	According to the industry group PhRMA, the average annual total compensation for biopharmaceutical workers in 2011 was $110,490, almost twice the average salary earned by all US workers (1). An American Association of Pharmaceutical Scientists survey lists the mean annual base salary for pharmaceutical scientists in the US, as of July 2014, as $143,800 (2). On paper, these salary numbers are impressive. However, the number of research, development, manufacturing, sales, and other positions eliminated in the bio/pharma industry, more than 155,000 since 2009 (3), is sobering.
	
	What is the employment picture for those professionals working in the biopharmaceutical development and manufacturing segments? In this issue, the editors of 

 address employment, compensation, workload, and other factors in our annual employment survey on pages 26-29.

		More than 54% of the respondents are contracted to work 40 hours per week; 24.1% say they work more than 50 hours per week.

		The respondents were experienced: 61% have more than 15 years of experience in the industry.

		The respondents are not impressed with the training for people newly hired for the industry; 78% said the new hires were adequately trained, but not exceptional and 13.6% of the respondents said the new hires were poorly trained.

		Almost 63% reported a salary increase from 2013 to 2014. Of the 52% of the respondents who received a bonus, 26% received larger bonuses than the previous year.

		While 75% of the respondents received at least two weeks of vacation time; 85% said they spent at least part of their vacation time doing work.

	In evaluating factors other than compensation, approximately 80% of the respondents said they did not experience discrimination; their skills were used to the fullest extent; and their work was valued by their employer. Some respondents, however, saw limited opportunities for professional development (35%) and career advancement (39%).

	When considering a job change, professional advancement and intellectual challenge ranked higher than salary respondents report, followed by job security and work/life balance.

	Salary is not the main reason respondents come to work, however. Challenging projects, intellectual stimulation were the top reasions, followed by a good work/life balance and job security. Salary was ranked with relationships with colleagues and supportive management.

	Overall, the respondents were tolerant of negative workplace factors; less than 15% percent identified a specific factor as a reason to quit their job. Low pay, discrimination and limited growth opportunities, and negative workplace attitudues were top concerns.

	On behalf of the BioPharm International team, I thank all biopharmaceutical professionals for their contributions to the industry and extend our wishes for a prosperous and successful 2015.

The Biopharmaceutical Industry Helps Strengthen the U.S. Economy

,” accessed Nov. 24, 2014.
	2. AAPS, 2014 

, (Arlington, VA, 2014).
	3. Loftus P., Falconi M., and Plumridge H.,“In Drug Mergers, There’s One Sure Bet: The Layoffs”,

l, April 29, 2014, accessed Nov. 24, 2014.


	Rita Peters is the editorial director of 

Articles

From the Editor

Industry professionals share the ups and downs of working in the biopharma industry.

The Biopharma Working Life

	A greatly expanded range of regulated food and drug products, now produced all over the world, has prompted FDA commissioner Margaret Hamburg to seek new ways for FDA to handle its more complex and far-flung regulatory responsibilities. Hamburg formed a high-level agency-wide group in 2013 to assess and make recommendations for improving alignment of FDA centers with its inspection field force. The result is a new Program Alignment Group (PAG) plan to integrate more closely center and field oversight functions through “commodity-based and vertically-integrated regulatory programs.”
	
	At the same time, the Center for Drug Evaluation and Research (CDER) is implementing a major reorganization designed to bolster programs and policies to ensure drug quality. After two years of planning, CDER director Janet Woodcock is establishing a new “super” Office of Pharmaceutical Quality (OPQ), a move that reflects Woodcock’s “one voice for quality” approach that coordinates review, inspection, and research activities related to drug quality.
	
	


	FDA’s program alignment process will revise inspection functions carried out by the Office of Regional Affairs (ORA), which manages operations for inspecting and overseeing compliance for all FDA-regulated products and companies in the United States and abroad. For drugs, a main initiative is to form an ORA pharmaceutical inspectorate, a cadre with specialized expertise to inspect and evaluate manufacturing facilities for both human and animal drugs throughout the world. CDER staff may participate in certain inspections and will provide more input into inspection scheduling, operations, and enforcement actions. Field force specialization will involve more training, and ORA laboratories will become more specialized (1).
	
	These operational changes will be spelled out in a five-year Pharmaceuticals Action Plan that will be developed in 2015 by ORA, CDER, and the Center for Veterinary Medicine (CVM). These parties will calculate future resource levels needed to shift from a regional oversight structure to a dedicated drug surveillance program, a process that will involve assessing the number of field investigators, compliance officers, and managers for the new program. The program will develop enforcement standards, policy guides, and guidance and clarify field and center responsibilities for issuing warning letters, enforcement actions, and decisions related to compounding, clinical disqualifications, and recalls.

	Key to formulating a multi-year, risk-based process for scheduling plant inspections and monitoring imports for ORA, CDER, and CVM is to overhaul and update manufacturer registration and inventory databases. This involves “harmonizing” center and ORA data systems, using common facility identifiers, product codes, and software platforms that permit all parties to access information on field inventory, applications, facilities, adverse events, and risk information. To this end, FDA issued guidance in October 2014 advising manufacturers to use DUNS numbers (Dun and Bradstreet’s Data Universal Numbering System) for a unique facility identifier (UFI) system (2).

	Once the program is established, CDER will supply ORA with an annual surveillance priority list that provides a basis for an ORA work plan for the coming year. A pilot for team-based domestic and foreign drug quality inspections has been launched to ensure that these changes enhance field and center agreement on where regulatory action is required.

	FDA’s Center for Biologics Evaluation and Research (CBER) should experience less disruption from this initiative to integrate field and center inspection activities, as an ORA Team Biologics has been in place since 1997 for cellular therapies and blood products, with CBER reviewers regularly participating in field inspections. Still, a Biological Products Action Plan will be developed to improve CBER’s plant registration data system and support a risk-based approach for setting priorities on facility inspections. In 2015, CBER and ORA will update existing Team Biologics procedures and identify gaps in training and policies.

	Another important PAG change is to establish a central Bioresearch Specialization Action Plan for agency bioresearch monitoring (BIMO) activities. A dedicated corps of ORA investigators will conduct BIMO inspections for drugs and biologics, as well as other regulated products.
	
	


	Meanwhile, CDER’s reorganization will go live Jan. 5, 2016, shifting to OPQ most functions of its Office of Pharmaceutical Science (OPS). OPQ will evaluate the CMC (chemistry, manufacturing, and controls) submissions for drugs, biotech therapies, and generic drugs and conduct research on drug formulation and manufacturing issues (3).
	
	OPQ also will oversee the process for scheduling and conducting preapproval and surveillance inspections now carried out by CDER’s Office of Compliance (OC). OPQ will become responsible for certain functions related to risk analysis and informatics in planning inspections now handled by OC’s Office of Manufacturing and Product Quality, and oversight of bioequivalence testing and non-clinical studies will move from OC to CDER’s Office of Translational Sciences. These changes will enable OC to focus on compliance and enforcement activities, including recalls, supply chain security, and unapproved drugs.

	Woodcock will head OPQ on an acting basis, assisted by deputy director Lawrence Yu, who has been serving as acting director of OPS for the past year. Steve Kozlowski will continue as director of OPQ’s Office of Biotechnology Products, and Cindy Buhse remains acting director of the Office of Testing and Research. New offices will process CMC applications for new drugs (acting director Sarah Pope Miksinski) and for lifecycle drug products (acting director Susan Rosencrance), respectively. Other new OPQ operations include an Office of Program and Regulatory Operations, an Office of Policy for Pharmaceutical Quality, and an Office of Process and Facilities. An OPQ Office of Surveillance will develop written standards and inspectional procedures, led on an acting basis by Theresa Mullin, currently director of CDER’s Office of Strategic Programs where she has headed up the development of quality metrics for assessing manufacturing operations and products.

