
Biologic-based drugs are increasingly part of the product-development strategies of pharmaceutical companies. The very nature of biologics such as monoclonal antibodies (mAbs), recombinant proteins, or vaccines require specialized manufacturing conditions compared with the chemical synthesis of small molecules. To gain a perspective on the key issues involved in upstream (i.,e drug substance) manufacturing and downstream processing (i.e., purification), Patricia Van Arnum, editor of 

, discussed these issues with Nigel Darby, vice-president of biotechnologies at GE Healthcare Life Sciences (Uppsala, Sweden). Darby will be a speaker at a biologics forum, 

The Rapid Evolution of Biomanufacturing and the New Supplier Reality

 organized by the Drug, Chemical, and Associated Technologies Association (DCAT) on Mar. 17 at the Waldorf-Astoria in New York City. The biologics forum is part of series of educational programs organized by DCAT during 

 Mar. 15–18 that focus on pharmaceutical industry market dynamics, manufacturing, and sourcing of pharmaceutical ingredients. 



 What are the  key trends and developments industry-wide in biomanufacturing, specifically in upstream technologies relating to manufacturing the biologic drug substance? How are advances in media and cell-line development contributing to improved yields or process efficiency?



 Cell-culture productivity expressed as product titer has increased to a level of2-4 g/L in established production processes and 4-6 g/L in preclinical and some clinical manufacturing processes. This is a combined effect: optimized expression systems turn the cells into more efficient production systems and culture-media developments, including the feed strategy, lead to significantly increased cell density in the bioreactor. Cells would be capable of even higher yields up to 10 g/L, but this benefit, more often than not, comes with 50–70% prolonged culture time and deletes part of the productivity gains made with high titers. In addition, longer culture times reduce the flexibility in production scheduling and may thus limit the benefits of cell-culture optimization to conditions where culture time can be kept to approximately 12 days. 

Overall, however, the improvements made with upstream processes have clearly enabled the manufacturing of ton quantities of therapeutic mAbs as required for some of the legacy mAbs. Twenty years after the first protein drug (tissue plasminogen activator) produced with mammalian cells, cell-culture technology has finally turned into an economic production tool for large-scale operations.



  What are key trends and developments in downstream processing  (i.e., purification) strategies of a biologic drug substance?



Downstream processing strategies follow two different trends: with mAbs still being high-dose drugs requiring relatively large-scale manufacturing, filtration steps need to cope with high biomass content in the initial steps and purification resins need to offer higher capacity while maintaining or improving the purification effect. Companies will continue to develop their manufacturing platforms and will aim to use robust downstream methods that work for the majority of their mAbs. As far as development, upstream processing is addressing some challenges: one is trying to reduce the number of main purification steps from three to two. Most recombinant proteins require significantly smaller product quantities (10-100-fold less), and each protein is very much more different than individual antibodies are different from each other. Platform approaches are more difficult to establish with recombinant proteins. Many processes for recombinant proteins still use four purifications steps. Higher capacity will be a benefit even here, but the focus will be on using steps with higher selectivity to reduce the number of steps. For all proteins, flow-through mode steps where impurities are adsorbed (instead of the much larger product amounts) represent a major trend in purification strategies and help to keep the column and buffer volumes small.



 Do you see disposables continuing to be an important component of biomanufacturing? In what specific unit operations do you feel that disposables are well-established and in what areas do you see future application?



