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BioPharm International, September 2011 Issue (PDF)

The United States may be in danger of losing its leadership position in biopharmaceutical research due to certain regulatory policies and reductions in reimbursement for new breakthrough therapies. Prescription-drug user fees are scheduled for reauthorization by Congress next year, and all parties anticipate a push for new policies to improve the drug-approval process. Although the broader goal is to spur biopharmaceutical research and new drug development, manufacturers fear that cost-cutting efforts by the Obama administration and Congress will curb resources for FDA and squeeze drug-payment policies. The rhetoric is heating up as industry moves to deflect measures it fears will limit support for discovery and for regulatory oversight of new medical treatments. 

A main message from pharmaceutical companies is that US policies that undermine investment in biopharmaceutical innovation will prompt manufacturers to shift R&D to more hospitable climes. The European Union's Innovative Medicines Initiative has earmarked $2 billion to fund collaborative research projects and build expert networks to support pharmaceutical innovation in Europe. The Chinese government is targeting the biopharmaceutical industry as part of a five-year economic development campaign, which includes providing $1.5 billion to invest in startup companies.  

At a press briefing in July 2011, John Castellani, president of the Pharmaceutical Research and Manufactures of America (PhRMA), explained how the biopharmaceutical industry has thrived in the US because of policies that protect intellectual property, support scientific research, and place a high value on medicines. Now, other countries, such as Germany and France, want to attract back biopharmaceutical firms, he warned. At the same time, Singapore and other emerging economies have identified the biopharmaceutical sector as crucial to their economies. Merck President Kenneth Frazier similarly observed in a 

 op–ed in July, that the designation of the US as the "medicine chest to the world" and its claim to be home to 82% of the world's biotech R&D activity will be undermined if the federal government imposes price controls on the Medicare drug program and establishes the Independent Payment Advisory Board (IPAB) (1).  

The price controls mentioned by Frazier refer to additional rebates on drugs covered by the Medicare Part D drug benefit, specifically those medicines consumed by low-income seniors who previously obtained medicines from state Medicaid programs that negotiate rebates with pharmaceutical manufacturers.  The shift of those "dual eligibles" to Part D plans eliminated those rebates, and industry critics, led by Rep. Henry Waxman (D-CA), have been pressing to recoup this pharmaceutical  "windfall" for several years.  

The Congressional Budget Office (CBO) estimates that rebates on drugs for some 10 million seniors who receive low-income subsidies under Part D would save $112 billion over the next decade, or $10 billion a year. That's a big number that will be hard for budget-cutters to ignore.  

PhRMA is fighting the rebate policy and other actions with analysis claiming that the policy could prompt biopharmaceutical companies to shift operations, and thus US jobs, overseas. A Battelle study for PhRMA calculates that a $10-billion reduction in on industry revenues would kill 130,000 high-paying jobs, thereby exacerbating the nation's already high unemployment rate.  

Even more troubling are suggestions that the rebate plan could destabilize the Part D program which has been a huge success in providing less costly medicines to seniors. Another report for PhRMA by the IMS Institute for Healthcare Informatics documents how Part D has led to lower spending on medicines for seniors. More important, a separate study published in the Journal of the American Medical Association finds that increased use of prescription drugs due to the Medicare drug benefit significantly reduced medical spending by seniors on hospital and nursing home care (2). Medicare reports that the program's total cost is 41% less than initial CBO estimates, partly because plans have negotiated hefty discounts from manufacturers. Layering on another level of rebates, says PhRMA senior vice-president Rick Smith, would be "a double whammy."  

If a Part D rebate plan does not end up in Medicare cost-cutting proposals as part of broad deficit-reduction legislation slated to come before Congress, it will be on the list of pharma-related reforms included in next year's legislation to reauthorize the Prescription Drug User Fee Act (PDUFA V). After a year of consultation with industry and other stakeholders, FDA officials and manufacturers reached a new PDUFA agreement this past spring; it faces further public discussion before it is formally transmitted to Congress in January 2012. The current user-fee program expires on Sept. 30, 2012, and a new program has to be in place before then in order for FDA to be able to continue collecting industry payments, which now support more than 60% of the cost of the approval process for new drugs and biologics.  

Members of Congress already are gearing up to add a range of pet programs to the user-fee legislation. A number of drug-related policies calculated to generate savings for government health programs will include bills to legitimize drug reimportation, reduce exclusivity for biosimilars, and curb brand–generic patent settlements. There will be a strong push to extend steep 340B discounts on drugs used by safety-net hospitals  to include inpatient treatment and orphan medicines.  

The basic PDUFA proposal is not radically different from the current user-fee program and by itself should win Congressional support fairly easily. FDA is looking to boost user-fee revenue by about $40 million per year, according to FDA  Director of the Center for Drug Evaluation and Research (CDER)  Janet Woodcock's testimony to the Energy and Commerce Committee—that's a "modest" 6% annual increase that will bring in nearly $700 million in fiscal year 2013. The most notable change gives FDA an extra two months to review applications, here in the guise of a 60-day "administrative filing period" after submission of an application; this timeframe will permit agency reviewers to fully vet the filing before starting the official review clock.  

More meetings will take place between reviewers and sponsors, with a new cadre of FDA liaison officials to enhance communications. FDA will assess meta-analysis methods, biomarkers, and patient-reported outcomes measures to improve clinical studies. The plan also calls for standardizing risk evaluation and mitigation strategies (REMS); boosting FDA's Sentinel system to improve postmarket drug-safety surveillance; and implementing an electronic submissions system for clinical data, something that has been in the works for years.  

Along with PDUFA, FDA and manufacturers are working on a new user-fee program for generic drugs, while also discussing a formula for fees for new biosimilar-product applications. Support for renewing pediatric-drug development and research incentives is strong, preferably on a permanent basis. The aim is to move away from the five-year sunset-and-reauthorization process linked to PDUFA for the Best Pharmaceutical for Children Act and the Pediatric Research Equity Act to encourage more pediatric product development.  

The Medical Device User Fee Act (MDUFA) also is up for renewal, and negotiations on that program have been much more contentious than those for drugs. FDA is embroiled in evaluating proposals for overhauling its 510k regulatory process for low-risk devices, which has device makers up in arms. A recent Institute of Medicine (IOM) report advises FDA to find a better way to assess the safety and efficacy of these products, an approach that industry feels will stymie medical device innovation and product development. FDA has to reduce fees for 2012 because it collected too much from industry this year. This situation, along with the larger device regulatory issues,  has not smoothed the process for negotiating future fees. 

As the PDUFA legislation emerges, pharmaceutical companies are looking to line up behind a number of drug-related measures, such as proposals to boost incentives for the development of new antibiotics and to update FDA's orphan-drug program. Industry backs efforts led by Rep. John Dingell (D-MI) to strengthen oversight of imported drugs and active ingredients, with added FDA authority for recalls and import controls and required registration and fees on foreign manufacturing facilities to cover the costs of overseas inspections. Companies also support Republican-backed efforts to make REMS requirements less burdensome and to revise FDA conflict-of-interest policies that exclude many qualified experts from seats on FDA advisory committees.  

The Biotechnology Industry Organization (BIO) recently unveiled its own wish-list of policy changes to spur biotech R&D. BIO wants to make FDA an independent agency, more like the Federal Trade Commission, and to depoliticize it by appointing the FDA commissioner to a fixed six-year term, separate from the presidential election cycle. BIO wants to require FDA to tell sponsors specifically why it's not approving an application, and also proposes a conditional or "progressive" drug-approval procedure that permits therapies for diseases that lack any effective treatment to come to market on a limited basis while the sponsor completes clinical studies. The list also includes reviving the Reagan–Udall Foundation, an independent research organization established by the FDA Amendments Act of 2007, but never funded by legislators.  

FDA laid out its goals for user-fee renewal legislation at House and Senate hearings in July 2011. FDA Commissioner Margaret Hamburg outlined for the Senate Health, Education, Labor, and Pensions (HELP) Committee how user fees support patient access to new drugs and medical products. Panel leaders expressed strong support for renewing user fees for drugs and devices, hopefully by next spring. But Sen. Richard Burr (R-NC) threatened to block PDUFA reauthorization if FDA doesn't change its approval process for medical devices. Hamburg acknowledged that devices raise problems, but blamed approval delays on poor quality applications that require reviewers to ask manufacturers for additional data not found in the original filing.  

Woodcock provided the House Energy and Commerce Health subcommittee with a fairly positive report on FDA's drug approval process, describing how proposed PDUFA V enhancements will further address drug access and safety issues. Most Democrats and Republicans praised the fee program, as did industry and patient representatives. 