	These changes aim to achieve uniform quality oversight for new drugs, generic drugs, and over-the-counter products by providing a single drug quality assessment “that captures the overall OPQ recommendation on approvability,” Woodcock stated. Manufacturers will benefit from feedback on quality deficiencies earlier in the review cycle, and FDA will be able to provide a more uniform quality program across domestic and foreign manufacturing sites, as well as for all drug product areas. The result, Woodcock believes, will be “consistent approaches, a transparent process, and clear standards to which the regulated industry must conform.”

	Woodcock has voiced these goals repeatedly in the past two years, emphasizing the need to instill a “culture of quality,” as opposed to compliance, throughout the bio/pharmaceutical industry. She emphasized at the FDA/PQRI conference in September the importance of moving from a “rule-based” to a “risk-based” approach based on common understanding of what constitutes real risk in pharmaceutical products. Field inspections will shift from “writing traffic tickets” to full product assessment--not just negative observations but what the manufacturer is doing well. This intelligence will support a “pharmaceutical platform” with a complete inventory of regulated facilities around the world (e.g., location, ownership, products, surveillance information). CDER has been piloting its team-based review approach this past year, and Woodcock anticipates “rapid evolution” of these initiatives over the next few years.
	
	

www.fda.gov/aboutfda/CentersOffices/ucm392733.htm

Specification of the Unique Facility Identifier System For Drug Establishment Registration, Guidance for Industry

 (November 2014).
	3. CDER, CDER reorganization, 

www.fda.gov/AboutFDA/CentersOffice/OfficeofMedicalProductsandTobacco/CDER/ucm418347.htm


	Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, jwechsler@advanstar.com. Read Jill's blogs at PharmTech.com/wechsler.

: When referring to this article, please cite it as J. Wechsler, "FDA Realigns Drug Inspection and Manufacturing Oversight," 

Regulatory Beat

Operational changes at FDA and CDER aim to improve global market monitoring.

FDA Realigns Drug Inspection  and Manufacturing Oversight

11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production

(1), which identifies various industry trends, almost all areas of R&D and manufacturing are at least in contention for some degree of outsourcing. CMOs are becoming sought-after partners as a result of their use of innovative technologies, single-use bioreactors, and other novel bioprocessing services.

Trend One: Popular Outsourcing Activities Continue to Expand


	This past year, BioPlan’s study noted a year-over-year increase in the use of many of
	the most popular outsourcing activities, such as:

		Toxicity testing (87% outsourcing to some degree, up from 75% last year)

	There was a general pullback, however, in the less commonly outsourced activities. These activities included downstream production operations, downstream process development, and design of experiments. Some of these downstream activities may have declined as facilities resolved problems and bottlenecks in purification steps. Despite these declines, current outsourcing levels for even those activities represented growth over levels in 2010.
	
	These data indicate that the most common outsourcing activities are becoming cemented in place as mainstream contract manufacturing activities. BioPlan expects that to continue, as the study also shows an increased willingness to outsource them to a greater extent in the years to come.
	
	

 Trend Two: Outsourcing is No Longer about Cost Cutting


	In years past, outsourcing was used as a way to cut costs and more efficiently allocate in-house capacity; BioPlan’s recent studies indicate that cost control is no longer a top priority when outsourcing. Indeed, when respondents were asked about the cost-cutting actions they undertook during the past 12 months, only 9% had outsourced manufacturing to domestic service providers for this purpose, down from 14% last year, and the proportion that outsourced manufacturing to non-domestic service providers (off-shoring) to control costs was essentially flat at 13%, after rising from 6% since 2011 (see 

	Similarly, the share of respondents outsourcing jobs in manufacturing, process development, and R&D to cut costs remained either flat or slightly below last year’s levels.
	
	In a related development, the BioPlan study revealed that, this year, cost-effectiveness was not the big priority it was last year when developers were considering contract manufacturing partners. Only 22% reported that it was “very important” to them that the CMO demonstrate the cost-effectiveness of their services, roughly half the proportion (42%) from last year’s survey.  

	Further, outsourcing budgets are expanding at a rapid rate, compared with other segments. And because outsourcing is a long-term and strategic decision, facilities don’t easily make changes in their outsourcing budgets, as they might for equipment purchases. This year, respondents reported having increased their budgets for outsourced biopharmaceutical manufacturing by nearly 4%, up significantly from each of the prior five years. Outsourcing is taking on a more strategic role, moving away from a simple cost calculus and toward a partnership based on quality and value.

Trend Three: Outsourcing Relationships Evaluated on Managerial Factors


	While contract manufacturers should of course be able to display their technical proficiency (particularly as they bid for high-value activities previously considered too “core” to outsource), data from the BioPlan study indicate that clients are increasingly basing their partner evaluations on a host of managerial and “people” factors.
	
	When biopharma decision-makers were asked about the issues they find important when considering outsourcing manufacturing to a CMO, of the 18 most critical areas indicated, the most important were:

		Establish a good working relationship (“very important” or “important” to 98.2% of client respondents)

	To put this in context, when evaluating only critical (“very important”) attributes, more decision-makers pointed to establishing a good working relationship (70.9%) than did compliance with the client’s quality standards, protection of intellectual property, or effective handling of cross-contamination issues.
	
	In other words, while technical competency is important, clients are recognizing that they are not enough on their own, and that effective partnerships are built on strong relationships.
	
	

Trend Four: It Doesn’t Matter Where the CMO is Located


	Assuming that the relationship is solid, the CMO’s location remains relatively unimportant to clients today--only 7.3% considered a CMO being local a “very important” attribute.  This runs contrary to what many CMOs have said they experience--they feel clients appreciate the opportunity to meet in person, often, and locally to watch the processes. Such in-person meetings, however, may have more to do with clients’ need to keep projects on track (a major concern), than with wanting to personally watch the CMO’s process development and manufacture.
	
	Although location remains at the bottom of the decision-factor list, respondents from different regions do display different preferences when it comes to potential outsourcing destinations. Western Europeans, for example, are becoming increasingly interested in China as a potential outsourcing destination: 47% of respondents from that region named China a potential destination in the next five years, representing a large increase from just 6% a few years earlier. Indeed, China drew level with the United States as a potential destination (one that is at least in the consideration set).
	
	Among US respondents, however, India may be the emerging market with more potential activity, while Singapore tops among Asian markets overall. In fact, Singapore topped the list of potential destinations for US respondents, 39% of whom cited it as a “possible” destination in the next five years (up from 28% in 2011). Singapore was followed in the rankings by Germany.
	
	

Trend Five: Biosimilars Will Expand the Global CMO Market


	The growth of interest in biosimilars, with more than 800 follow-on products in the pipeline, will provide a significant upswing in business for CMOs who are primed to be the biggest beneficiaries of this emerging trend.
	
	Biomanufacturers, who have cut back on their in-house capabilities in recent years, may not use their remaining capacity for biosimilars manufacturing, given that these drugs will be lower cost and lower margin relative to innovator products. As a result, larger players may be expected to outsource the manufacture of these products to CMOs. Additionally, newer entrants to the market may well follow a business model in which they license-in follow-on products from smaller players and then outsource the manufacture of those products. Indeed, CMOs are anecdotally already reporting business increases of up to 15% from biosimilars services.
	
	


	Many of the trends identified in this year’s annual report will likely continue apace next year. Outsourcing will take on a higher-value dimension that puts cost behind other considerations, and the outsourcing market will increasingly globalize, a trend that will be fueled further by the advent of biosimilars. All in all, it’s a time of growth for biopharmaceutical outsourcing.  
	
	


	Eric Langer is president of BioPlan Associates, tel. 301.921.5979, elanger@bioplanassociates.com,
	and a periodic contributor to Perspectives on Outsourcing.

: When referring to this article, please cite is as E. Langer, "Year in Review: Key Outsourcing Trends in Biopharmaceutical Manufacturing," 

Perspectives on Outsourcing

Outsourcing is taking on a greater role in the biopharmaceutical manufacturing industry.

Year in Review: Key Outsourcing Trends

A key component of the quality-by-design (QbD) approach to pharmaceutical manufacturing is the implementation of process analytical technology (PAT) for ongoing monitoring and adjustment of production processes to ensure the production of biologic APIs with consistent quality that meet specifications every time. Implementing PAT for bioprocesses presents unique challenges given the greater complexity of cell-culture and fermentation processes, the variability of raw materials (particularly living organisms), and the move from stainless-steel to single-use equipment. The recent emphasis on establishing a thorough understanding of the manufacturing process from the earliest process design stages through the use of process characterization studies is, however, a key enabler of PAT approaches, according to Kumar Dhanasekharan, director of process development at Cook Pharmica. Advances in high-throughput systems, Raman and near-infrared (NIR) spectroscopy, high-performance single-use sensors, and chemometric methods are also helping manufacturers of biopharmaceuticals overcome these hurdles.


	The key to successfully implementing PAT for bioprocesses is the availability of robust, reliable, low-cost, easy-to-use online/atline analyzers; a complete understanding of the variability inherent in the process and the variability introduced by raw materials; and sufficient time to develop a process that is amenable to the application of PAT during manufacturing, according to Rajesh G. Beri, head of mammalian research and technology for Lonza Custom Development and Manufacturing. In addition, PAT is much more than just one sensor integrated into a process. “Effective PAT implementation implicates the use of various measurement and control devices and hence requires a commitment to sophisticated automation solutions,” says Mario Becker, director of marketing and product management for PAT and automation at Sartorius Stedim Biotech.
	
	Because bioprocesses are complex and dependent on multi-factor interactions between the process variables, using PAT for biotherapeutics can be more challenging than for small-molecule drug manufacturing. “Real-time in-process measurements of critical quality and performance attributes of raw and in-process materials and processes are not always possible for biologics due to the complex nature of most analytical methods and the reaction systems,” says Dhanasekharan. Using spectroscopy for the analysis of a complex broth of cells, where the active ingredient often remains in the cell bodies, is difficult, adds Ivo Backx, manager of business and project development for the pharmaceutical industry at Siemens. “Often, secondary metabolites and related parameters must be detected as critical process parameters and monitored to track the batch status in real time, which requires a lot more process understanding,” he explains.
	
	According to Becker, as biotechnology has advanced, the number of factors and setpoint accuracy and precision of control have become more demanding. At the same time, regulatory agencies have continued to press for tighter controls, greater understanding, and higher consistency. “Therefore, each step of the process requires a level of PAT that is balanced between financial investment, legal implications, and profitability. In the end, it is all about risk mitigation,” Becker asserts.
	
	Further complicating the use of PAT for biologics is the complexity introduced by the variety of raw materials and the variability in raw material lots/quality used in product manufacturing. “It is possible with extensive experience in biologics manufacturing to be able to identify critical sources of variability; however, much work remains to be completed in order to gain control over the variability posed by raw materials,” says Beri.  
	
	The shift from classic stainless-steel equipment toward smaller production skids, most often based on disposables, is also presenting challenges for measurement methodologies, according to Backx. Finally, implementation of PAT for bioprocesses implies the extensive use of the design-of-experiment (DoE) approach. “The cost for DoEs in the biopharmaceutical industry can be quite high, and DoEs can also be quite time consuming, making the use of PAT difficult. One solution may be to work with small volumes and run several experiments in parallel,” Backx says.
	
	


	Although upstream processes tend to be more challenging and the sources of variability (raw materials and process) are reduced in downstream processes (e.g., after Protein A purification for monoclonal antibodies), PAT has been more widely used in the production fermenter or bioreactor. The increased use of PAT for upstream processes is driven by the fact that most of the critical quality attributes of a product, the product yield, and the quantities of process-related impurities are determined.
	
	For biologics that are extracellular and present in relatively large concentrations, there is a good potential for direct detection through the use of spectroscopic measurement techniques. This type of biologic is better suited for PAT applications, according to Kjell François, manager of the PAT data management team at Siemens. He adds that nutrient uptake can often also be measured using NIR as a soft sensor. If the cell metabolism is known, the detection of changes as secondary indicators can be adopted as PAT techniques for process monitoring, even if the active compound to be produced cannot be detected explicitly. “Using PAT as a tool to control the process based on secondary or derived parameters is more difficult, although there are some cases where feed rates are controlled using PAT in order to maintain optimal reaction conditions,” François notes. For example, Dhanasekharan points out that during cell culture, adaptive feed strategies for glucose and other nutrients are becoming more routine due to technologies for fast turnaround on metabolite analysis, such as advanced real-time glucose analyzers and, in some cases, Raman spectroscopy.
	
	With respect to the use of PAT in downstream bioprocessing, François suggests that a lack of good real-time online measurement techniques may be a limiting factor. There has, however, been significant progress in the application of rapid methods for microbial testing and control, as well as the determination of protein concentration, according to Dhanasekharan. “At-line A280 measurements of protein concentrations are now routinely used in downstream operations for real-time control. There have been recent advances in UV-Vis spectroscopy that do not require dilution, allowing for the direct determination of protein concentration without sample preparation, thus increasing speed and accuracy,” he explains.
	
	


	High-throughput process development systems and rapid analytical methods have the potential to reduce both the labor and time required to study both the many different variables associated with bioprocesses and the variability introduced by raw materials, according to Beri. “By working closely with manufacturers of high-throughput bench scale systems, we are currently making them more suitable for achieving increased process knowledge while simultaneously reducing the labor and time required to gain this knowledge,” he adds.
	
	One challenge with using high-throughput techniques, however, is that they generate more data than can be handled by commonly used Windows-based software programs. As a consequence, real-time PAT Q-data management systems and multivariate analysis programs are increasingly being used.
	
	


	The continuous real-time quality control and assurance that is highly desired in biopharmaceutical manufacturing can be achieved using sophisticated process control strategies based on multivariate monitoring techniques, according to Becker. “Multivariate monitoring is based on models representing the relationship between parameters, whereas traditional process monitoring is based on univariate rules incapable of revealing correlation patterns, and sometimes results in misleading conclusions,” he comments.
	
	Software systems for multivariate data analysis (MVDA) in real-time are highly efficient tools for process monitoring and control of previously established design spaces based on current process parameters and analytical data, according to Becker. The software permits early detection of process deviations and provides user guidance for identifying potential root causes of these deviations by displaying easy-to-understand graphics, resulting in not only improved health, safety, and environmental (HSE) performance, but also enhanced control and assurance of the overall process and product quality. Systematic cost savings also can be achieved, and these systems can be fully integrated into the automation architecture of single-use unit operations.
	
	“MVDA techniques are being increasingly used for scale- and batch-to-batch comparison investigations to support or derive process understanding and to ultimately improve the quality, safety, and efficacy of a drug product,” says Becker. DoE, meanwhile, is a standard technique for accelerating process development tasks and gaining additional process understanding with the fewest number of experiments. “Nowadays,” Becker adds, “chemometric software can even be fully integrated into supervisory control and data acquisition (SCADA) systems and therefore can easily be integrated into standard working procedures in a process-development environment.”
	
	“Lonza and many other companies have been very successful in prospectively applying MVDA to increase process performance and control product quality. Some biologics manufacturers have also implemented online MVDA to enable more real-time process monitoring and control, which Lonza is also actively implementing,” comments Beri.  