 Disposable equipment and hardware components play a significant role in manufacturing strategies seeking a high degree of flexibility, short startup time, and quick changeover between production campaigns. In other words, they are important in busy facilities and in lean operations, where all nonvalue-adding activities are removed from the workflow. However, if the facility design, the workflow, and the scale-up strategies are not adopted to the features of disposable equipment, the economical benefits may be difficult to realize. For example, in a very busy facility, the large quantities of disposable equipment to be purchased represent a significant cost factor, the more batches that are run, the higher the cost. The cost benefit can best be realized, if the facility is as small as feasible and the fixed cost part of production has been reduced already at the facility-design stage. Currently, disposable equipment is most widely used to store buffers and intermediate product and also in seed-train operations in the upstream process (relatively simple, low-cost storage bags and GE Wave bioreactors). Virus filters and sterile filters are disposable components in the process. More complex functional equipment such as bioreactors and chromatography columns are still not very widely used in regular production. However, there is a clear trend towards single-use bioreactors (SUBs) wherever production scale does not need to exceed 1000 L. Acceptance of these SUBs is gradually increasing among cell-culture engineers. Disposable chromatography columns have also been introduced and are being considered as 'campaign-use' rather than 'single-use.'



 What have been some of the significant advances relating to vaccine development, including cell-culture-based technologies? What are some of the challenges and benefits of using cell-culture technology compared with traditional egg-based technologies?



 Some of the major developments in vaccine technology include novel approaches to the core design of the vaccine. For example, virus-like particles and recombinantly produced components of the infectious organism can trigger an immune response without the presence of the virus, bacteria, or toxin in inactive, weakened, or even live form. These novel vaccine designs carry the promise of excellent safety. Production technology used for vaccines is generally old technology for most legacy products, both upstream and downstream. The introduction of cell-culture-based production of viral vaccines has probably been a trigger for significant new development efforts also for downstream processing of such vaccines. Versatility and relative simplicity of scale up are the main benefits of a cell-culture based production strategy. A major surge in vaccine demand is difficult to respond to with the egg-based production route, if not impossible, if one really aims for high vaccination rates in very large populations. One challenge with the change towards cell-culture-based production is, of course, the need to develop an entirely new downstream process and to adopt to different purity and safety risks upon the change of production source.



 Looking ahead five years from now, can you outline some specific areas in which the industry is working to improve upstream and downstream processing in biomanufacturing?



 Following successful increase of productivity from cell culture, the new theme for upstream processing will be the reduction of quality variability in the product, including the reduction of impurities such as aggregates, glycosylation variants, and other product-related impurities. This is a trend that can already be seen in clone-selection strategies and the use of high-throughput methods in the effort of finding the best producer cell as well as in characterization of the product and the impurities. Ideally, cell viability could also be an improvement area. 

On the downstream processing side, handling the increased biomass from the reactor is a challenge. The harvesting steps will be more and more combined with precolumn purification, which would allow for two-step purification for mAbs and possible three-step purification for most recombinant proteins. A number of groups are working with alternative purification methods such as extraction, precipitation, and crystallization,  looking for replacement of the capture step in the purification train, or more generally for reduction of the overall number of steps. For purification resins, capacity increase will still be a theme in the coming five years, often paired, however, with improved selectivity and operated in flow-through mode.

Articles

Biotech

Nigel Darby, vice-president of biotechnologies at GE Healthcare Life Sciences and speaker at the Drug, Chemical, and Associated Technologies Association (DCAT) upcoming educational program on biologics, offers insight into the current and future state of upstream and downstream processing of biologics.

The Opportunities, Challenges, and Trends in Biomanufacturing

Companies providing outsourced services to the biopharmaceutical industry seem to be weathering the impact of the global financial crisis as many biomanufacturers seek to develop strategic partnerships and increase their outsourcing despite increased internal cost-cutting.  

 Outsourcing and budget projections are an early indicator of industry performance. BioPlan Associates conducted its 2010 biopharmaceutical manufacturing survey to quantify how these factors may translate to capacity problems. The results provide a global view from executives at more then 400 biopharmaceutical manufacturers and contract manufacturing organizations.   