Energy and Commerce Committee Chairman Fred Upton (R-MI) laid out top Republican concerns: REMS requirements may be thwarting new drug development, and "rigid and unrealistic" conflict-of-interest policies keep top scientists off advisory committees, thus preventing these panels from vetting new drug candidates in a timely manner. Marc Boutin, executive vice-president of the National Health Council, backed conflict-of-interest policy changes, noting that the rules have created "alarming" committee vacancy rates.  

Woodcock credited the 20-year-old user-fee program with establishing a more efficient, predictable drug approval process that has sped up the review process for new drugs and biologics "without compromising the agency's high standards for demonstration of safety, efficacy, and quality of new drugs." FDA has provided patients with access to more than 1500 new drugs during the past two decades, she commented, including important cancer therapies that a recent study shows are available to US patients before reaching the market in Europe.  

Woodcock also reported that FDA is on track to approve more new medicines in 2011 than in recent years, with 20 new drugs already okayed at the mid-year point;  the number rose to 21—the 2010 total—soon after when FDA added AstraZeneca's Brilinta to the list. Woodcock also noted that CDER's rate of first-cycle approvals for priority new molecular entities (NMEs) is going up, citing recent action on landmark treatments for hepatitis C and for late-stage melanoma. And she noted how the REMS program can facilitate access to high-risk products, such as a new thyroid cancer treatment that FDA approved with a REMS to limit product use to truly needy patients.  

The real problem, she said,  is not slow approvals, but that too many experimental drugs continue to fail during development. PDUFA support for more FDA–sponsor meetings will help, along with added resources to develop further guidance and new methods for testing and evaluating experimental drugs.  

Many of these undertakings are included in a CDER report identifying science and research needs that can enhance the development of new drugs and biologics. This July 2011 publication from CDER's Science Prioritization and Review Committee builds on the Critical Path Opportunities reports of 2004 and 2006 in citing research projects that FDA would like to pursue, ideally in partnership with industry, academia, or other government agencies (3). The topics include ways to improve analysis of postmarket data, product-quality assessment, clinical trial design, and individualized treatments.  

Washington editor, Chevy Chase, MD, 301.656.4634, 

 3.  CDER Science Prioritization andReview Committee, "Identifying CDER's Science and Research Needs Report," (FDA, Rockville, MD,  July 2011). ? 

Regulatory Beat

PDUFA renewal legislation sets stage for new policies affecting revenue, research, and oversight.

Manufacturers and FDA Gear Up for User-Fee Action

The biopharmaceutical industry relies on change to make progress in a commercial environment that simultaneously demands higher productivity, higher quality, and lower costs (1). Recombinant protein titers have improved from tens of milligrams to more than 10 grams per liter during the past 20 years, and at the same time, batch volumes have increased so that industry faces the real prospect of batch yields exceeding 100 kg of protein in the next decade (2). Over the same period, regulatory demands have become more onerous, and the pressure to reduce costs has increased as more biopharmaceuticals come off patent and overseas manufacturers begin to take an interest in Western markets (3, 4). Indeed, the unthinkable is increasingly becoming inevitable—biopharmaceuticals will at some point be regarded as commodities, and manufacturing on the ton scale will be necessary for certain products that are required in large, repetitive doses, such as topical antibody formulations. 

There is no doubt that progress in the industry has been impressive, but the polished bodywork of bioprocessing hides an engine of despair that groans under the strain of current demands. Most of the increases in productivity that have been achieved in previous decades have resulted from improvements in the upstream production phase, with more efficient bioreactors and better media formulations sharing the limelight with cell lines that are intrinsically more productive due to the development of more effective screening technologies to identify the most productive clones (5). Downstream processing is now routinely found to be the bottleneck in biopharmaceutical manufacturing because its capacity has not kept pace with upstream production (1). In some cases, the lack of downstream processing capacity can seriously affect the profitability of a new pharmaceutical product and even result in its failure. Manufacturers facing shrinking margins and less bountiful product pipelines are therefore looking for opportunities to increase the efficiency of downstream processing without inflating the cost of goods sold. 

Perhaps the major challenge facing the biomanufacturing industry today is that downstream processing has no economy of scale (i.e., higher titers translate linearly into higher manufacturing costs) (6). Looking back, we can almost consider the first 15 years of biomanufacturing as a golden era, where manufacturers had the luxury of using inefficient processes because the product itself was far more important (3). Most biopharmaceuticals were required in small doses, and demand was sufficiently low to allow plenty of slack in the system. It was also pointless investing in process efficiency when any tweaks and modifications would arouse the suspicious eye of regulators. It was better to let sleeping dogs lie and be satisfied with the status quo. In this environment, innovation was considered a burden rather than a bonus. 

Inevitably, this relaxed attitude to process efficiency resulted in an immense amount of waste because up to 50% of product batches failed to meet specifications (3). To address this, FDA ordered that processes be designed with quality attributes taken into account (7, 8). The process was no longer a means to an end to achieve the product, but rather the process became part of the product. As the economic screws began to tighten and demand increased, manufacturers turned to the age-old strategy of scaling up their production to achieve cost savings. It was at this time that industry began to flounder.  

Whereas upstream production can be scaled up almost indefinitely by increasing the productivity of cells growing in a bioreactor, downstream processing has limits imposed by physics and chemistry. Downstream processing is driven by the mass of product. If one makes more product per batch, one needs correspondingly larger volumes of buffer, larger storage tanks, preparation areas, larger filters, and most importantly, larger amounts of chromatography media. For the production of antibodies (where Protein A resin is typically used in the primary capture step), the costs of scaling up are in some cases greater than the extra revenue made possible by the increased upstream productivity. Manufacturers find themselves in the paradoxical situation that there is no longer an economy scale in manufacturing, but rather an economic depression reflecting the physical limits that constrain the size of the apparatus used in separations (e.g. chromatography columns and the associated piping, skids, and buffer reservoirs). So far, the extra demand has been absorbed by contract manufacturers offering their spare capacity to fulfill quotas, but this is a short-term measure that cannot cope with the predicted increases in demand as industry faces hundreds of products in clinical development, all requiring at least pilot-scale manufacture according to GMP (9).  

How can this productivity dilemma be addressed? With constant scaling up no longer a viable approach, the sector must return to its roots and innovate to succeed. Three solutions are currently being considered by manufacturers, all inspired in some way by the more encouraging regulatory landscape that rewards rather than punishes innovation. This article examines several issues: the streamlining of existing processes, the revisiting of simple technology solutions currently employed in the bulk-chemical industry, and the use of innovative technologies from the biopharmaceutical research sector. These innovative technologies have the potential to introduce game-changing processing options into an industry still mired in technologies that were the state of the art 20 years ago. On a cautionary note, however, technologies from the research sector can fail, and the rash adoption of new and untested technology platforms can punish an eager company seeking innovative solutions. This is the new dilemma in downstream processing. 

STREAMLINING AND REDESIGNING EXISTING MANUFACTURING PROCESSES

Many processes for biopharmaceutical manufacturing were designed at a time where process efficiency was considered unimportant (3). More recently, manufacturers have sought to increase the efficiency of each unit operation, but they are only now starting to consider redesigning the entire process train to see whether cost savings can be made. The trend toward process streamlining owes a lot to FDA's quality-by-design (QbD) principles, which are derived from the design-of-experiments (DOE) concept. The design space of a manufacturing process is littered with efficiency peaks and troughs, but there is not always a simple path leading to the most efficient process. Therefore, process design incorporating efficiency and quality from first principles involves going back to the drawing board and evaluating the critical attributes that contribute to an efficient process. 

Most companies are applying these principles and actively streamlining their processing strategies wherever possible. Antibodies take center stage because they represent more than half of all biopharmaceutical products in development, and their common properties make it possible for companies to share process efficiency data that are applicable across platforms (10, 11). It is for this reason that antibody manufacturing has benefitted from the development of so-called generic platform processes, which are broadly similar for all antibodies but can be tweaked to match the specific properties of individual products (12).  

Antibody manufacturing provides an excellent example of the application of process redesign and streamlining principles to increase productivity, cut costs, and maintain product quality. Most manufacturers use three chromatography steps for antibody purification, starting with a very expensive Protein A capture step that is placed immediately after clarification, followed by anion exchange (AEX) chromatography in flow-through mode to extract negatively charged contaminants, such as host-cell protein (HCP), endotoxins, host DNA, and leached Protein A. Then, either cation exchange (CEX) chromatography or hydrophobic interaction chromatography (HIC) in retention mode is used to remove positively charged residual contaminants and product related impurities, such as aggregates and degradation products (13). Modern platform processes also serve as orthogonal strategies for virus removal. 

Realizing that no further cost savings could be gained by scaling up the above process, Pfizer explored the design space around the standard process and found that certain modifications could reduce costs considerably without affecting the quality of the antibody (14). The company introduced two types of process modifications, one in which the order of the polishing steps was reversed and another in which different separation technologies were used to increase process capacity (i.e., using membrane absorbers for the flow-through chromatography step and replacing the depth filtration step with continuous centrifugation) (15). These changes increased the efficiency of purification to such an extent that, for some antibody products, the cation-exchange step became unnecessary, reducing the process from three columns to two columns or even a single column. Not only did this save the direct costs of column resin and buffers, but also reduced the process time by > 45% which doubled the productivity in terms of batch processing (14).  

The capacity crunch in downstream processing has been avoided or overcome in other industries by adopting simple and inexpensive technologies (16). In bulk-chemical, conventional pharmaceutical, and food and detergent industries, expensive processing solutions, such as chromatography, would never be considered because the costs of implementation would not be sustainable in these high-volume, low-margin processes. This simple approach could be applied to biopharmaceutical manufacturing. 

Several recent developments suggest that simpler technologies could find a niche in biopharmaceutical manufacturing, particularly in the early processing steps where the complex mixture of particulates and solutes have the most potential to foul expensive membranes and resins (16, 17). Tangential flow microfiltration, depth filtration, and (continuous) centrifugation are the current methods of choice for the clarification of the feed stream, and one or more of these processes may be employed in series to remove larger particulates until finally a polishing depth filter or dead-end filter can be used to remove fines and thus reduce feed stream turbidity (18). Efficient and inexpensive clarification becomes more challenging with higher-titer cell culture processes because these are characterized by a greater cell density and often a longer process time, resulting in a higher solids content, more particle diversity (size and physical properties), and—most challenging of all—a greater proportion of fine particles that escape coarse filtration.  A technology that is widely used in the beverage industry and in wastewater processing is the use of  flocculants to link small particles together and create aggregates that are easier to remove. Flocculation is achieved using polymers that bind simultaneously to the surfaces of several particles through electrostatic interactions, creating larger particles that may sink under gravity, or may be removed more easily by centrifugation or filtration.  

In the bioprocessing industry, flocculation has been used to help remove whole cells from fermentation broth, but more recently it has also been used to remove fine cell debris and proteins. A simple and inexpensive strategy recently applied in antibody manufacturing is the creation of a calcium phosphate precipitate by adding calcium chloride to a final concentration of 30 mM and then potassium phosphate to a final concentration of 20 mM. Precipitation traps cell debris in larger particles, allowing removal by centrifugation for 10 min at 340 X g and yields a clear supernatant with the recovery of ~95% of the antibody (19). Interestingly, this strategy also removes some soluble host cell proteins and nucleic acids. Flocculation does not introduce any additional impurities to the feed stream because the flocculant is removed along with the aggregated particles. 

Precipitation is widely used as a purification approach in the bulk-chemical industry, and given that precipitation can be induced by simple changes in the environment, such as varying the temperature or pH, increasing the salt concentration (i.e., salting out), or adding organic solvents, it should be easy to apply the same principles in bioprocessing (20). Precipitation has therefore been used to remove soluble impurities from the feed stream during antibody manufacturing, and these solids can then be trapped by filtration or pelleted by centrifugation leaving a clear feed stream relatively enriched for the target protein (20). In an innovative adaptation of this approach, the antibody can be precipitated under mild conditions and recovered from a collected pellet, thus removing many contaminants in a single step (21). This is possible because the mild precipitation conditions allow the protein to be redissolved without loss of activity. Several groups have developed methods to precipitate antibodies in large-scale processes, and this method could replace Protein A chromatography in the long term (22, 23). Precipitation methods using 

-octanoic acid are used for the removal of contaminants in at least two industrial antibody manufacturing processes (24, 25). 

In the final purification steps, another traditional technology that is being considered for use in biopharmaceutical manufacturing is crystallization. Crystallization involves the separation of a solute from a supersaturated solution by encouraging the growth of crystals. The crystallization process involves the formation of a regularly structured solid phase, which impedes the incorporation of contaminants or solvent molecules, and therefore yields products of exceptional purity (26). It is this purity which makes crystallization particularly suitable for the preparation of pharmaceutical proteins, coupled with the realization that protein crystals enhance protein stability and provide a useful vehicle for drug delivery (27). Protein crystallization has been developed into a commercial technology for drug stabilization and delivery, and several current manufacturing processes involve crystallization including the production of recombinant insulin, aprotinin, and Apo2L (28). 

Although process redesigns and traditional technologies can contribute to the development of downstream processes, they provide only incremental improvements that marginally increase process efficiency. Incremental or evolutionary technologies have been the mainstay of the bioprocessing industry for the past 20 years, and column chromatography provides one of the best examples of this phenomenon in action (29). However, these slow marginal gains are already beginning to decline, and it is becoming difficult to envisage how sustainable processing can continue without a major injection of downstream-processing capacity.  

One way to address this concern is to embrace genuinely novel technological approaches that change the rules of the game. The fringes of the biopharmaceutical industry are populated by companies that survive on innovation, and some of these innovations are disruptive in the sense that their influence on the industry is unpredictable and could contribute to a radical change in bioprocessing. 

Most technological innovations in bioprocessing have been incremental, but there are several recent examples of disruptive innovations that have challenged the established business model and caused real grass-roots change in the industry. Again, many of these changes have affected upstream productivity first (e.g., disposable bioreactors and buffer/media storage bags), but we are also seeing examples in downstream processing (e.g., the introduction of simulated moving bed chromatography, expanded bed chromatography, monoliths, and membrane adsorbers) (1). These innovations have taken hold in niche markets but are now beginning to adopt mainstream positions. Disposable modules for downstream processing occupy a more mature status in the development cycle (30). The use of disposable filter modules is now an industry standard and where filters first left their footprint, membrane adsorbers are set to follow (31). 

Disposable membranes adsorbers are beginning to replace traditional chromatography in a number of settings, just as disposable membrane filters replaced steel mesh filters. Indeed, membrane filters have evolved into charged filtration devices that use the principles of both sieving and chemical selection to improve filtration performance, thereby creating a precedent for the use of membrane chromatography in downstream processing.  After a period of inertia, the benefits of membrane chromatography are now fairly well established, and manufacturers are willing to consider them as a genuine alternative to fixed columns rather than a step in the dark (32, 33). In contrast to resin-based flow-through processes, membrane chromatography involves the use of thin, synthetic microporous or macroporous membranes stacked in layers within a disposable cartridge (34). The footprint of such devices is much smaller than columns with a similar output. A range of membranes is available with functional groups equivalent to the corresponding resins (e.g., membranes containing activated quaternary ammonium groups for anion exchange, or phenyl groups for hydrophobic interaction chromatography [HIC]), and a relatively new variant also allows salt tolerant interaction chromatography (STIC) in high-salt buffers (35, 36). The availability of STIC membranes is an important and innovative advance in biomanufacturing because even the most recent generation of membrane adsorbers fall short of some manufacturing requirements when challenged with the high-conductivity feed streams often produced in high-titer processes. STIC ensures more flexibility in process design and improves the clearance of host-cell proteins and viruses in buffers containing high concentrations of salt (see Table I). These new adsorbers therefore allow polishing to be carried out at higher load densities without an interstitial dilution step after product capture, reducing process time and circumventing the need for additional buffer preparation and holding. 

Table I: Broader polishing operation window with salt-tolerant membrane chromatography. 

Table I demonstrates that Sartobind STIC provides higher binding capacities for BSA, DNA, and model viruses compared with a Q anion exchanger under high salt conditions (150 mM NaCl), thereby increasing the design space for polishing operating conditions.  

In a recent example described by the Italian biopharmaceutical company Philogen, membrane adsorbers were substituted for the flow-through and bind-and-elute steps for the polishing of a new monoclonal antibody fusion protein in Phase I–II clinical development, achieving 90% recovery and 99.9% purity (37). The performance benefits of membranes provide value for the user, but the complete elimination of cleaning and validation requirements is often cited as the major advantage because this avoids the costs of the chemicals, personnel, and record-keeping, and more importantly avoids the inevitable process down time while cleaning takes place. Spent modules are simply replaced with prevalidated new ones, available in a range of sizes and configurations for maximum flexibility (32). 

The performance advantage of membranes over resins reflects the transport of solutes to their binding sites mainly by convection, while pore diffusion is minimal (see Figure 1a). Because of these hydrodynamic benefits, membrane adsorbers can operate at much greater flow rates than columns, thereby considerably reducing buffer consumption and shortening the overall process time by up to 100-fold.  The use of membrane adsorbers can be viewed as the equivalent of shortening traditional columns to near zero length to allow large-scale processes to run with only a small pressure drop at high flow rates. For example, polishing with an anion exchange membrane can be conducted with a bed height of 4 mm at flow rates of more than 600 cm/h, and provide a high frontal surface area-to-bed height ratio (see Figure 1b). Small-volume disposable membrane chromatography devices can now handle up to 50 L /min/bar/m

 . Even at these high flow rates, the membrane pores provide adequate binding capacity for large molecules such as viruses and DNA, so they can play an important role in the overall viral clearance strategy for antibody purification (38, 39). 

Figure 1: (a) Mechanistic comparison of solute transport in bead resins (left) and membrane adsorbers (right), where thicker arrows represent bulk convection, thinner arrows represent film diffusion and curved arrows represent pore diffusion. (b) Comparison of bed height in columns (left) and membrane adsorbers (right). Using membrane adsorbers is functionally equivalent to shortening columns to near-zero length, resulting in a similarly small pressure drop that allows extremely high flow rates, thereby reducing overall process times up to a 100-fold. In this example, both formats have a 1350 cm2 frontal surface; the column has a bed height of 15 cm; and the membrane adsorber has a bed height of 0.4 cm. The height to frontal surface ratio is approximately 100 for the column and nearer to 3500 for the membrane device. (ALL FIGURES ARE COURTESY OF THE AUTHORS) 

The flexibility of disposable modules is arguably the most important benefit in the context of the whole process, and this reflects the broad industry perspective that manufacturing flexibility is now perhaps at least as important as capacity considering the large numbers of products in clinical development. Process development can be streamlined and expedited because different modules can be tested in various combinations to arrive quickly at the best overall set of process options, and the absence of cleaning and validation requirements can shorten the time required to develop a finalized process by months or years. The ability to replace each module completely also makes it easier to assemble process trains for new products in existing premises without cross-contamination. The flexibility is most noticeable during scale-up because disposable devices are generally modular and available in various sizes, and scaling up simply involves swapping one module for another with a higher capacity. It is thus apparent that membrane devices can be scaled up with none of the attendant disadvantages of column resins, thereby making the goal of polishing 100-kg batches of antibody entirely possible without oversizing. 

Figure 2: Selection guide for convective media, such as membrane adsorbers. HIC is hydrophobic interaction chromatography. STIC is salt tolerant interaction chromatography. (ALL FIGURES ARE COURTESY OF THE AUTHORS) 

Innovations that take into account the current state of the industry as well as potential challenges and demands are likely to be the most successful in the long term. At the same time, technologies borrowed from the edge of research always come with risks that must be evaluated by manufacturers looking at major investments into capacity. The perceived bottleneck in downstream processing can be addressed with lower-risk approaches, such as streamlining current production processes, with moderate-risk approaches, such as introducing technologies that have already proven suitable in other industry settings, or with higher-risk approaches involving the incorporation of novel technologies.  

In several cases, these novel technologies have already proven their credentials in several processes and companies following the paths set by the first adopters, the trailblazers of the industry, can be assured that the technologies involved now have established their credibility.  

The future of biomanufacturing is likely to rely more on innovation and flexibility than on traditional strengths, such as large facilities and the financial muscle to invest in them. Disposable manufacturing is likely to play an increasingly important role as companies maneuver in a crowded market to protect their R&D investments while more and more generics become available. The ability to scale up or down quickly, to switch to new campaigns rapidly and to produce multiple products in the same facility will be a key metric of success. Ultimately, the future of bioprocessing will require industry players to embrace the need to change.  

 2. D.L. Hacker, M. De Jesus, and F.M. Wurm, 

 4. W. Berthold, Proceedings of BioManufacturing World 2010 (Shanghai, China, 2010). 

Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach

PAT Guidance for Industry: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance

Features

The author reviews the state of downstream processing, including a look at the streamlining of full processes and borrowed technologies.

The Future of Downstream Processing

At a recent industry workshop, I heard an FDA speaker clarify the concept of "compliance" into four simple statements: Say what you do. Do what you say. Prove it. Improve it. Companies usually use their standard operating procedures (SOP) to show that they have control over their processes, thereby demonstrating compliance with regulatory expectations. The "say what you do" phrase equates to the written SOP that defines the steps taken to achieve compliance to a regulatory requirement. "Do what you say" equates to following the SOP. This concept seems simple enough to follow. However, for years, FDA has been citing industry for failure to follow SOPs. Many of the 483s and Warning Letter observations issued in 2010 began with the words, "Failure to follow procedures..." (1). Digging a little further, I went to the FDA reading room  and started looking at the 2011 Warning Letters issued to date. Once again, the phrase, "Failure to follow procedures..." was prevalent throughout (2). 

This trend is disappointing. Numerous webinars, seminars, and workshops designed to train personnel in the art of writing and following SOPs are presented every year. A myriad of articles, books, and manuals discuss the who, what, when, where, and how of SOPs. There are numerous companies, consultants, and experts that a company can hire to write, review, and critique these procedures as well. 

Every company in the pharmaceutical industry has training programs to ensure that employees are provided with—and understand—current SOPs. When considering the various tools available to the industry regarding such procedures, it's unclear why industry still has trouble following its own instructions. 

One reason may be the need for customized SOPs, which are often required by clients of contract manufacturing organizations (CMOs). Contract organizations typically write SOPs to accommodate diverse opinions on how a particular process should be implemented in order to guarantee compliance. These SOPs are presented to prospective customers as a part of due-diligence activities. Occasionally, a customer will insist on supplying the CMO with its own version of the SOP activity and demand that the CMO implement the procedure when manufacturing its product. This approach can be disruptive to the CMO for several reasons. For starters, the CMO's employees need to be trained on two procedures for one activity, and they must understand when and why, and in what situations they should use one SOP over the other. 

Consider the following scenario: CMO A has an established SOP for performing visual inspections on final filled vials before packaging them. The SOP indicates the predicted reject rate associated with various vial defects that might occur as a result of the manufacturing process. Examples of some of the indicated defects are cracked vials, misplaced stoppers, poor crimps, and so forth. Each defect has an established reject rate based on production capabilities. Company A, a new client, has just qualified CMO A as an alternate supplier for their life-saving medicine because its primary supplier is unable to keep up with market demand. Company A would like CMO A to use its inspection SOP for visual inspection purposes. There are major differences between the two SOPs, including the defect categories, the established reject rates for defect categories, and the inspection report forms. Company A's SOP has more defect categories, and the reject rates are tighter than CMO A's SOP, which prompts the use of the different inspection report form. 

As a further example, an experienced, trained employee at the CMO is performing the vial inspection for Company A's product and forgets that there is a custom SOP for this process step.  The employee completes the inspection and turns in the results to the manufacturing quality assurance (MQA), which detects the error and initiates an investigation. The lot in question must be reinspected using Company A's SOP, and the appropriate acceptable quality levels (AQLs) must be applied to the product lot in question. This reinspection delays the release of the product by several weeks and can cause a stock-out situation in the field. 

Another problem CMOs face when using customized SOPs is how to handle conflicting SOPs.  Consider the following scenario: CMO B has just been selected by Company B to manufacture its product. 

CMO B has an SOP for identifying and investigating incoming raw materials for foreign matter. The SOP requires CMO B to characterize foreign matter as either inherent or aberrant. If the foreign matter is deemed inherent to the raw material, a description of the foreign matter is recorded as part of the raw-material release. The foreign matter is then removed and the raw material is used in product formulation. If the foreign material is determined to be aberrant, then the raw material in question is put on hold, and an investigation is initiated to determine the identification of the foreign material in question. 

Most of CMO B's clients are comfortable with the SOP, but when manufacturing Company B's product, CMO B comes across some black particles in sucrose, a raw material used in the manufacture of Company B's product. CMO B uses its foreign material SOP to record the incident. The foreign-material report indicates, under high magnification, that the black material is burnt sucrose. Because burnt sucrose is inherent to sucrose (the raw material), it is deemed suitable for manufacture. CMO B releases the batch record and the associated product to Company B for review, approval, and release. Company B refuses to release the product because its internal SOP, which was not provided to CMO B, specifies that foreign matter found in raw materials must be sent for molecular identification. Until the discrepancies between the SOPs are resolved, product manufactured for Company B is required to be released by exception. 

The practice of using customized SOPs also presents a logistical problem for the CMO: Which SOP should be presented to the regulatory authority during a cGMP inspection? For product-specific inspections, only those SOPs associated with the product should be presented to inspectors. However, when a general inspection is combined with a product-specific preapproval inspection, for instance, two SOPs for the same process must be provided to inspectors. Invariably, inspectors will investigate the areas where the firm may have internal challenges and in all likelihood, will leave the CMO or the company with a  an observation that it "failed to follow written procedures..." 

There are no easy solutions to the situations described. CMOs and their clients, however, can minimize these and similar types of circumstances through open communication. CMOs must seek to understand their clients' needs while clients must seek to understand their CMOs' quality systems. Although we are all in the same industry, we do not always share a common language with respect to describing our internal systems. Establishing a common language between the two parties makes it easier to determine what, if any, changes need to be made to a CMO's quality system to accommodate the client's needs.  If the two parties can effectively communicate and eliminate the need for redundant SOPs, their chances of avoiding unfortunate compliance mishaps will greatly increase."  

 is vice-president of quality at OSO Biopharmaceuticals, 

www.fda.gov/ICECI/EnforcementActions/WarningLettersdefault.htm

Compliance Notes

Why SOPs are rarely followed, often cited, and in great need of follow-through.

Following Our Own Instructions

Biologics comprise a huge variety of different molecules, activities, and applications and mostly try to mimic functions of natural molecules. Generally, they are of a rather complex nature and often consist of different functions on the same molecule (e.g., F

 receptor and antigen-recognition site of an antibody). Typically, proteins can present different possible modifications, such as glycosylation, disulfide bridges, specific carbon and nitrogen terminal groups, or they have been chemically modified, such as pegylated or conjugated proteins. Biologics may be based on carbohydrates (e.g., the meningitis vaccine), peptides (e.g., insulin), lipid structures, parts of microorganism cell walls, complete cells (e.g., stem-cell treatments, or Bacillus Calmette-Guérin (tuberculosis vaccines), or nucleic acids (e.g., plasmids and genome DNA for gene therapy). Furthermore, the active substance or complex does not consist of one molecule, but a mixture of different ones, such as congeners and isoforms. The ratio of each molecule within the mixture of the family can be crucial for activity. The importance of this ratio becomes more and more visible as analytical methods advance. 

This extremely large variety of molecules necessitates a broad range of production systems, and analytical characterization and quantification methods. Most first-generation biological products were extracted from natural sources, such as animal tissue, human plasma, and wild stem microorganisms, and further separated with basic techniques (e.g., precipitation, centrifugation, and filtration). However, because of the risk of contamination and incompatibility, these traditional techniques have been replaced by more advanced biotechnologies, such as recombinant techniques or methods that can significantly reduce the potential level of contaminants. These methods include solvent, heat, gamma irradiation and microwave treatments, nanofiltration, and anion exchange chromatography. Initial hybridoma monoclonal antibodies or fusion proteins have also been replaced by humanized ones, and the third generation of biologics now focuses on further defined structures with less microheterogeneities and fewer aggregates to avoid adverse immune reactions. Another focus of new technologies is the expression of antibodies or antibody fragments that provide certain functions by, for example, being linked to cell-killing antibody drug conjugates. 

In the 1990s and the early 2000s, much progress was made in biological upstream processing with productive high-expression systems, effective clone selection, defined culture media, process intensification and single-use components. Progress also was made with regard to improvements in analytical methods, which were developed to further characterize and quantify molecules in terms of structure, identity, activity, purity, microheterogeneity, quantification, and safety. These advances were crucial for downstream development because they helped to further characterize starting materials, thereby providing more insight into quality and mass balance during processing. As such, target specifications are now stricter and more demanding compared with early biologics. 

These upstream developments create challenges in downstream processing to ensure that the biologics achieve the new quality and safety specifications. Other challenges for downstream processing include treating high upstream quantities in time, integrating new chemistries, purifying molecules in a contained system that enables the handling of antibody drug conjugates, and, of course, ensuring that processes are cost effective. Recent developments in the downstream area, however, are helping to overcome these challenges. 

The development of more effective analytical methods has enabled better control over critical quality and quantity attributes online and atline during downstream processing. FDA encourages the use of these technologies and defines them as "a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performances attributes of raw and in-process materials and processes with the goal of ensuring final product quality" (1). 

Cycle time, sample preparation, and the nature of the analytical method are key to determining whether on-line or at-line measurement can be developed. Several other factors also need to be considered when implementing a PAT solution. These factors include the following: the design of the fluid pathway; communication between the measuring software and process software; knowledge about the analytical methods' stability, reproducibility, repeatability and precision; linearity; and limits of quantification combined with processcontrol needs. It also is important to determine whether the techniques should be applied only in process development or in the production of commercial material as well. Systems for in-line dilution (ILD) of buffers or clean-in-place (CIP) solutions are examples that have been installed at the industrial scale. The principle of an ILD system is the preparation of buffers and cleaning solutions by using concentrated stock solutions that are diluted with water to the desired final concentration. These systems must be robust to compensate for the pressure changes of the water preparation loops, backpressure from process units (e.g., tangential flow filtration (TFF) or chromatography), and changes in buffer composition and dilution rates. The principle of ILD is shown in Figure 1. 

Figure 1: Principle of in-line dulition. TFF is tangential flow filtration. (ALL FIGURES COURTESY OF THE AUTHOR)			

Depending on user requirements, different technical solutions can be used for the dilution itself (e.g., pumps coupled with mass flow meters, analogue or proportioning valves) to ensure that the inlet pressure is adequately controlled, and the control of the composition after the dilution (e.g., conductivity feedback control on the pumps or valves). Cost analysis has shown that these rather simple solutions can save up to 20% in capital expenditure for new downstream plants (2). 

Another example of PAT application concerns atline monitoring and product quality control during the chromatographic elution of a mixture of lipidic compounds, which ensures that the correct chromatographic fractions are selected. In one particular case, because the compounds are not ultraviolet active, a light-scattering method was developed to follow the elution profile. In a second step, an analytical method based on mass spectrometry was implemented to control the composition of the different lipids. The work commenced with off-line analyses at bench scale and continued with experimental at-line analyses, including split streams. After the initial laboratory-scale phase, the process and analytical tools were scaled up to find the optimal technical solution for implementation in an industrial cGMP environment. Figure 2 presents the evaporating lightscattering detection (ELSD) at-line measurement, coupled with a preparative high-performance chromatography (HPLC) system, which was used in the study. A very small part of the elution stream that comes from the HPLC is directed to a splitter and transferred to the light-scattering detector. Because organic solvents are used, a nitrogen purge box is necessary. Using this solution, the time for in-process sample analysis was reduced to one day, compared with approximately two weeks with initial analytical methods. The investment and the time of implementation and validatioin need to be balanced with the gain of operational time. 

Figure 2: Principle of at-line measurement using evaporating light-scattering detection (ELSD). HPLC is high-performance liquid chromatography. (ALL FIGURES COURTESY OF THE AUTHOR)			

The introduction of single-use components into biological production processes started in the early 1970s with liquid filters and tubings, but by the end of the 1980s, bags also became available for storing small volumes. The beginning of the 2000s saw the development of fully-disposable upstream harvest lines and further development of bufferpreparation systems. Today, single-use cell culture reactors up to 2000 L and bioreactors up to 500 L are available on the market. Research also is ongoing to find high-quality, economical solutions for TFF and chromatography single-use systems. 

There are many advantages associated with single-use systems, including reduced changeover times (i.e., cleaning, setup, and storage), reduced cross-contamination risks, availability of fully contained systems, reduction of initial capital expenditure (in most instances), reduced set-up time, and reduced cleaning validation. These benefits, however, also must be balanced with other factors, including risk of leachables, compatibility problems, integrity failures, supply-chain interruptions, scalability limitations, waste management, and operational cost evaluations. A detailed case-by-case evaluation should always be conducted, particularly for routine production. Figure 3 shows an image of single-use TFF cassettes used for concentration, diafiltration, and the formulation of biologics. 

Figure 3: Tangential flow filltration cassettes. (ALL FIGURES COURTESY OF THE AUTHOR)			

Specific ligands and  chromatographic media

Being able to obtain a high-quality product after only two or three purification steps is a real achievement in the process development of biologics. However, the process also needs to be scaleable with high productivity. Specific ligands coupled to rigid chromatographic media for the targeted product can be beneficial in this process. One prominent example is a typical antibody capture step with Protein A ligands, which can reach up to 90% purity. Ligands can also be developed to polish impurities, such as residual host cell proteins and transmissible spongiform encephalopathies particles. In the case of polishing, the capacity is less important, so ligands could be coupled onto membranes to create membrane adsorbers. 

With regard to the specificity and stability of the ligand, the structure (i.e., particle size, size distribution, pore size, pore distribution, mechanical and chemical stability) of the chromatographic beads and the coupling chemistry are also important. Optimized chromatographic media can increase process performance. In terms of mechanical and chemical stability, pore size, pore size homogeneity and the coupling chemistry are important for membrane adsorber development. 

Traditional production processes for biologics are batch based, which means that almost every process flow is collected after each step in one or several tanks, and often checked for product quality before processing in the next step. Based on development data, processes could often be more intensive.  

In addition to the biopharmaceutical industry, the process intensification phase is mandatory for other industrial biotechnology sectors such as the processing of antibiotics, amino acids, organic acids and food ingredients. One recent example where a process migrated from an industrial biotechnology platform to biopharmaceutical production is sequential multicolumn chromatography (SMCC). This process allows the use of processing time as another dimension; therefore, velocity, resin volume, and the number of columns can be calculated to fit in a predefined processing time. A significant increase in productivity can be reached (Examples on Protein A antibody capture showed up to a threefold increase). Buffer and stationary phase consumption was also cut by at least half (3). This process also can enable continuous downstream processing, where the process steps are connected to each other to obtain a continuous process flow up to the bulk stage. 

Figure 4: Principles of a sequential multicolumn chromatographic (SMCC) process and comparison with a batch one. (ALL FIGURES COURTESY OF THE AUTHOR)			

Cost studies on monoclonal antibody downstream processing performed by BioPharm Services showed up to a 79% reduction in operational cost when processes were transformed from batch to continuous ones (4). Additionally, process simulation tools are important to optimize process dimensioning, production and investment costs, which also can be a support for process characterization and validation. Figure 4 shows the principles of the SMCC process and compares it with a batch one. Figure 5 shows an industrial system that enables the operation of SMCC processes. 

Figure 5: Example of an industrial system that allows sequential multicolumn chromatography. (ALL FIGURES COURTESY OF THE AUTHOR)			

In light of the numerous challenges in biologics processing, such as the wide variety of molecules and applications, increased quality and regulatory requirements, and cost pressure on drug financing, the development of new downstream processing technologies is essential.  

Applying PAT systems, such as ILD systems and at line monitoring, can significantly increase process control and aid cost reduction. Further development of chromatographic media or membranes through the use of specific ligand technologies and optimal media design, with single-use materials, are additional solutions that also can improve quality and productivity. These improvements can be coupled with new process design, such as semicontinuous or continuous processing, which can greatly enhance process intensification while simultaneously reducing costs.  

The author wishes to thank Henri Colin, PhD, consultant at Ulysse Consult, Laurent David, senior scientific expert at Novasep Process, and Velvet Mitchem-Thery, event and web coordinator at Groupe Novasep. 

PhD, is R&D and technology director at Novasep Process Process Eiffel, BP 50 Blvd de la Moselle, Pompey, France, 54340, tel. + 33 383 497021, fax +33 383 497003, 

PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance

 2. M. Holzer, "Impact and Benefits of PAT in Industrial Downstream Processing," presentation at the BioProcess International Conference (Raleigh, NC, Oct. 2009). 

 3. L. David, "Evaluation of the Process Performance and Economical Impact of Sequential Multi-Column Chromatography in Downstream Processing," presentation at IBC Biopharmaceutical Development & Production Week (Bellevue, WA, Mar. 2011). 

 4. A.Sinclair, "Continuous Downstream Processing:  The Improvement of Tomorrow for Biological Production —Economic Analysis,"  presentation at the BioProcess International Conference (Düsseldorf, Germany, Apr. 2009). ? 

The author describes recent developments to help overcome the downstream-processing bottleneck.

Technologies for Downstream Processing

The successful evolution of biotech companies has resulted in their expansion into complex multisite international structures. This transformation requires the establishment and coordination of various distributed functions, including manufacturing, manufacturing support (MS), and process development (PD). While such decentralization may offer some advantages, such as fast responses to local crises, use of local talent, cost reductions, and certain regulatory benefits, decentralization also poses significant organizational challenges. To address these challenges, companies have to find the right balance between site autonomy and functional centralization, so that the potential of each site is fully enabled, while a high level of coordination between sites is maintained. This article analyzes several structural alternatives for global PD organization, versions of which can be found in the biotech industry today. Two global structures that can potentially provide a practical solution for most cases will be proposed. These models are idealized, not reflecting any particular organization.  Although this discussion focuses on PD, some of the solutions are fully applicable to MS. In the long term, the global PD and MS functions are unlikely to remain static. The evolution of every company requires periodic review and optimization of PD and MS, so that they adequately reflect the needs, size, and the maturity of the organization as it becomes a well-engineered global enterprise. 

The authors discussed the PD organization structure issues with the management of multiple large biotech and biopharmaceutical companies involved in therapeutic protein manufacturing (1). The focus was on the following: 					

Definition of responsibilities, in particular in the area of overlap between manufacturing and development

Allocation of PD and MS functions in the global decentralized company

Additional cross-functional means for enhancing coordination.

While all companies have their own structures, there are general concepts and patterns that are reproducible. Using the gathered information in combination with the authors' own experience, organizational models were developed that cover a broad spectrum of options spanning from complete decentralization to full centralization. These models do not represent the structure of any particular company, but capture the essence of the existing opportunities. 

The existing structures are not static but continue to evolve, thus reflecting the progress and the specifics of each organization.  Despite many differences, often resulting from the personal preference of top management, there is a clear trend towards global alignment. 

Most companies have separate MS and PD functions. Furthermore, the MS groups are always colocated with the manufacturing departments they are supporting. Because this model is common and offers some important advantages, the authors considered it as a standard in the analysis. The advantages of this approach include speed of response to urgent manufacturing needs and shielding of PD from short-term daily problems in the plant, so that resources are focused on long-term strategic projects and innovation (2). In some cases, a central MS group is responsible for the coordination and standardization between the distributed MS networks. 

Table I summarizes the responsibilities of the MS and PD groups. In this illustration, the MS groups serve as the first line of defense. Because speed is one of the main requirements, local presence, including on-the-floor support, is essential. MS focuses on the manufacturing processes at the particular site and is often a structural part of the manufacturing organization. It is responsible for the day-to-day issues, including deviation investigations, continuous improvement, process monitoring, data mining, and process transfer to the local site. Typically, MS is not involved in complex, exploratory, long-term projects. These projects are handled by PD, and developed in close coordination with MS and manufacturing. 

Table I: Responsibilities of process development (PD) and manufacturing support (MS).			

On the other hand, PD is responsible for larger life-cycle management projects, development and transfer of new processes, new technology platforms, and manufacturing support of complex projects requiring intense experimental and analytical work. The PD group can be centralized or decentralized, residing at several sites that provide remote services to various internal customers. 

While a definition of the responsibilities of MS and PD is helpful, it is difficult to define a clear line between the two.  Accepting a certain level of healthy overlap and ambiguity is practical, because this can serve as a bridge between the two functions, thus preventing dangerous gaps. The complexity of biotech manufacturing results in a continuum of projects, some of which cannot be clearly allocated to only MS or PD. 

The coordination between MS and PD is a critical element of the biotech enterprise. Structurally, these groups exist as independent departments under different management. As such, it is essential that their activities, procedures, objectives, priorities, and methodology be aligned. This alignment can be achieved by properly designed business processes involving both organizations, including but not limited to joint teams, committees, periodic reviews, and symmetrical functional structures. Proper alignment allows for an optimal response to rapidly changing priorities, fluidity, coordinated resource allocation, and global utilization of knowledge generated at different locations. 

A PD structure that gives priority to site autonomy is shown in Figure 1. The assumption is that PD departments exist at various locations (Sites A, B, and C). One of the sites may play the role of a central or corporategroup. Another assumption is that each PD department is organized functionally into subgroups, including cell culture, purification, and formulation–fill–finish units. Not all functions may exist at any one site, however, this structure is considered for completeness. In some organizations, other functions can be part of PD (e.g., analytics, cell-line development, and pilot plant), but for simplicity, these are not included in Figure 1. Well-developed analytical function is a critical element of PD, and usually all PD departments have an analytical group that provides routine assay support. However, the location of the assay-development activity varies significantly from company to company. 

Figure 1: Fully-decentralized process development (PD) structure. (ALL FIGURES ARE COURTESY OF THE AUTHORS)			

According to this model, each PD group reports into the local site head, who reports to a corporate executive, fully empowering site autonomy.  The line responsibility for the coordination and alignment between the PD groups from different sites is moved high up in the company hierarchy to the level of the corporate executive. Except for various teams and committees that can help the cross-site alignment, no formal links support global coordination. While this model facilitates speed and focus on site priorities, it does not adequately support global alignment and integration of the PD organization. This type of organization creates silos of PD resources and minimizes the opportunity for setting common priorities and flexible distribution of projects and resources. 

The model in Figure 1 may work well when different sites use completely different technology platforms, which makes the need for harmonization less critical. However, usually the platform technologies are similar, particularly when one product is manufactured at multiple sites. In this circumstance, decentralization may create problems, such as incremental technological drift of sites away from each other in terms of procedures, methods, instrumentation, and development philosophy. When left unmonitored, this drift can be difficult and costly to reverse. 

The second model (see Figure 2) shifts the balance towards centralization. Each PD group reports into a global PD head, who is responsible for all PD activities in the company. Site management still can have an administrative link to the local PD groups, usually achieved through dotted lines. The global PD head is responsible for the coordination and alignment between sites, which is an essential part of his or her role. The focus on integration is stronger, and the responsibility for it is shifted lower in the company hierarchy. 

Figure 2: Site-focused process development (PD) integration. (ALL FIGURES ARE COURTESY OF THE AUTHORS)			

The third model (see Figure 3) provides full functional alignment. The responsibility for coordination is moved to an even lower level. For example, all cell-culture PD departments at different sites report to a global cell-culture head. The other functions are integrated similarly. This model provides a high level of coordination, which is rooted deeper in the organization. Furthermore, it requires a symmetrical organization of all PD groups, which streamlines communication, responsibility, definition, and resource allocation. This model is generally appropriate for more mature organizations where all PD departments are already functionally structured. 

Figure 3: Global functional alignment of process development (PD). (ALL FIGURES ARE COURTESY OF THE AUTHORS)			

The fourth model (see Figure 4) represents a fully centralized PD organization that assumes colocation of all PD resources at one place. With the objective of maximizing coordination, some large companies have elected to concentrate all their development activities at a single site. Clearly, this structure defines the opposite end of the organizational spectrum compared with the fully decentralized model depicted in Figure 1. 

Figure 4: Fully-centralized process development (PD) structure. (ALL FIGURES ARE COURTESY OF THE AUTHORS)			

The MS models can be similar to these of PD, with the exception that the MS groups by definition are colocated with their corresponding manufacturing units. Therefore, the fully centralized model (see Figure 4) is not applicable. Although individual MS groups are ultimately focused on supporting their local manufacturing units, global coordination between them in terms of business processes, priorities, best practices, and instrumentation is essential. As such, the models in Figures 2 and 3 are appropriate, and their features apply fully to MS. Tight harmonization is particularly critical for multisite production of the same drug. 

Tangible benefits should be associated with the symmetrical organization of PD and MS, which would enable simplified coordination and communication to better handle the typical push–pull dynamics between the two functions. It is easy to imagine and implement additional organizational tools that link PD and MS, including teams, committees, task forces, and a global project management function. These supporting elements are simpler to construct when the PD and MS organizations are compatible and structured the same way. 

The dynamics of the biotechnology business imposes challenging demands on the individual sites and on the global multisite functions. Achieving a simultaneously high level of site autonomy while maintaining global coordination is a difficult task that requires proper organizational structure for PD and MS. However, these objectives are not mutually exclusive. The PD models outlined in Figures 2 and 3 provide a reasonable balance between the conflicting needs. These structures can incrementally evolve, reflecting the maturity of the entire organization. The proposed models also enable the smooth integration of newly acquired companies within the existing structures, without the negative effect of a complete reorganization or relocation of the new entities. Variations of the proposed models can be found in the biopharmaceutical industry today. In most real cases, however, the organizational structures are complicated by exceptions caused by historical or other reasons. Despite the model diversity, there is a clear trend towards globalization of the distributed PD function. 

Missing the opportunity to strike a balance between site autonomy and global coordination entails a significant cost. If the PD groups are left disconnected, there will be a growing drift in direction, which will eventually result in inefficiencies, technology platform misalignments, and lost opportunities. The opposite is also true: overwhelming central control may stifle the creativity and innovation at individual sites. The organizational structure itself is an essential, but not sufficient, requirement for these models to work. Active management using the power of global reporting lines is necessary to promote common goals, priorities, learning, and standards. 

Properly aligned global PD organizations have the following:  					

Fast corporatewide distribution of best practices and technology platforms across the PD network

Ability to globalize innovation sourced from different sites

Flexible resource allocation, rapid responses to changing priorities

Improved efficiency through standardization of scale-down models, data- and knowledge- management systems, instrumentation, and business practices

Minimized redundancy and common priorities

Global PD management shifted to a lower level in the hierarchy.

In addition to the right organization of PD, a symmetrical structure of MS can provide additional benefits, making a step forward to the truly agile, ambidextrous enterprise capable of optimal management of short-term urgent projects, incremental improvement, and disruptive innovation (2, 3).

The authors appreciate the open discussion with the management of several leading biopharmaceutical companies. The support of Dr. Eliana Clark of Genzyme is acknowledged with gratitude. 

is  vice-president of commercial process development and 

is  vice-president of project management, both at Genzyme. 

 1. K. Konstantinov et. al., presentation at the IBC Bioprocess International Conference (Anaheim, CA 2008). 

 (Harvard Business School Press, 1997).  

How to strike a balance between site autonomy and global coordination.

Organizational Structures of Process Development and Manufacturing Support

I have often gotten the impression that FDA's quality-by-design (QbD) initiative remains somewhat mysterious to pharmaceutical manufacturers, even though it's been about seven years since FDA first introduced the concept in its 2004 report, Pharmaceutical Quality for the 21st Century: A Risk-Based Approach. FDA must have had that impression as well because the agency commissioned a study to gauge the industry's rate of adoption of the concept as well as its understanding of it, the results of which FDA officials present in the September 2011 issue of 

. The study findings support anecdotal accounts of industry attitudes towards QbD. 

 The report quantifies the degree of adoption among different industry sectors. Not surprisingly, innovator companies (called "New Drug" in the report) have embraced the program most fully. Twenty-two percent of new drug companies are categorized as "fully implemented" in the report, meaning that these companies incorporate QbD principles in almost all of their development programs. These companies also have a "systematic, comprehensive review and redesign of in-line products." In contrast, no generics or biologicals manufacturers fall under the fully implemented category.  

At the other end of the spectrum, generic-drug manufacturers appear to be most resistant to the program, with 40% of them being characterized as "novice," which is defined as a company "that is skeptical about the value of QbD," and uses "conventional development practices and has no QbD platforming." In other words, they're non-adopters. Biological manufacturers lie somewhere in the middle, with an impressive 67% venturing tentatively into "pilot" territory, defined as companies trying it out, but uncertainly. These results mirror responses 

 obtained in its 2011 Equipment and Machinery Survey (the results of which were published in PharmTech's March 2011 issue), where approximately 58% of innovator companies, and 55% of biotech companies, but only 35% of generic-drug manufacturers reported that QbD had a "high" or "medium" impact on their equipment-purchasing decisions.  

 The reasons for skepticism cited in the FDA article also mirror what we've heard anecdotally. Quality professionals have a hard time getting management to buy into the concept—what the report referred to as a "disconnect between leadership and middle management." An additional misconception, which the report attempts to squelch—is that QbD is costly to apply.  

But there's also great uncertainty within industry, bordering on frustration, about what FDA wants. The report notes—and we've heard this ourselves—that industry perceives internal inconsistencies within FDA as to how the agency assesses a company's QbD efforts. Companies also express some degree of discomfort about talking with FDA at all. And again, I've heard individuals say that FDA might ask people to implement QbD in theory, but gives them a hard time when they try to put it into practice. FDA for its part intends to spend the next five years developing more internal consistency and clarifying expectations both within FDA and the industry.  

At its core, the QbD initiative asks manufacturers to understand how variables—temperature, pressure, humidity, for example—govern the behavior of their reagents and their effects on product quality, principles we all learned in our high school science classes when we were first introduced to the experimental method. And that's the most mysterious thing of all. How did a science-based industry manage to unlearn these concepts in the first place? 

From the Editor

A report commissioned by FDA evaluates the QbD paradigm.

Retrospection and Introspection at FDA

Could the European debt crisis be the event that consolidates the dose CMO industry? That thought might seem like a stretch, but the financial turmoil roiling Europe could definitely have a big impact on the CMO industry. 

Much of the media coverage of Europe's debt crisis has focused on the ability of governments in the so-called PIIGS countries—Portugal, Ireland, Italy, Greece, and Spain—to repay or refinance their national debt. It is much more than that, however. 

The European debt crisis is potentially a banking crisis as well because the banks hold much of the sovereign debt. If the PIIGS were to default, the banks would be forced to write down the value of their bond holdings, and the resulting losses would reduce their equity and the capital ratios that they must maintain under international and national regulations. That scenario would force the banks to raise more capital and/or reduce their lending to bring assets back in line with their capital. The reduced lending would be felt throughout Europe because the affected institutions, especially the big trans-European banks, such as Deutsche Bank, are major lenders throughout the Euro zone. 

Another concern is that government austerity programs, combined with reduced bank lending, will severely weaken the already fragile economies of the PIIGS countries. Those economies are already a mess, plagued with low demand, high unemployment, and low tax revenues. Lower government spending, tighter private-sector credit, and higher interest rates will further suppress overall economic activity and household incomes in the coming years. 

In fact, the bank pullback already is under way. Recent reports in the financial press (as of the writing of this article in early August) indicate that the European banks are reducing their private-sector lending in the PIIGS countries in an effort to reduce their exposure to the weakening economies. 

The deteriorating European financial situation will play out to the detriment of European CMOs in two principal ways: undermining their operating performance and affecting the availability and cost of debt needed to finance their businesses. 

The deterioration of the operating performance already is occurring because expenditures on drugs are falling sharply through reduced volumes and lower prices. These lower volumes and prices are especially apparent in countries where the national healthcare systems are a primary buyer and distributor of drugs and therefore affected more by reduced government revenues and spending. The deteriorating economies also will impact privately financed spending on drugs. 

CMOs are feeling the effect of reduced spending on drugs through lower production and demand from clients for lower prices. Furthermore, many European CMOs also are generic-drug manufacturers that use their excess capacity for contract manufacturing. The reduced spending also is taking a toll on their generic-drug business.  

Even before the financial crisis, many European CMOs and generic-drug companies were plagued by low utilization and narrow profit margins. Further deterioration of operating profitability has a range of deleterious implications for the CMOs, ranging from deferred maintenance and capital investment, all the way to receivership. Any sustained deterioration in operating profitability will reduce the credit worthiness of CMOs and threaten their access to bank credit. 

The availability and cost of bank credit could impact a number of CMOs, including those that are owned by private-equity companies. Private-equity firms typically use the debt capacity of the companies they own to reduce the amount of equity they have invested in the companies and even as a means of generating cash that they pay to themselves as a dividend. In the case of European CMOs, even though the owners in most cases didn't pay much or anything for their facilities, the owners could have borrowed against their assets and they could be highly leveraged. Even where companies don't depend on debt for financing assets, any deterioration of operating performance could affect CMOs' ability to get lines of credit for basic operating needs. 

The financial crisis will hurt the CMO industry by making it more difficult for their clients to get external financing. Financial crises always make investors more risk averse, and investing in new drug development is inherently risky. Europe has always been a difficult place for early-stage companies to raise venture capital, and the deteriorating economic situation is likely to make it worse.  

The financial crisis is hitting the European CMO sector at a time when it is already weak. According to the PharmSource ADVANTAGE database, Europe has nearly twice as many contract dose manufacturers as North America, including 100 solid dose CMOs and 70 injectables CMOs. Only about one-third of these CMOs are FDA-registered, meaning most of them are limited to competing for business to supply European or emerging markets. As a result, competition for the available business already is intense, thereby pushing pricing and operating margins to barely sustainable levels. 

The overcapacity problem has come about because it is so difficult to close redundant manufacturing facilities in Europe. Faced with huge severance costs and negative publicity if they close a facility, global bio/pharmaceutical companies have preferred to give away facilities to management teams and private-equity firms that are willing to run them as CMOs. That approach gets rid of the headache for the pharmaceutical company, but it has created an unsustainable situation for the CMO industry. 

Under these dire circumstances, we believe that a number of CMOs face significant risk of insolvency in the near term. While most of them are privately  held companies that don't publish their financial statements, the situations where we can see the financial results show very poor operating margins and minimal debt capacity. The precarious state of the European financial system and the implications of that weakness may be enough to push some of those companies over the edge.  

Bio/pharmaceutical companies that depend on European CMOs face a major due diligence challenge. They need to monitor their European CMOs closely, gain a thorough understanding of their balance sheets and cash flows, and be  aware of their exposure to negative developments in the credit environment. For CMOs owned by larger entities, the oversight should extend to the corporate parents as well. There are some major CMOs whose corporate parents have extensive interests in sectors outside pharmaceuticals that are heavily exposed to the financial crisis, such as retailing and property development. Bio/pharmaceutical companies also will need to have alternate sourcing plans in place in the event that financial developments interrupt product supply. 

is president of PharmSource Information Services, Inc., and publisher of Bio/Pharmaceutical Outsourcing Report, tel. 703.383.4903, fax 703.383.4905, 

Perspectives on Outsourcing

The EU debt crisis portends of possible negative repercussions for the dose CMO industry.

The EU Debt Crisis and CMOs

As we enter the brave new world of biosimilars, the first obstacle for FDA and the industry will be developing the approval standards. Although the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) creates an approval pathway for biosimilar and interchangeable biological products, it provides little guidance as to its implementation. As a November 2010 FDA hearing made clear, there is no general consensus as to the proper standards for biosimilarity and interchangeability, or even a consensus as to how and when those standards should be created (1). 

Given the significant safety and efficacy issues involved in biologics, these standards will determine the impact the BPCI Act has on the biologics industry. Those biosimilar companies who go to FDA early and often and who can effectively advocate for the desired approval standards for particular products will be the ones who are initially successful in this nascent industry. The issues highlighted by the November hearing provide a good starting point for any biotechnology company to assess its strategy going forward. 

First, and perhaps most significant, FDA seems to be undecided in its approach to issuing guidance documents for approval standards. Specifically calling back speakers to answer the question, the November panel sought opinions on whether it should seek to first issue guidance documents of a more general nature rather than of a product-specific nature. "Innovators"—that is, the companies that make the original reference product—advocated for issuance of broadly applicable guidance documents and a stay of approvals until such documents are issued. Those companies interested in seeking biosimilar approvals advocated for product-specific guidances as well as standards on a case-by-case basis. FDA's willingness to accept suggestions in this area shows that early advocacy for the desired approval standards will likely influence the ultimate biosimilars landscape. 

Possibly equally significant, FDA sought comments at the November hearing on interpretation and implementation of the exclusivity provision of the BPCI Act. The representative from Knowledge Ecology International as well as a representative for US Sen. Bernard Sanders (I–VT) pointed out that the provision may violate Article 20 of the 

Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects

 by forcing duplicative studies instead of allowing reliance on innovator data. Consumer groups and biosimilar proponents expressed worries of the potential for evergreening, encouraging stringent standards for determining when a modification to the structure of a reference product results in "a change in safety, purity, or potency" sufficient for eligibility for a second 12-year exclusivity provision. This position was directly contradicted by innovators who argued that any change in safety, purity, or potency (improvement or otherwise) is sufficient for new exclusivity under the Act. 

If the BPCI Act generously grants new exclusivity to minor structural changes in reference products, this could effectively negate the provisions of the Act allowing for follow-on biosimilar products. If innovators use this provision, as the hearing suggests they might, to keep on-the-market products under successive 12-year exclusivity, biosimilars will not be able to effectively come to market as a follow-on product. 

The most stark line of division with regard to approval standards between innovators and biosimilar proponents at the hearing was the respective views on the appropriate standards for interchangeability. Innovators stressed "product is process" to argue that interchangeability was simply not feasible at this time. They also asserted that interchangeability should be demonstrated for all indications, given that doctors and insurers would likely treat interchangeability in that manner. The panel expressed concern about the problem of drift—that is, postmarket changes to the reference product caused by manufacturing changes. The panel asked whether interchangeability could ever work given that the two products would change separately. 

While innovators shared this worry, biosimilar proponents used drift to advocate for lower interchangability standards—because FDA already does comparability studies to approve process changes for already marketed reference products, it should be able to similarly approve biosimilars. One interesting proposition put forward was the possibility of a postmarket system for interchangeability, which would rely on strong pharmacovigilance and reporting to allow biosimilars to achieve interchangeable status after the product can be observed on the market. 

The issues underlying interchangeability were emphasized by the concerns of patient-interest groups. These groups stressed opposition to allowing substitution of reference product for "interchangeable" biosimilars at any point prior to the patient-doctor decision. Above all, they stressed the importance of patient and doctor education, and the ability to make informed choices. 

The issues presented at the hearing regarding interchangeability suggest that this is going to be the biggest battle for biosimilar proponents. Those who plan on seeking interchangeable status need to focus their efforts on advocating for approval of interchangeability and may choose to stress product-specific interchangeability before advocating for more general standards. The key for companies planning to develop products to meet interchangeability standards will be to develop robust scientific data to support such a determination by FDA. 

FDA weighs multiple views regarding the Biologics Price Competition and Innovation Act.

BioPharm International-09-01-2011