	Near-infrared (NIR) and Raman spectroscopy are attracting a lot of attention as PAT techniques for bioprocesses. Spectroscopy techniques specifically tailored for bioprocess applications are important solutions for non-destructive process analysis, according to Becker. “We are excited about the use of Raman and NIR probes for biopharmaceutical manufacturing because these probes have the ability to provide real-time information about the process and product in the bioreactor,” observes Beri. “As a result, companies can use this knowledge to help control the process so that it delivers product that meets predefined specifications while also maintaining a high product yield,” he adds.  
	
	When combined with chemometrics tools, Becker explains that NIR enables the acquisition of data that otherwise would be unavailable with conventional wet chemistry. “In addition to cell parameters (density and viability), nutrients, and metabolites, NIR is capable of predicting process trajectories, reflecting the overall state of an entire process as a sum parameter,” Becker says. “This functionality allows a real-time comparison of the current batch with the ideal process state, or the so-called ‘golden batch,’” says Becker.
	
	He continues, “With standard adaptation via Ingold ports, compact and robust designs, and an attractive total cost of ownership, spectroscopy will become a standard tool for in-process monitoring and control during commercial manufacturing,” Becker concludes. Process adaptations for single-use unit operations are also under development.
	
	

Sensors for single-use and smaller-scale production


	The increased use of single-use technologies in biopharmaceutical production processes has resulted in a strong demand for robust and reliable single-use sensors that enable the application of PAT as a basis for effective automation and optimization, according to Becker. “In addition to established multi-use offline sensor technologies, such as those for temperature, pressure, pH, dissolved oxygen, conductivity, flow rate, and basic molecular percentages, PAT has shifted to inline/online methods including the determination of cell, nutrient, and metabolite concentrations and cell viability using spectroscopic measurement techniques. These sensors, which have been developed for and utilized in stainless-steel multi-use systems, now need to be fully integrated and function equivalently in single-use unit operations,” he says.
	
	Most importantly, interface issues between single-use components, sensors, and local control and SCADA systems must be addressed to ease the implementation, qualification, and performance of PAT-enabled unit operations. “Stable and robust processes require sophisticated monitoring and control of critical process parameters based on reliable data acquisition, storage, and evaluation capabilities from inline/online sensors and process analytics,” Becker asserts.
	
	Sartorius recently extended its bioreactor portfolio with automated glucose-feed-control and integrated real-time measurement of viable cell density for automated induction, infection, and harvesting processing routines based on fully integrated single-use sensor technologies. This functionality significantly reduces sampling frequency and, therefore, operator influence, according to Becker. In addition, it increases the level of process automation, thus reducing batch-to-batch variability and out-of-specification production.
	
	Along with the shift to single-use technologies, there is a move in the biopharmaceutical industry to smaller-scale production operations as interest in the local production of drug products designed for local markets and personalized medicine increases. This shift is driving the use of fast and reliable atline analyzers for the determination of numerous biologically relevant parameters using a small amount of sample, according to François. “These techniques are needed to support the smaller scale of batch fermentations expected as the concept of personalized medicines filters down to biologics production operations. Combining such atline analyzers with real-time spectroscopic techniques should allow the effective monitoring of bioreactor farms with small-scale reactors,” he notes. Siemens is also exploring synergies with the analytical techniques applied for the healthcare sector, such as blood gas analyzers, to biologics production. “Sharing technologies looks quite promising and provides new perspectives,” says François.
	
	At the same time, there is a clear trend toward smaller, more dynamic production skids that enable continuous production using PAT, integrating upstream processes with downstream processes, in a feed-forward, feed-backward manner for overall process control, according to Backx. “This shift can fundamentally change the production landscape in the (near) future, and PAT will be a key element in the success of this approach,” he states. “Importantly, because there is no intermediate offline, time-consuming QA control between the different steps, every operation should be monitored and controlled in an optimal way driven by PAT.”
	 


	Vol. 27 No. 12
	Pages: 18-21
	Citation: When referring to this article, please cite it as C. Challener, "Improving PAT for Biologics with Online Spectroscopy and Multivariate Data Analysis," 

Features

MedicalRF.com/Science Photo Library-ANDRZEJ WOJCICKI/Henrik Jonsson/Stocktrek Images; Dan Ward 

Improving PAT for Biologics

	A more positive outlook for growth in the biopharmaceutical market, improving job security and satisfaction, and an uptick in restructuring and M&A activity are trends identified by respondents in the 2014 installment of 

’s annual employment survey (1). Compensation was a leading indicator of improving employment conditions; 62.8% of survey respondents indicated that they make more this year than they did last year, compared with nearly 51.5% who reported a salary increase last year (2).
	
	 


	The respondents to this year’s survey represent a range of roles including research, development, and formulation; analytical studies; quality control and assurance; process development; manufacturing; and regulatory affairs. The respondents work for biopharmaceutical manufacturers, academic institutions, contract service providers, or other companies supporting the industry.
	
	The respondent audience is geographically diverse. Of the survey participants, 51.8% are from the United States and nearly 30% are from Europe. The respondents are employed by both large and small companies; 30% of the respondents work in companies with more than 10,000 employees, and of these large companies, 64.3% are in the US.
	
	Among all business sizes, respondents rated knowledge of ICH guidelines (63.2%), good manufacturing practices (62.8%), analytical techniques (59.8%), chemistry (50.8%), and general principles of management (44.6%) as very important.


	More than 45% of the respondents reported an increase in business at their company; however, only 26% said their employer hired more people.
	
	Almost two-thirds (62.2%) of participants say that business at their company will continue to expand and improve in the future, a number that is more optimistic than last year’s projection, in which 52.7% said business would improve. Nearly 54% of participants said their company had been through a merger, acquisition, or restructuring in the past two years, a jump from the 46.5% reporting similar changes in 2013.
	
	

	The positive business outlook had mixed results in personal employment conditions. Job security, a key indicator, showed a positive upswing. In 2014, 22% of the respondents said they felt more secure in their jobs compared with the previous year, up from 18.3% in 2013. The percentage of people who fell less secure in their position year to year dropped from 33.9% in 2013 to 31.1% in 2014.
	
	In 2013, 35.7% of respondents reported that they worked more hours than in the previous year; in 2014, the number dropped slightly, with one-third reporting that they worked more hours this year compared to last year. Workloads remained relatively stable to 2013. In 2014, 64.3% reported their workload has increased this year, compared with 62.3% who reported an increase in 2013. Of those who reported an increased workload, 70.1% attributed it to the expansion of business without corresponding staff increases.
	
	

	As the economy continues a slow recovery, compensation prospects are looking up for employees in the biopharmaceutical development arena. In 2014, 62.8% of the respondents reported that they received a raise in 2014, compared to 51.5% in 2013. Even with salary increases, however, compensation levels are not satisfactory for more than half of the respondents; 55.3% say that they are either paid below market value or in the low end of their salary range.
	
	When contemplating a job change, salary is not the top factor; 35.5% of the respondents said that they would leave their current jobs for salary alone, a decrease from the 41% of 2013 respondents who said they would change jobs based on salary alone. Professional advancement was listed as the top reason for changing jobs: 37.6% of respondents said this was the most important motivating factor prompting a change.
	
	

	Biopharma professionals responding to the survey reported a more positive view of the job market. Although 63.3% of the respondents expressed some certainty that they will not leave their jobs within the year, more than half said they would leave their current job if given the opportunity and 21.8% were absolutely certain they would leave if given the chance. Last year, 60.8% of survey participants said they were confident they could find a job comparable to the one they currently hold; in 2014, 67.7% said they could find a similar job now if they were to look for another opportunity.
	
	


	Women represented 30.9% of survey respondents, with a proportionally larger representation (62.7%) from the US compared to the overall survey sample. Nearly 85% of all respondents said that gender is not a factor in determining or limiting professional advancement; however, only 69.1% of the female respondents said they do not feel gender plays a significant role in professional advancement.
	
	Women reported a higher percentage of salary increases than the entire sample (74.6% compared with 62.8%). Almost two-thirds (61%) of women felt they were paid in the low range or below market value, a higher percentage than for the whole survey population (55.3%). This salary discrepancy may be explained by a smaller proportion of women in managerial roles. When broken down by gender, only 39.7% of females managed other people. More then half (52%) of the male respondents were managers.
	
	


	Regional differences between the answers in the US and those of Europe are not surprising. In Europe, 58.8% of respondents had 4
	6 weeks of vacation, compared with 31.9% of those in the US getting that much time. Additionally, Europeans rated health insurance as the lowest priority, with 24.4% of respondents in Europe saying health insurance would have no impact on a decision to change jobs. This is likely due to the fact that most European countries have universal health coverage.
	
	Apart from insurance and vacation, notable differences include the activity of contract manufacturing organizations (CMOs). Several respondents from Europe mentioned that the employment conditions are due to too much outsourcing, and competition is getting tougher for CMOs overseas. More than a few participants said that more CMO opportunities are emerging in Asia, with one specific mention about China’s entrance into the CMO market.
	


	*Due to rounding, some percentages may not add up to 100%. Some questions allowed multiple answers.
	Results based on 2014 

When referring to this article, please cite it as R. Hernandez, "Job Security and Salaries Trend Upward," 

Biopharma employees report gains in compensation and job satisfaction, as industry growth continues.

Job Security and Salaries Trend Upward

	Peer-Reviewed
	Article submitted: Aug. 25, 2014.
	Article accepted: Oct. 16, 2014.

	Determination of the soluble aggregate levels in protein pharmaceuticals has historically relied upon size-exclusion chromatography (SEC). In recent years, however, there has been a realization that SEC can provide incorrect estimates of the actual aggregate content for a variety of reasons. As a result, orthogonal methods have been evaluated as alternatives to SEC for estimating the amounts and sizes of aggregates in protein products. Of these orthogonal methods, two have been preferred, both in the literature and by regulatory agencies: sedimentation velocity analytical ultracentrifugation (SV-AUC) and field-flow fractionation (FFF), especially asymmetrical-flow field-flow fractionation (AF4). This review describes the relative disadvantages and advantages of these various methods. In doing so, the use of orthogonal methods to SEC is discussed and examples are presented showing how analytical ultracentrifugation (AUC), AF4, and SEC compare in aggregate quantitation.

	Quantitative assessment of aggregate levels is required by regulatory agencies for any protein therapeutic. Historically, the primary method for measuring the size and amount of soluble aggregates in protein samples has been size-exclusion chromatography (SEC). While SEC can be an effective tool in terms of sensitivity, precision, and throughput, there are some significant technical limitations of SEC that can lead to erroneous estimates of aggregate levels in protein products (1). These shortcomings have been described and discussed in detail in the literature (1--4). A list of the advantages and disadvantages of SEC is given in 

	As a result of these shortcomings, there has been an emphasis on identifying analytical techniques that can provide information on protein aggregate content using alternative separation approaches. Given the concern over the potential connection between aggregation and immunogenicity, regulatory authorities, such as FDA, have been encouraging applicants to develop analytical methods that provide an estimate of aggregate content obtained with orthogonal methodologies and verify the results of SEC measurements (5, 6). While not routinely used as methods to release products to market, regulatory agencies realize that alternative orthogonal methods might be informative. It is expected that  orthogonal methods will be used more often in the future as quality control methods for biopharmaceuticals.

	The two most common orthogonal methods are analytical ultracentrifugation (AUC) and asymmetrical-flow field-flow fractionation (AF4). These are termed orthogonal methods in that they separate species of various sizes by different mechanisms and are used in addition to primary methods of separation. Orthogonal methods also allow the separation of aggregates of widely differing sizes. For example, the resolution of large soluble aggregates with SEC reaches its size limit at the void volume. While this size resolution is column-dependent, it rarely exceeds 10

 Daltons, corresponding to an upper size limit near 100 nm (7). By comparison, the size range for AUC and AF4 can easily extend into the micron-size range. Given the different separation methodologies that are available, estimates of aggregate levels may, and do, vary. This review describes what has been reported about orthogonal methods as they apply to protein aggregation, not only in terms of quantitation but also in terms of characterization and size determinations.


	Currently, there is a concern that underestimation of aggregate content in protein drug products might lead to deleterious health effects when these products are used. As a result, there have been efforts to develop improved SEC techniques and approaches. Some fundamental limitations to SEC remain, however, namely that SEC tends to underestimate aggregate content in protein samples. Consequently, a recent review states, “SEC is also an accurate method if confirmed with an orthogonal method…” (4). While the accuracy of aggregate quantitation by SEC can be improved by changes to the mobile phase composition and detection methodology, there is no doubt that SEC exhibits better precision than most analytical methods, including the orthogonal methods described herein (8--10).

	One limitation of SEC is the potential for adsorption of the protein to the stationary phase of the column. More specifically, there have been reports of the aggregate preferentially adsorbing to the column (3, 11, 12), leading to an underestimation of the aggregate content. As a result, it has been proposed that adding compounds, such as arginine (Arg) or nonaqueous solvents, could help enhance solubility and reduce adsorption (13--16).

	While UV absorbance (whether at a single wavelength or with a diode array detector) is by far the most widely employed detection scheme in SEC, there can be distinct advantages to using other types of detectors or even multiple detectors. The use of a fluorescence detector has been reported to aid in quantitation of aggregates for interferon-∝ (17), monoclonal antibodies (mAbs) (18), and erythropoietin (19). In addition, use of fluorescence detection can be beneficial if polysorbate is present, as the interference from this surfactant can be minimized using this technique. Comparison of the relative UV-absorbance at two wavelengths (214 nm and 280 nm) is another strategy that has been shown to improve sensitivity (20).


	Analytical ultracentrifugation (AUC) employs a high-speed centrifuge equipped with a rotor with various cell compartments. AUC can be operated in two different modes: sedimentation velocity and sedimentation equilibrium. In terms of using AUC as an orthogonal method to SEC, one is primarily concerned with sedimentation velocity measurements, even though it will be denoted as AUC in this review. In sedimentation velocity mode of operation, samples are spun at high rates of speed, with larger species sedimenting to a greater degree than the smaller ones (21). The velocity and shape of the moving boundary is used to estimate the sedimentation coefficient, which can then be related to molecular weight once shape information is obtained or assumed (8, 22). Even though the resulting distribution of various size species looks somewhat like a chromatogram, these profiles are the outcome of mathematical modeling and thus are not a direct measure of content, as is the case with chromatographic methods. The ability to analyze and interpret sedimentation velocity analytical ultracentrifugation (SV-AUC) data has no doubt been facilitated by newer software algorithms, such as SEDFIT (23, 24). More details about AUC methodology can be found in numerous review articles (9, 21, 25).

	As with any analytical method, there are advantages and disadvantages to AUC (

) (9). The resolution of oligomeric species, such as dimers and trimers from the monomer by AUC, appears to be better than it is for SEC or AF4. Consequently, this can be considered to be a significant advantage of the SV-AUC technique. At the same time, AUC can measure species as large as several hundred million Daltons in molecular weight (26). The ability to make measurements without the dilution effects characteristic of SEC is worth noting (

). It should also be pointed out that one can often make accurate determinations of aggregate content by AUC directly in the formulation buffer.

	One disadvantage of AUC compared to SEC is its higher limit of detection (LOD). The LOD issue was examined by Pekar and Sukumar (27), where they found the LOD of AUC was about three times higher than that of SEC. Another disadvantage of AUC is that excipients such as sugars and polyols can create density gradients, which can increase the limit of quantitation (22). These factors may cause one to underestimate aggregate levels, but there are modeling approaches that may help account for these effects (22).

	The greatest overall disadvantage of AUC is its low throughput, as samples must be spun for many hours to reach equilibrium. Additionally, proper analysis of AUC data requires a significant amount of time and experience, which limits throughput as well. While newer software algorithms have improved the ease of use, the long data collection and analysis times required for SV-AUC result in relatively few samples being analyzed compared with AF4 or SEC.


	There have been some noteworthy direct comparisons of AUC and SEC for aggregate quantitation. For example, the two methods, when used for measuring aggregates of ∝-glucosidase, are correlated (28). In this particular study, however, the authors note that the detection limit for SEC is much better than AUC, with a LOQ that was near 3% aggregate for AUC and 0.2% for SEC. In another study, SV-AUC and SEC were comparable when measuring dimer levels in three different protein samples which had dimer contents ranging from 1% to 12% (29). In this same study, the two methods produced analogous results for a highly aggregated sample; the aggregate content was 17.2% for AUC and 17.9% for SEC (29). When aggregate contents are low, it appears that the orthogonal methods tend not to agree, likely because the techniques separate aggregates by different principles and across different size ranges. However, as the aggregate content increases, the numbers become more similar, although some exceptions to this trend have been reported (8).

Asymmetrical-Flow Field-Flow Fractionation


	The second, predominant orthogonal method to SEC is asymmetrical-flow field-flow fractionation (AF4). A number of articles on AF4 have now been published (30-33).

	Since AF4 separates protein species in an open channel, concerns over analyte adsorption to packing material (such as that which is present in SEC columns) are largely eliminated (

). However, adsorption of analyte to the membrane used in an AF4 system is still a possibility (34, 35). Separation in an AF4 system is achieved by applying a cross-flow perpendicular to the direction of sample/analyte flow in the AF4 channel. Upon application of the cross flow, analytes accumlate near the semipermeable membrane and the lagging edge of the channel laminar flow. Because low molecular-weight species have larger diffusional coefficients than high molecular-weight species, they diffuse more readily into the faster moving region of the laminar flow (farther above the membrane), and thus, have faster elution times than larger species. As with HPLC methods, the cross flow can be programmed to be constant or applied in a gradient fashion, which allows one to fine-tune resolving power for a given set of analytes. The relative effects of various operational parameters in AF4 on peak shape and position have been described in some detail by the existing literature (32). There has been at least one report on the effect of mobile-phase composition on the separation of proteins (36), but this aspect has been largely overlooked to date. AF4 can be run with a wide variety of mobile phases, and an AF4 separation in the actual formulation buffer can also be conducted.


	For a long time, the lack of commercial instrumentation hindered further development of AF4 as an orthogonal method. With the advent of vendors providing AF4 instruments (e.g., Wyatt Instruments, Postnova), the field has developed rapidly over the past decade. During this time, studies using AF4 to characterize higher-molecular weight species, such as nanoparticles (40, 41) and protein aggregates (40), began to appear in the literature.

	Some of the first comparisons of SEC and AF4 were quite striking in their differences, in that aggregates levels measured by the two techniques varied quite significantly (42). One example of this from the literature involves the measurement of aggregates in a granulocyte colony-stimulating factor (G-CSF) sample (43). While SEC determined the G-CSF samples contained <3% aggregate, AF4 found as much as 49% aggregate. Different instrumentation or protocols could have the potential to change these estimates of aggregate content, but this is purely speculative and remains to be demonstrated.

	The earliest example of a comparison of SEC and AF4 was published more than 20 years ago (44), before AF4 was commercially available. In this work, a mAb was evaluated by both techniques. The authors showed that the precision of AF4 was not as good as SEC. As for quantitation of aggregates, SEC measured an aggregate content approximately half of that determined by AF4 (11.2% by SEC compared with 23.3% by AF4 for one mAb, 7.1% by SEC compared with 15.6% by AF4 for another mAb). The reasons for these differences were not discussed, but they could have arisen from variations in mobile phase composition, or they may reflect the differences in the mechanism of separation between SEC and AF4. In another study, where a mAb was exposed to UV light, both AF4 and SEC were used to measure loss of monomer and appearance of fragments and aggregates (45). In this study, it was determined that the two methods were comparable, but AF4 was less effective than SEC at quantifying fragments (46).

	A comparison of SEC and AF4 on stressed IgG formulations found that AF4 detected fewer dimeric species than SEC when samples were unstressed or heated to 70º C. When the temperatures were increased to 80º C, however, where aggregation was significant, the SEC method underreported high molecular aggregates relative to AF4 (18).

	In another study examining severely heat-stressed mAbs, AF4 was found in every case to provide better separation and more complete recovery of the sample than SEC (38), however, AF4 underestimated the level of fragments relative to SEC. In a final aggregation study comparing SEC and AF4, it was found that a highly aggregated mAb sample had similar, but not identical, aggregate levels with the two techniques (29.8 % by SEC and 26.0 % by AF4) (32).

	A limited number of studies have evaluated all three methods (SEC, SV-AUC, and AF4) simultaneously. In one such study, all three methods were used to examine aggregate contents of mAb samples stressed under a variety of different conditions (47). For unstressed material, the aggregate content by SEC was found to be 0.4%, while it was determined to be 4.2% by AUC, a difference of more than an order of magnitude (47). The aggregate content found using AF4 was 2.4%, a value in between those found with the other two methods. However, when the samples were subjected to heating, the aggregate content levels became much more similar across all three methods (values ranged from 15% to 17% aggregate). It is possible that some of the differences seen between the various methods could be attributed to the shape of the aggregates, because shape, as with end-to-end assembly, affects the mechanism of separation and how the aggregates are sized by each method. Finally, the lower precision of AF4 compared with SEC was another likely cause for the difference in aggregate levels measured by the two methods.


	The precision and accuracy of AUC and AF4 have evolved to the point where they can be used as orthogonal methods to SEC to determine the aggregate content of protein pharmaceuticals. Other orthogonal methods have been explored, but their use is not as routine or the methodologies not as robust as AUC and AF4. As the case studies in this review illustrate, AUC and AF4 may provide different estimates of the extent of aggregation relative to SEC. While the reasons for the differences may not always be obvious, they do allow one to obtain additional insight into the stability of a product as well as serve as added methods to assess purity and quality. As regulatory agencies continue to request information above and beyond SEC data, there will be an increasing need for these orthogonal methods to be refined and employed. Finally, as more case studies appear in the literature, the context for proper interpretation of the results will become more clear.


	Ryan R. Manning is president, Great Lakes Bio Design LLC; Ryan E. Holcomb is scientist, Legacy BioDesign LLC and research associate, department of chemistry, Colorado State University; Glenn A. Wilson is president, West Coast BioDesign LLC; Charles S. Henry is professor of chemistry, department of chemistry, Colorado State University; and Mark Cornell Manning is chief scientific officer, Legacy BioDesign LLC and affiliate faculty, department of chemistry, Colorado State University (corresponding author). Email: manning@legacybiodesign.com; Phone: 001-970-231-9744.


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When referring to this article, please cite it as R. Manning et al., "Review of Orthogonal Methods to SEC for Quantitation and Characterization of Protein Aggregates," 

Peer-Reviewed Research

The use of orthogonal methods to SEC is discussed and examples are presented showing how analytical ultracentrifugation, AF4, and SEC compare in aggregate quantitation.

Review of Orthogonal Methods to SEC for Quantitation and Characterization of Protein Aggregates

	When a biopharmaceutical and life-sciences (PLS) company encounters a quality issue, FDA warning letters and consent decrees are usually addressed directly to the chief executive officer (CEO), explicitly placing the responsibility for quality with the head of the organization. The typical PLS CEO, however, has neither the background nor the tools available to sufficiently address quality--especially at the level of regulatory oversight.  Responsibility in the absence of tools or background is a precarious position that the PLS industry needs to meet head on.
	
	At its core, this situation stems from the historical fact that the life-sciences industry often perceives quality management systems (QMS) as compliance-driven rather than as an effective process to realize continuous improvement in product and process quality. This was the case dating back to 1987, when the International Organisation for Standardisation (ISO) developed the original QMS framework--ISO 9000.  While the PLS industry never fully embraced ISO 9000, over time different regulatory agencies in the PLS space created various QMS frameworks to fit their own purposes.
	
	In this environment, current QMS standards have not kept pace with a growing variety of products and technological complexity. In many instances, the high cost of change and the associated regulatory approvals deter companies from implementing quality improvements. Further complicating matters, companies typically have separate quality management systems across the GxP lifecycle spectrum and, because of acquisitions, across divisions as well. As a result, current QMS frameworks are complex and not scalable.
	
	Companies that have been hit by regulatory action are often keenly aware of the technical issues at hand, and, in many cases, they have tried to implement solutions. Those solutions, however, often fall victim to organizational resistance, lack of resources or funding, or management’s insufficient understanding of the importance of establishing a “quality first” culture. At the end of the day, the C-suite must own quality issues and take appropriate action when problems arise.
	A new QMS framework is needed to inject heightened effectiveness and efficiency into the industry quality processes. To meet this challenge, PricewaterhouseCoopers (PwC) proposes QMS 3.0, a holistic solution that provides the tools CEOs need to take control of quality matters and significantly reduce the corporate risk associated with noncompliance.


	Forward-looking members of the C-suite know that QMS is ultimately a culture rather than a regulation. QMS 3.0 recognizes the power of executive management to promote a positive quality culture. It elevates technical regulations from the realm of scientists, clinicians, regulators, engineers, and production operators to the C-suite and board level. Because it is driven by executive management, QMS 3.0 promotes accountability throughout the entire company. Ultimately, it is about driving culture change to achieve quality excellence. Linking compliance with product quality, operational performance, business results, and patient safety is the first step toward achieving a strong corporate quality culture.
	
	At its core, QMS 3.0 aims to simplify the quality management process by promoting executive responsibility and leadership and ensuring a mutual understanding of quality measures and goals across the industry. From this perspective, QMS 3.0 is similar to the financial budgeting process, which allows executive management to “own” the financials without getting into the specifics. This new approach to PLS quality control encourages executive management to align its business interests and quality objectives. Doing so helps companies reap the most from their quality-control investments by reducing compliance risks and avoiding potentially costly fines and remediation efforts--all to the benefit of patients and stakeholders alike.
	
	A next-generation, industry-wide QMS framework holds the potential to help standardize quality in an industry that has become too complex for the patchwork systems that currently attempt to govern it. This new framework (see 

) should, at a minimum, accomplish four objectives:
	
	• Emphasize the alignment between compliance, product quality, business performance, and, ultimately, patient safety
	• Focus on end-to-end process improvements rather than just having procedures in place
	• Become a tool for executive management to drive quality
	• Create a single, integrated QMS framework across GxP that becomes the standard for all industry segments and regulatory agencies.
	
	To realize such a goal, regulators and the industry need to work together. But companies’ executive management must lead by example and promote quality as part of the corporate culture that governs individual organizations.
	The benefits of QMS 3.0 include the following:
	
	• It creates a culture of driving improved patient outcomes as well as business benefits by aligning quality, compliance, and operational improvements.
	• It emphasizes controlling end-to-end processes and measuring a balanced set of metrics, rather than focusing on individual standard operating procedures (SOPs).
	• It provides the tools for executive management and the business to “own” quality and drive continuous improvement, just as budgets are a tool to manage financial performance.
	• It is a next-generation framework that integrates various quality management systems across GxP and industry segments to create a single, simplified quality structure without replacing current regulations.
	
	


	The QMS 3.0 framework that PwC proposes has four elements: strategy and governance, culture and organization, processes and procedures, and tools and infrastructure (see 

). As companies grow in maturity in their approach to QMS, these elements build upon one another. The strategy and governance and culture and organization elements are cultural in nature, while the processes and procedures and tools and infrastructure elements are more technical. While the four elements are not unique by themselves, QMS 3.0 emphasizes the integrated nature of the elements required to ensure a patient-centric approach.  


	The approach that QMS 3.0 takes toward strategy and governance represents the biggest difference between QMS 3.0 and the earlier generations of quality management. Strategy and governance is the most important link between executive management and a company’s quality organization. While clinicians, scientists, and operators affect quality on a day-to-day basis, QMS 3.0 elevates quality and translates it into a language that management can understand and apply. When a company is struggling with quality management, this element is typically the weakest one.
	
	


	One of the main factors resulting in poor quality control is an overemphasis on business performance without the counter-balance of stressing quality. Management may communicate and reward the achievement of quarterly financial numbers and yet be silent on quality matters, for example. Employees may interpret that silence as a justification to cut corners on quality issues. Instead, management must regularly demonstrate its willingness to make difficult decisions to ensure a positive quality culture (and, ultimately, patient safety) by prioritizing quality over financial performance.
	
	


	Traditionally, companies have focused on SOPs to anchor their quality initiatives. QMS 3.0 focuses instead on end-to-end processes (see 

). Only end-to-end processes can be analyzed for critical control points to drive measurable improvements in both quality and operational performance. A focus on end-to-end processes also allows companies to establish business process owners who can drive continuous improvement across a company’s various functions and divisions. With solid processes in place, companies can reduce and simplify their number of SOPs while also improving quality. Well-vetted processes can align business interests with quality objectives.
	
	From the process and procedure perspective, QMS 3.0 articulates three subsystems to integrate the various quality system frameworks in existence (see
	

). Rather than having six or seven subsystems at various levels of detail, the QMS 3.0 framework has three subsystems of equal magnitude: management controls, lifecycle controls, and operations controls. These subsystems do not introduce any new regulations; rather, they logically restructure regulations that already exist. Not incidentally, this framework is easier to communicate to (and is better understood by) executive management.
	
	


	It is in this foundational element that all of an organization’s actual work is conducted. Whether it is a scientist in a lab, an engineer using computer-aided design (CAD) systems, a physician evaluating a patient, or an operator turning valves on a bioreactor, everyone needs tools and infrastructure. The facilities, equipment, and IT systems that make up a company’s tools and infrastructure work together to design, manufacture, test, document, and evaluate the output of their work processes. In the process, employees collect, approve, store, and manage objective evidence.
	
	


	Although QMS 3.0 does not introduce any new regulatory requirements, it does introduce the necessary processes that enable a company’s executive management to own its quality systems. In this way, it is analogous to a company’s financial planning and budgeting process. The planning and budgeting performed by a company’s financial department enable executive management to plan for the future, establish financial targets, manage revenue, and control spending without having to monitor every financial transaction.
	
	Financial regulations and accounting rules can vary significantly from country to country and industry to industry, but financial planning and budgeting can easily adapt to those differences. Similarly, QMS 3.0 allows management to oversee quality without getting mired in variations among regulations for different technologies and countries. While the finance department “owns” the budgetary process, management owns the budget itself, making it ultimately responsible for a company’s financial performance. Similarly, while a company’s quality unit facilitates the quality control process, executive management assumes ultimate responsibility for quality itself. Yet not many managers understand what that means to them.
	
	Management can use QMS 3.0 as a means to drive compliance and quality objectives without needing to be involved in the details of quality control. Just as a company typically has a three- to five-year financial plan and an annual budget, it should also have a three- to five-year quality plan with annual quality objectives. And just as a company’s management reviews its budget plan on a quarterly basis, it should review its quality objectives just as frequently. Budget reviews drive managers to adjust their financial decisions regularly to increase revenue or cut costs. Similarly, quarterly quality reviews can drive management to implement and adjust continuous improvement efforts as necessary.
	
	


	The introduction of a new quality system can often spur a wave of batch rejects and recalls. Over time, however, the new controls are likely to cause the number of adverse events, recalls, batch rejects, and overdue medical device reportables to decrease. It can also require a significant investment as companies revalidate their products and processes and implement new organizational capabilities, cultural changes, procedures, and IT systems. Ultimately, these efforts likely pay for themselves in the form of reduced compliance risks, decreased quality costs, and improved efficiencies.
	While risk reduction is a major benefit of QMS 3.0, once implementation efforts have had a chance to “mature,” the new system can drive improved efficiency, higher-quality products and processes, and additional business benefits. The operational improvements catalyzed by QMS 3.0, for example, can be measured in terms of improved product yields, reduced batch release cycle time, reduced last-patient-out to database lock cycle time, and reduced number of complaints and recalls. Businesses can quantify these operational improvements, which in some cases produce a competitive advantage and increased market share.
	
	This next generation QMS 3.0 is a framework that incorporates the legacy of QMS while also moving ahead to meet the marketplace’s new challenges. QMS 3.0 builds on the industry’s major improvements in quality and compliance over the years to define the next generation of quality management. It provides a common management framework across all the components of GxP throughout an entire company. It allows for technical differences across regulations while also recognizing that it is possible to standardize the management of quality. When it is fully implemented, management can use the QMS 3.0 framework to establish quality objectives, set targets, and monitor progress over time.
	
	QMS 3.0 also has intangible benefits. Because it is driven by executive management, it promotes accountability at the C-suite level as well as throughout the entire business. It creates a common language within and among regulatory agencies, quality experts, and functional managers, simplifying communications among them and ensuring common objectives are understood and me.
	
	


	Jan Paul Zonnenberg is a Principal in PwC’s Health Industries practice.

	ALL FIGURES COURTESY OF THE AUTHOR 
	
	

: When referring to this article, please cite it as J.P. Zonnenberg, "A Next Generation of Quality Management,"

Quality Management

The author proposes a quality management system that uses the power of executive management to promote a positive quality culture.

A Next Generation of Quality Management

 contributing editor Cynthia Challener about the challenges associated with establishing residue limits for cleaning process validation in the biopharmaceutical industry.
	
	

Challenges of establishing residual limits

: What are the challenges that companies face today when establishing residual limits for cleaning process validation of biopharmaceutical manufacturing processes?
	

LeBlanc (Cleaning Validation Technologies)

: The fact that biotech actives are almost universally degraded by cleaning processes using hot, aqueous, alkaline cleaning solutions is the main challenge. The residues left after cleaning are not the native protein (the API), but rather degradants of that protein. It is generally believed that those degraded fragments are less of a hazard (or no worse a hazard) than the native protein, in part due to the immunotoxicity of proteins, which is known to be a function of molecular weight (smaller molecular weight proteins are of less concern). Because of the degradation issue, some companies will actually perform laboratory simulations to measure degradation that may include evaluations to identify smaller fragments (using sodium dodecyl sulfate polyacrylamide gel electrophoresis [SDS-PAGE]) and/or a biological activity test to confirm that the degradants are not biologically active in the same manner as the native protein. The unknown question is whether those fragments are associated with some new toxicity concerns. There is no simple and practical way to answer this question, unless the structure of the API itself can explain the concerns related to the degradants.
	
	Separately, the use of carryover calculations on the bulk manufacturing side of biotech is problematic. Total organic carbon (TOC) and total protein analyses are used for biopharmaceutical cleaning process validation because a specific analytical method for residue determination is not appropriate due to the fact that API residues are degraded. If the total surface area of the equipment train is utilized, however, the ratio of the batch size to the surface area drives limits so low that they are not measureable using these techniques. This issue can be balanced by the fact that it is a reasonable scientific expectation that residues from earlier cleaning steps following fermentation and harvesting will be removed by the various chromatographic purification processes used in downstream processing. For this reason, many companies choose to do a carryover calculation for bulk manufacture based on the equipment surface area after purification. In carryover calculations of this type, one assumes that all of the TOC (if that is the analytical method) is due to the native protein, even though it is known that what is being measured are degraded fragments of that protein and other organic materials.
	
	It has been my belief, however, that the major risk on the bulk side of biotech is not that residues will carry over to the next product and cause a safety concern, but rather that residues will carry over and interfere with the manufacturing process and cause problems, such as a low yield or contamination of the product with extraneous proteins.
	
	

: Have the challenges changed over the past decade or so?
	

: The newer challenge is setting limits based on a toxicological evaluation, such as the establishment of Acceptable Daily Exposure (ADE) limits to support the Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) issued by the International Society for Pharmaceutical Engineering (ISPE) and the Permissible Daily Exposure (PDE) limits established by the European Medicines Agency (EMA). In one sense, setting limits doesn’t make things any easier or any more difficult, because the degraded fragments that are the residues can still carry over to the next product. However, it is still difficult to relate toxicological measurements of the native protein to real safety concerns presented by the residues, which are the degraded fragments.
	
	

: What are the best strategies for overcoming these challenges?
	

: The best strategy for overcoming these concerns is to perform adequate degradation studies in order to demonstrate that degradation does, in fact, occur. When I bring this up to protein chemists, they generally say that the proteins are degraded from hot aqueous, alkaline, cleaning solutions. They are correct, but it is better to have data that demonstrate that degradation has occurred and the degree of said degradation (molecular weight), as well as data to confirm the lack of biological activity of the proteins (or, at least, the same biological activity as the native protein). A second method for dealing with the “soft” manner in which limits for bulk biopharmaceutical cleaning process validation are set is to establish action/alert levels for TOC or conductivity as part of the routine monitoring of every cleaning event. Such action levels are considered to be part of what  FDA calls “continued process verification” in its process validation guidance (1). These actions can be implemented in order to establish a process capability with trend charts, which can in turn help demonstrate that the cleaning process remains in a state of control.
	
	

: If inappropriate residual levels are selected, what are the potential consequences? What are the best strategies for dealing with inappropriate residual levels?
	

: If inappropriate residue levels are selected for validation protocols, it may lead to production issues for the next product, safety issues with the next product, and/or regulatory inspection issues. The best way to avoid such situations is to stay current with the issues related to cleaning validation in general, and cleaning validation for the biotechnology industry specifically. Using the available resources (such as PDA’s Technical Report #49,

 Points to Consider for Biotechnology Cleaning Validation

 (2), it is possible to design an approach to reduce the safety risk to patients and the business risk to manufacturers of excessive residual levels.
	
	

: Has the shift to smaller, more flexible manufacturing facilities that produce multiple products had an impact on the risk of residues?
	

: The shift to smaller manufacturing facilities has, to my knowledge, been more related to process development and to the fact that more concentrated proteins can be prepared. It has also been tied to the use of disposable (single-use) equipment, which for a development project can shorten the timeline and reduce capital costs. Of course, there are issues with these options, such as extractables and leachables, that require careful consideration. The use of disposables does, however, remove the need to do cleaning validation, although a cleaning and/or decontamination step may still be required for proper disposal.
	
	

Guidance for Industry, Process Validation: General Principles and Practices

Performing degradation studies is the best strategy to evaluate toxicity risk.

BioPharm International-12-01-2014

The Biopharma Working Life

FDA Realigns Drug Inspection and Manufacturing Oversight

Year in Review: Key Outsourcing Trends

Improving PAT for Biologics

Job Security and Salaries Trend Upward

Review of Orthogonal Methods to SEC for Quantitation and Characterization of Protein Aggregates

A Next Generation of Quality Management

Degradation, Carryover, and Toxicity Assessment Challenges in Process Cleaning Validation

Purification Resin Increases Efficiency

BioPharm International, December 2014 Issue (PDF)