Drug innovators outsource operations for a variety of reasons, including competitive pressures, lack of access to capital and funding, lack of internal expertise (i.e., available staff), accelerating time-to-market (particularly important for smaller companies), lack of available capacity, and a need for enabling technology (e.g.,expression systems and downstream processing). In making the decision to outsource, the preliminary survey results (see Figure 1) indicate that the critical factors companies use to evaluate outsourced manufacturing are not cost-driven, but rather are focused on quality (67% of respondents said so), effectively handing   product contamination (65%), and establishing a good working relationship (60%). These results show that drug manufacturers are increasingly considering contract manufacturing and outsourced services more as an asset to drive strategic manufacturing decisions than as a simple way to save money. We are likely to see this trend continue as the biopharmaceutical services industry matures, and risk-sharing and partnering agreements between service suppliers and drug innovators grow.  

Figure 1: Critical factors when outsourcing biopharmaceutical manufacturing. (FIGURE 1 COURTESY OF AUTHOR) 

Since 1999, the biotechnology and pharmaceutical industries have backed away from the concept of fully vertically integrated business models. Then, virtual companies were getting funding, and investors were recognizing the value that contract manufacturers and other outsourcing firms added. The biotechnology industry has since matured, and companies have gained experience managing their contract suppliers. For example, the industry is now at an equilibrium with about 48% of biomanufacturers outsourcing at least some of their production during the last three years, according to BioPlan's 2009 biopharmaceutical manufacturing analysis.   

Today, the industry has dramatically shifted from traditional tactical outsourcing of testing, clinical supplies manufacturing, and finishing/packaging, and has extended outsourcing to other functions based on long-term company requirements rather than just cost savings. In BioPlan's 2010 survey, we asked respondents where significant increases in outsourcing activities will take place over the next two years. We found that nearly one-quarter plan to outsource their fill–finish operations, where they had not in the past, and 21% will seek validation services (see Figure 2).  

Figure 2: Projected levels of increased outsourcing by 2012. (FIGURE 2 COURTESY OF AUTHOR) 

This emphasis on strategic biopharmaceutical outsourcing recently was expressed by Wolfgang Noe, vice-president of process development at the biotechnology company Biogen Idec (Cambridge, MA) in an interview with BioPlan Associates in late 2009. "Quite a number of CMOs with a considerable track record are on the market, and companies with idle capacity even offer a 'consortium approach' to cover costs." Noe, who is also responsible for the company's outsourcing strategy, notes, "Processes are sufficiently documented now that we can consider outsourcing and expect reliable, long-term relationships from our manufacturing partners." 

is president of BioPlan Associates, tel. 301.921.5979, 

Outsourcing

Strategic rather than tactical considerations are driving biopharmaceutical outsourcing.

A Bio View of Outsourcing

Following its $68-billion acquisition of Wyeth (Madison, NJ), Pfizer (New York) is integrating its manufacturing and outsourcing activities. In a joint 

 discusses Pfizer's plans for manufacturing integration with Tony Maddaluna, senior vice-president of strategy and supply-network transformation at Pfizer Global Manufacturing. The podcast is moderated by Laura Bush, editor-in-chief of 

Manufacturing

Following its $68-billion acquisition of Wyeth, Pfizer is integrating its manufacturing and outsourcing activities (Podcast).

Pfizer Outlines Postacquisition Manufacturing Strategy


Contract manufacturers of active pharmaceutical ingredients (APIs) and intermediates unveiled capacity and service expansions at Informex, the exhibition of custom manufacturers, which was held in San Francisco last month. Below are some highlights from the show. 



 (Baton Rouge, LA) formed a partnership with 

 (High Point, NC) to provide manufacturing capabilities to PharmaCore customers with projects requiring high-volume capacity. Albemarle’s custom-manufacturing capabilities include a network of manufacturing assets in South Haven, Michigan; Tyrone, Pennsylvania; and Orangeburg, South Carolina.  



 (Craigavon, United Kingdom) will be opening two new laboratories as part of the group’s new $120-million North American headquarters in Souderton, Pennsylvania. The laboratories will offer analytical support services and a solid-state chemistry service supporting the development of APIs from invention to launch. 

In formulation news, Almac added an Xcelodose 600S precision powder microdosing system to its product-development capabilities for preclinical and early-phase clinical supply of material produced by current good manufacturing practices (CGMP). The Xcelodose 600S (Capsugel, Peapack, NJ) is a powder microdoser and automated encapsulator that has the ability to fill formulations or APIs directly into capsules with a high level of accuracy. The system also includes an Xcelohood system that provides containment when filling capsules with APIs of high or unknown toxicity.  



 (Mississauga, Ontario, Canada) recently completed $2 million in expansions to support its API-development capabilities. The expansions increased capacity for CGMP manufacturing of APIs at the kilogram scale, improved process-chemistry research and analytical services capacity, and increased the size of the company’s facility to 40,000 ft 

 (Albany, NewYork) announced that it has acquired Excelsyn (Holywell, UK),  a provider of contract chemical-development and manufacturing services, for $19 million in cash. Excelsyn has 60 employees and generated revenue of $15 million in 2009. The acquisition includes a kilo laboratory, pilot plant, and large-scale manufacturing facilities in North Wales. 



 (Detroit, MI) was recently honored for achievement in environmental, health, safety, and security (EHS&S) performance. At the annual dinner of the Society of Chemical Manufacturers and Affiliates (SOCMA), the US-based trade association representing custom manufacturers, in December, Ash Stevens received two Silver Awards for its commitment to performance improvements in EHS&S Planning and Operations as well as Employee Training and Engagement. Those are two of the five core principles of SOCMA's ChemStewards program, which ensures compliance and continuous improvement in the area of EHS&S performance. The 2009 SOCMA Awards captures EHS&S activities during calendar 2008. The awards are based on an individual facility's achievements toward meeting and exceeding one of the core principles of the ChemStewards program.

The Pharma Ingredients and Services business unit of 

 (Ludwigshafen, Germany) formed a partnership with 

 (Soeborg  Denmark), which will allow BASF to make CGMP spray-drying tests and pilot productions of APIs at GEA Niro’s pharmaceutical test station for spray drying in Copenhagen.  



 (Charlottetown, Prince Edward Island, Canada) recently signed agreements with 

(Princeton, NJ), the US-based generics arm of 

 (Basel, Switzerland), for Sandoz to commercialize and market the abbreviated new drug application (ANDA) for docetaxel for injection, the generic version of the anticancer drug Taxotere. BioVectra reached commercial marketing and supply agreements with Sandoz to extend specific marketing rights within the United States. The ANDA was filed in June 2009.



 (Bubendorf, Switzerland) inaugurated its new high-potency API facility at the site of its parent company, 

 (Ahmedabad, Gujarat, India), in late January. The facility’s large-scale capacity (currently up to 1600 L) will be capable of producing multi-metric ton quantities of high-potency APIs (as low as 3). The new facility complements Carbogen Amcis’s high-potency API facilities in Bubendorf.  



 (Redwood City, CA), a biocatalysis company, has formed a strategic partnership with the contract manufacturer 

 that covers the use of Codexis’s proprietary biocatalysis technology for the manufacture of building blocks, intermediates, and APIs for innovator-drug companies. The alliance will enable Codexis to offer production of intermediates and final APIs using its biocatalysis technology. 

In a separate deal, Codex also signed a biocatalysis agreement with the contract manufacturer 

 (Rancho Cordova, CA), which specializes in high-energetic chemistry and other custom synthesis. 

The private equity group Aurelius (Munich) has agreed to buy 

 (Paris), the fine-chemicals unit of the French chemicals company 

 (Paris). Isochem is a provider of fine chemicals, including phosgene derivatives. Isochem has four manufacturing sites in France and one in Kazincbarcika, Hungary. 



 (Pompey, France) and the pharmaceutical company 

 (Marseille, France) announce the successful validation by Novasep of a CGMP manufacturing process for Proveblue (methylthioninium chloride), a methylene-blue-based API. