "For somebody who is interested in medicine and biology, it is certainly a career I would encourage them to pursue."  

Overall, a career in the biopharmaceutical industry is satisfying for most of our survey respondents (Figure 7). The vast majority (89%) of our respondents are satisfied with their jobs, with more than half of those (47% of the total respondents) describing themselves as "extremely satisfied" or "very satisfied" with their jobs. "I still get up in the morning and feel energized and great about my job," said one project manager. Krause agrees. "There is a lot of good science being done in this industry," he says. "I would suggest a career in this industry," he says. "It is rewarding and exciting."  

"With over 30 years in healthcare, one learns that the industry and economy naturally cycle between expansion and contraction," says Bader. "We all generally feel rather secure during expansion and insecure during contraction. I doubt that this will ever change." Thus, Bader believes leading companies will continue to focus on recruiting a talented and diverse workforce and recognize the need to create growth opportunities, excitement, and recognition in the workplace. "These trends have steadily increased over the past three decades and will likely continue in the future, leading to more empowered and highly skilled employees."  

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Will the global economic crisis affect your job? BioPharm International's third annual salary survey finds out.

Buckle-Up Biopharma

Increasing upstream yields have led to the need for downstream purification capacities. In this article, a new chromatographic process for the purification of biomolecules is presented. Its working principle is explained and possible areas of application in monoclonal antibody and polypeptide purification are discussed. For an industrial polypeptide purification problem, experimental work showed that a multicolumn countercurrent solvent gradient purification (MCSGP) process could raise the productivity 25-fold, compared to the current batch chromatographic step in production.

The majority of the therapeutic proteins undergoing late-stage development or entering the market are monoclonal antibodies (MAbs). Because high doses of these products are needed per patient, relatively large amounts of protein must be produced and purified. The past decade saw tremendous advances in cell culture technology producing higher yields. As a result, purification has now become a bottleneck, or at least a major cost driver with a high potential for cost cutting. Consequently, MAb purification has received a lot of attention in academia and industry and a variety of solutions have been proposed, including but not limited to crystallization, (i.e., ion-exchange), Protein-A mimetic ligands, liquid–liquid extraction, and non-affinity chromatography in batch or continuous operation. The non-affinity chromatography used in a continuous process such as multicolumn countercurrent solvent gradient purification (MCSGP) shows high potential to replace current standard MAb purification schemes, as seen in a recent presentation by Merck-Serono.

The benefits of continuous chromatographic processes such as MCSGP have spurred interest in using their technology for other purification challenges, such as the purification of polypeptides.

  In the past years, a revival of polypeptides for therapeutic purposes has been seen, particularly for treating diabetes. Polypeptides are produced by either synthetic routes or fermentation. Because polypeptides have a higher production cost than MAbs but are generally produced in lower quantities, the major concern in the purification of these molecules is yield.        

Conventionally, the purification of polypeptides is performed using reversed-phase chromatography in a batch operation. Often, two or more chromatographic steps with different mobile phases are used to achieve the specified purity. Continuous processes are ideally suited for such difficult purification steps because they can significantly improve the separation efficiency compared to conventional batch chromatography. The best known continuous chromatographic process is the simulated-moving-bed (SMB) process.

  In the pharmaceutical industry, that method has been applied successfully at commercial scale for the purification of small, chiral molecules. The challenge in such purifications is to separate two enantiomers from a racemic mixture. But the SMB technology is generally of no use in the purification of therapeutic polypeptides or proteins because it can perform only binary separations where gradient chromatography cannot be properly implemented. For very specific purification problems, however, academia has investigated the use of SMB and SMB-derivatives for the purification of biomolecules.

  A detailed comparison of the existing continuous chromatographic process has been published elsewhere.

It is also worth noting that the SMB technology can only perform binary separations i.e., producing two streams, such as an early stream eluting waste and a later stream/eluent product or two product streams (product A and product B). The purification of therapeutic polypeptides and proteins in non-affinity chromatography, however, requires ternary separations, i.e., three streams containing the early eluting waste, the product, and the late eluting waste. Unlike the SMB process, the MCSGP process is suited for ternary separations using gradient chromatography and can therefore be used for the continuous purification of therapeutic polypeptides and proteins. 

 Recently, the MCSGP process was tested for the purification of the polypeptide Calcitonin (a growth hormone) in a joint project with Novartis Pharma AG (Basel, Switzerland), ChromaCon AG and ETH Zurich (both in Zurich, Switzerland). 

In this article, the purification challenges for the reversed-phase chromatography of Calcitonin are described and the experimental results of the purification of this polypeptide with the MCSGP process are shown. A comparison is given in terms of purity, yield, and productivity between the MCSGP process and the conventional batch process for the purification problem presented. 

The working principle of the MCSGP process can be explained using a conventional batch elution chromatogram, as shown in Figure 1. The x-axis in the figure indicates operating time. The following steps are taken sequentially: 1) load the column with feed, 2) wash the column to elute nonadsorbing impurities, 3) gradient elution, 4) clean-in-place (CIP) or wash with a strong eluent, and 5) wash with a weak eluent for regeneration. The next batch elution can then be started by loading the column again.  

The molecules eluted during the gradient operation can generally be classified into the following three categories: early eluting impurities, product, and late eluting impurities. These categories will be abbreviated as follows: W for early eluting or weakly adsorbing, P for product, and S for late eluting or strongly adsorbing. These three categories are indicated schematically in Figure 1 by three triangles: the first triangle represents W and ends at time t

. In general, the elution time windows of W–P and P–S overlap in the time intervals t

, respectively, as indicated in Figure 1. In conventional batch chromatography, the P eluted in the overlapping regions would have to be discarded (or could be recycled in peptide purification) and only the P eluted between t

 is the collected product meeting specifications. 

In the MCSGP process, the same elution scheme as shown in Figure 1 is maintained, but the process is operated with three small columns instead of the one large column used in batch chromatography.  

The three columns used in the MCSGP process are operated either in the connected mode (upper flow path in Figure 2) or in batch mode (lower flow path in Figure 2). Each flow path is operated for a fixed time, which can be the same for the batch and the connected mode, but does not need to be. The arrows in Figure 2 show how a single column is switched through the different positions.  

Tracking a single column, the following tasks are carried out: in the first position in the lower right corner of Figure 2, the column is loaded with the feed so that a first portion of the W is eluted from the column, but no P is eluted. This task corresponds in batch chromatography to the elution of all molecules from t = 0 to t = t

. Before any product is eluted, the column is switched to the middle position in the connected mode. 

At this position, the overlapping fraction W–P (i.e., t

 in Figure 1) is eluted. It should be noted that this fraction that is being eluted from the middle column in the connected mode is not leaving the process, but gets mixed with the stream coming from a gradient pump before it enters the column in the upper right position, where it adsorbs. 

The column is then switched to the lower middle position, where the pure P can be eluted, equivalent to the time interval from tB to tC in the batch chromatogram in Figure 1.  

Before any S is eluted into the pure product outlet stream, the column is switched again to the upper left position where the overlapping region P–S is eluted, but because of the connected mode, it stays in the process. This corresponds to the elution time interval tC to tD in Figure 1. Now the remaining molecules that are still in the column all belong to the category S. 

Therefore, the column is switched to the lower left position, where it is treated with a strong eluent to wash the column. If necessary, an additional, more rigorous treatment with another eluent can be considered.

It is not in the scope of this paper to provide a detailed description of the principles or design of the MCSGP process. A typical application for MCSGP will be shown in the following section. More details about the design of the MCSGP can be found elsewhere.

THE PURIFICATION OF A THERAPEUTIC POLYPEPTIDE

The purification of polypeptides is generally challenging because of the presence of many impurities that are very similar to the target molecule. An average polypeptide consists of 20–40 amino acids and many of the impurities have a variation in just one amino acid compared to the target molecule. For such purification problems, reversed-phase (RP) chromatography has emerged as the major tool and it is often applied two or three times sequentially with different eluents (different buffer species, different organic solvents). 

For this work, a single RP-chromatography step of a polypeptide has been investigated. The current, optimized purification process which is operated with conventional batch chromatography, has been taken as a benchmark. The aim of the present work was to use the same eluent and stationary phase used in the batch setup and apply it to a continuous chromatographic process, i.e., the MCSGP process, to show the benefits of the latter process in terms of yield, productivity, and solvent consumption. The specifications in terms of the overall purity and the largest single impurity were equal for both processes. 

For the purification of the polypeptide, a benchtop MCSGP unit was used with three columns in C18 stationary phase. Each column was 0.75 cm i.d. x 5 cm to minimize the amount of crude material needed. The operating conditions for the MCSGP-process, including flow rates, gradients, and switch times, were calculated following an explicit procedure that uses mainly information from existing batch elution chromatograms.

  After the operating conditions were set, the unit was started and samples taken at regular time intervals. As with every continuous process, the MCSGP process undergoes a transient phase until it reaches a steady state. This can be observed by the fact that the outlet concentrations, averaged over one cycle, are constant over time. Using the steady state values regarding productivity, yield, and solvent consumption, the comparison with the batch chromatographic process can be carried out. An overview of the experimental results is shown in Figure 3.  

All experimental results of the batch and the MCSGP processes are compared in terms of yield and productivity, under the constraint that the same purity specifications are met. The productivity values are given as mass of purified target product per time and per column volume. The squares in Figure 3 show the experimental results of the MCSGP process. Some variations of the default operating points have been investigated, such as different load volumes, different switch times, etc., so the performance in terms of yield and productivity is different. The circles with the error bars in Figure 3 indicate the performance of the current batch purification process, where the left square shows the performance of a single batch run and the right circle shows the performance of several batches including one recycle run with impure side fractions. Consequently, the single batch run has a lower yield compared to the batch-plus-recycle run, but it has a slightly higher productivity. This is because the same material has to be handled twice to run the recycle chromatography, which reduces productivity. 

Figure 3 shows that for the purification problem presented, the productivity of the best MCSGP operating point is about 25 times higher than for the current batch purification process. In terms of yield, all operating points of the MCSGP process showed higher values than the batch-plus-recycle purification scheme. For the best operating points, solvent consumption could be reduced by 60%. 

To exploit such a performance improvement in the chromatography step in production, various scenarios may be possible. In the most likely scenario, the same amount of material should be produced in the same amount of time. With an increase in productivity of 25 times using the MCSGP process, the column volume could be reduced 25 times, e.g., instead of 50-L column in batch chromatography, the MCSGP process would need only three columns, each with a volume of 0.7-L. This would significantly reduce the footprint of the chromatography unit and the surrounding tanks. Together with higher yields, the cost savings this setup would offer are very promising and indicate payback times for the MCSGP unit of less than one year. 

The principle of the MCSGP process and its characteristics with respect to existing technologies, such as SMB, has been explained and promising areas of application have been discussed. For polypeptide purification, a batch chromatography step has been compared to the experimental results of the MCSGP unit. It has been shown that strong performance improvement in yield and productivity are possible in the MCSGP setup. The best MCSGP operating point showed a 25-fold improvement in productivity and yields that were 5–7% higher than the batch purification. 

Because of the significant potential of the MCSGP process to reduce the cost of chromatographic steps for challenging biomolecule purifications, further applications are foreseeable.  

 is chief scientific officer, all at ChromaCon AG, Zürich, Switzerland, +41 44 633 7748, 

, is professor for chemical and bioengineering at ETH Zürich, Zürich, Switzerland. 

 is head of technology group 1, CHBS, at Novartis Pharma AG, Basel, Switzerland. 

 1. Aumann L, Morbidelli M. A continuous multicolumn countercurrent solvent gradient purification (MCSGP) process. Biotechnol Bioeng. 2007;98(5):1043–1055. 

 2. Aumann L, Stroehlein G, Morbidelli M. Parametric study of a 6-column countercurrent solvent gradient purification (MCSGP) unit. Biotechnol Bioeng. 2007;98(5):1029–1042. 

 3. Aumann L, Morbidelli M. A semicontinuous 3-column countercurrent solvent gradient purification (MCSGP) process. Biotechnol Bioeng. 2008;99(3):728–733. 

 4. Stroehlein G, Aumann L, Mueller-Spaeth T, Tarafder A, Morbidelli M. Continuous processing—the multicolumn countercurrent solvent gradient purification process. Supplement to BioPharm Int. 2007 Feb. 

 5. Aumann L, Morbidelli M, inventors; ChromaCon AG, assignee. European patent, EP 05405327.7, EP 05405421.8, 2005.  

 6. Stroehlein G, Aumann L, Mueller-Spaeth T, Morbidelli M. A continuous, countercurrent multicolumn chromatographic process incorporating modifier gradients for ternary separations. J Chromatogr A, 2006; 1126(1–2),338–346. 

 7. Mueller-Spaeth T, Aumann L, Melter L, Stroehlein G, Morbidelli M. Chromatographic separation of three monoclonal antibody variants using multicolumn countercurrent solvent gradient puri?cation (MCSGP), Biotechnol Bioeng. 2008;100(6):1166–1177. 

 8. Kornmann H. Purification of MAbs: Performance comparison of batch and continuous chromatography (MCSGP); BioPharm Scale Up 2008, Geneva. 

 9. Tarafder A, Aumann L, Mueller-Spaeth T, Morbidelli M. Improvement of an overloaded, multi-component, solvent gradient bioseparation through multi-objective optimization. J Chromatogr A, 1167(1):42-53, 2007. 

10. Miller L, Grill C, Yan T, Dapremont O, Huthmann E, Juza M. Batch and simulated moving bed chromatographic resolution of a pharmaceutical racemate. J Chromatogr A. 2003;1006(1–2),267–280. 

11. Paredes G, Stadler J, Makart S, Morbidelli M, Mazzotti M. SMB operation for three-fraction separations: Puri?cation of plasmid DNA. Adsorption. 2005;11:841–845. 

12. Li P, Xiu G, Rodrigues AE. Proteins separation and puri?cation by salt gradient ion-exchange SMB, AIChE J. 2007;53(9):2419. 

Protein Peptide Purification using the Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) Process

The following is a transcript of a podcast interview recorded at the 2008 BIO International Convention held in San Diego.

 What are the biggest challenges in a technology transfer process? Are the challenges different at different stages of tech transfer?

 I think they are and they fall under a couple of categories. The first is the technical area. The processes that come to us arrive at different levels of development. If a process is already well developed, then it is essentially a pure technology transfer. But if it's only partially developed, or not developed at all, then there is a lot more process development on our side. Some challenges arise when a process is very limited in development and then it takes some time to put in a new process. On the communication or people side, we have learned that it is important to set clear objectives and the scope, and for our project managers to work closely with the project manager or project director at the client. And this has worked well for us.

 What are the key areas a biopharmaceutical company should focus on while planning for tech transfer to a CMO?

 Well, I think the first step is to assess the state of your technical knowledge about the project in the form of a detailed technology transfer report that you would provide to a CMO. And out of that, you then produce a smaller subset of information that you need for a request for quotation. The request for quotation is what we begin with. Before we respond to it, we sign a confidential disclosure agreement with our customers so that they are free to talk about the technical aspects of their project and our scientists can talk to their scientists and assess how we could best do the work.

 How important is communication and documentation? Which routes of communication would you suggest to a biopharmaceutical involved in tech transfer?

 I think any CMO would say it's all important, and it has to be done the right way. For example, a lot of people prefer e-mail as the communication vehicle, and e-mail has its strengths in terms of speed and details, and in terms of transfer to other people, but it can also make it difficult when you are trying to have a discussion. We also shy away from e-meetings or e-discussions because there we want to have either a face-to-face meeting or a telephone conversation.

	And communication has to be frequent, too. For most of our projects, we have a weekly project team meeting with key members of each company's team. This is typically a teleconference, although it could be face-to-face, depending on the location of our customer. That is followed up by more frequent communication between our project manager and the respective key contact at the customer. If there is something important, we don't wait for the regular weekly meeting; the project manager will do that right away.

 In a recent webcast with BioPharm International, you talked about the use of pilot plants in tech transfer. Does using a pilot plant change the process significantly? 

Yes it does, and it has a couple of benefits that aren't immediately apparent if you don't have this kind of facility that is dedicated to producing engineering runs. By putting that in place, we created a nice spot where we could transfer the technology in a hands-on fashion between the development and the manufacturing staff at Laureate Pharma. And we can also have the client present, as we have always encouraged them to be. When we designed the plant, we put in large viewing windows so that the client could be on the outside, without having to gown up, and still be able see the process and check on it periodically. This way, the person in the plant can interact more easily with us.

 How can a biopharmaceutical company efficiently handle the scale-up aspect of tech transfer? 

Again, having that pilot plant or engineering-run facility is really important for scale-up because it allows people in the key development and manufacturing groups to work together on their documentation as well as the process. What we have learned is that the process development people can sort of teach the process to manufacturing and the manufacturing people can also teach the process development people aspects of the large-scale equipment.

 What is the role of the analytics group? How can methods transfer from analytical development to quality control be enhanced?

 The analytics staff are really the eyes and ears of the development and manufacturing groups because what they provide is the key information that you need, like titers in a bioreactors, how much did the cells make, and product quality, in terms of how much contaminant is removed in each step of the purification process, or was the protein inadvertently damaged or aggregated by a particular process step. Without the analytics group, you can't really know that. Without good analytics, you are flying blind. So analytics are part of every good process development strategy.

 With biopharmaceutical production being increasingly outsourced across the country and even across the ocean, how can a biopharmaceutical company handle the "distance" challenge?

 There are a couple of routes to it. We do have some distant customers from Europe and Asia. Sometimes they will bundle their travel with some other needs they have on the East Coast of the US where we are located. At other times, we use a lot of teleconferences, and we sometimes do that very early in the morning or late at night to accommodate the time-zone differences. And as one of our Australian customers said, "We are far away from almost everyone, so we understand we have to go a long way to work with you from a time zone and meetings aspect."

This conversation has been edited for length and clarity.

, is senior director of biopharmaceutical development and operations at Laureate Pharma, Inc., Princeton, NJ, 609.919.3390, 

How to ensure smooth technology transfers.

Facilitating Technology Transfer to Your CMO

A rally in the capital markets in the two days either side of the Thanksgiving holiday helped improve the fortunes of a number of industrial sectors, including biotech. The upswing came as welcome news for investors, because at one point late in November the Dow had slipped to 7550, dragging all sectors down with it. By month's end, the Burrill Biotech Select Index, a price-weighted index tracking 20 of biotech's blue-chip companies, closed down almost 7% with the Dow down 5% and the NASDAQ 11% for the month of November.   

Although the past two months have been ugly, with biotech's blue-chip companies shedding 17% of their value, their fundamentals of strong sales and robust pipelines will see them recover, but it will take some time. It is the small-cap biotech companies that will face the greatest challenges. The Burrill Small-Cap Biotech Index dropped 13% in November and 34% since the end of September. Among the 370 publicly listed biotechnology companies tracked by the monthly Burrill Report, 54% of them now have a market cap well below $100 million. We are starting to see a clear pattern evolving for these companies. They are rapidly restructuring as a result of the negative capital markets. Staff is being reduced and many R&D programs have been put "in the refrigerator" until better times prevail. 

The Burrill Report identified 15 North American biotech companies that announced restructuring in November. This list will certainly grow in the months ahead as biotech companies look to ride out the prevailing economic conditions. Many may be forced to combine for survival and focus on the one key program between them that has the greatest opportunity for value creation and funding.  

There will also be reverse mergers. Many of these will be into public shells or "burnout" companies that have seen their product fail, but still with cash. In such cases, the merger will increase their funding options and provide a pathway to liquidity for their venture capital and private equity investors. 

Reverse mergers were once considered by the investment community to be tertiary financing vehicles. They are becoming more widely accepted by venture capitalists as a potential financial event, taking the place of the more traditional biotechnology initial public offering—the IPO window being firmly closed. 

Recently, Novacea, Inc. of South San Francisco, which abandoned work on its prostate cancer drug after unfavorable clinical trial results, merged with privately held Transcept Pharmaceuticals. Inc. Under the reverse merger, Transcept will acquire a NASDAQ listing and about $90 million to develop its insomnia drug Intermezzo and other products. 

If not restructuring, biotech companies will be acquired at bargain basement prices. For example, Roche snapped up its partner Memory Pharmaceuticals for $50 million. The whopping 319% premium that Roche paid has to be put in perspective since Memory was trading at $0.15 and a market cap of $12 million the day before the announcement. The acquisition means that Roche gains full access to the partnered drug candidates in Alzheimer's disease and schizophrenia it had with Memory as well as its R&D that will augment Roche's own research and development portfolio.  

Big Pharma can certainly continue to take full advantage of the fragile global economy to buy assets at a discount. They have the luxury of sitting back and waiting for the right opportunity and then acquiring biotech companies at what represent 1990 prices. 

The collective market cap of the industry closed November at $375 billion, down 10% for the month (20% since the end of September and 16% year-to-date). Genentech's market cap closed the month at $79 billion; Amgen was at $59 billion and Gilead Sciences at $41 billion. 

As tough as these data reveal, three years from now, we will look back at this moment as one of the greatest buying opportunities ever. Some of these small biotechs are great companies with great products and pipelines with superb management that are trading at prices unheard of in their recent past.  

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

Small biotechs were forced to restructure and downsize.

Small-Cap Biotech Companies Conserve Cash to Ride Out The Prevailing Economic Conditions

The issuance of the FDA's guidance in 2004 advocating a risk-based approach to current good manufacturing practices (cGMPs) has changed the basic paradigm for quality in the biopharmaceutical industry. This guidance advocates using scientific inquiry as a foundation for developing quality initiatives that will ensure ongoing product quality. Managing risk in the product development lifecycle presents the industry with an opportunity to optimize the time, resources, and cost of developing a drug product. This same opportunity extends to the establishment of our quality argument and all of its related systems.     

The challenge in embracing this new approach to quality is shifting from the traditional mindset based on blanket inspection and testing to one driven by control and monitoring. We must change our approach and quality standards for troubleshooting and prevention if we are to realize the agency's vision of quality and business synergy. In an industry where the ratio of quality to operations personnel can reach 3:1, as is often seen in large biopharmaceutical operations, the concept that quality can operate synergistically with the needs of the business is a radical departure from what we have experienced for the last 50 years.  

With this shift in philosophy by both industry and the regulatory bodies, we find ourselves reinventing our approach and expectations to fundamental quality activities, such as root cause analysis (RCA). RCA is an approach to problem solving aimed at identifying the basic drivers or causes for problems or events. The philosophy behind RCA is predicated on the belief that problems are best solved by attempting to correct or eliminate root causes, as opposed to merely addressing the immediately obvious symptoms.  

In investigating a problem or event, there are three basic components we need to understand. We have the symptom, which is the failure observed against the expected performance; the mechanism that drove the failure; the contributing state or events that may have supported the failure; and the actual root cause of the failure. Separating these components is the key to an effective root cause analysis. The relationship among these components is shown in Figure 1.  

Figure 1. Relationship among the components of root cause analysis. 

By directing corrective measures at root causes, it is hoped that the likelihood of problem recurrence will be minimized. However, we recognize that complete prevention of recurrence by a single intervention is not always possible. To be effective, RCA is often a highly iterative process, and is frequently viewed as a tool for continuous improvement. 

There is no single approach to RCA: it is an amalgam of different tools, processes, and analyses applied appropriately to identify the source of the problem or event. Even so, RCA exercises have not always been completely objective. We have all seen the corrective action and preventative action (CAPA) documents which have been closed, with the recommended root cause and corrective action being operator retraining. In such cases, the problems invariably reappear later because the corrective action was off the mark. An effective corrective action based on an effective RCA should eliminate the problem or event from happening again. In the absence of this reality, the RCA was not effective. 

The lack of a disciplined approach to RCA has undermined the effectiveness of CAPA programs and often leads to recurring issues with products. As a result, the focus of many FDA inspections has been the quality and defensibility of RCAs, which are often used to close out a CAPA. Nevertheless, the emphasis in the biopharmaceutical industry on moving toward a more process-centric rather than a product-centric philosophy for quality assurance has laid the groundwork for a more effective RCA exercise. The emergence of operational excellence initiatives has rekindled interest in structured problem solving techniques such as Kepner-Tregoe that methodically drive the analysis toward an objectively defensible final conclusion. But the one thing we have learned as an industry is that there is no magic bullet, no one-size-fits-all solution that we can just buy and implement to meet this shift in quality philosophy. However, a common framework defines all good investigative processes. This article describes and illustrates the application of one approach that is very effective in integrating the basic tenets of Quality by Design and risk management as purported by ICH Q10 as a methodology for an effective RCA.  

The RCA roadmap borrows heavily from best practice methodologies for process development and characterization. It consists of eight steps designed to identify the metrics for success, the sources of variation in the process, and their success remediation steps, as follows: 

The purpose of defining the project charter is to clearly establish the metrics for success for the project. We are often simply told we have a failure or a problem and to fix it. Defining the specifics of the issue is essential to setting the scope and direction of the investigation. Any structure may be used for this exercise, but the establishment of the charter should be objective and include definitive metrics for the current process and the future desired metrics that would represent a successful RCA exercise. If a product is failing or trending out of specification on stability, then a summary of the historical performance of the product should be a starting point for comparison. The charter also should establish the priority for resolving the RCA exercise. If there are regulatory, safety, or business implications driving the RCA, then a sponsor for the exercise will be essential to gain the right organizational support for the investigation. Clearly identifying this individual and gaining his or her buy-in for the effort is critical to a successful RCA. The project charter also focuses the team on the primary goals and scope of the project and milestones for completion. Another measure of value may be to analyze the cost of poor quality, both internal and external to the company. Understanding the cost exposure of dealing with deviations, failures, and recalls contributes to the urgency and priority that should be assigned to the RCA in the organization. 

Setting the project scope is a critical activity during the chartering process. RCA exercises too often get derailed by issues that are not related to the fundamental problem or event. For example, if a tablet is failing potency on stability because of the presence of escalating degradation products, do not worry about the content uniformity or tablet breakage issues that production may be struggling with. Although there could be a relationship between these characteristics, it is better to let the investigation and the data drive the conclusion rather than pursue all paths simultaneously.  

Before any RCA exercise can begin, the investigating individual or team must have a baseline understanding of the process or product and the steps and variables involved in the process. Although there is no absolute set of tools to use for this exercise, a successful sequence for establishing process understanding is shown in Table 1.  

Table 1.  A successful sequence for establishing process understanding 

Based on these analyses, a clear list of what we do and do not know should now be apparent. This should drive activity to address the missing information. A fundamental truth for RCA activities is that we cannot effectively implement a corrective action if we do not understand the drivers of variation in the process.  

Before delving too far into the failure mode data analysis, it is important to establish that the measurement systems used to steer and measure process or product performance are capable of distinguishing a good process or product from a bad process. Most analytical methods in our industry go through a rigorous method development and qualification. However, saying a method is validated is not good enough to ensure the level of resolution necessary to identify the root cause of the problem. Depending on the test or the company's quality policy, method errors of 5–7% are often deemed acceptable. This could be a problem when looking for subtle changes in a process or problem that can be driving the observed failure mode. Understanding the variation that is native to the method, the sampling technique, and the raw materials is crucial to deciphering what is really happening with the process. Studying variation in a process is the quest to differentiate between common cause variation that is native to a controlled process and special cause variation that is driving the failure mode. 

Look at the error allocation between the equipment, process, method, and operators. This is often confirmed by a simple gauge repeatability and reproducibility study that will determine whether the measurement method is capable of distinguishing good from bad product. If the method is deemed unsuitable, then an alternate measurement scheme will be required by the team. When conducting an analysis of your measurement system, consider the following four questions: 

2. Are you able to measure differences in the process? This is needed to be able to drive process improvement. 

Optimize time and cost of product development by managing risk.

BioPharm International-01-01-2009

Quality by Design: Industrial Case Studies on Defining and Implementing Design Space for Pharmaceutical Processes (Part 2)

Revitalization, Reform Ahead for The FDA

Buckle-Up Biopharma

Protein Peptide Purification using the Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) Process

Facilitating Technology Transfer to Your CMO

Small-Cap Biotech Companies Conserve Cash to Ride Out The Prevailing Economic Conditions

Integrating Risk Management as an Effective Approach to Root Cause Analysis

Taking on 2009

Serving Two Masters: Reconciling EMEA/GAMP 5 and FDA/cGMP Phase 1

Standardized, Hands-on Biomanufacturing Training is Essential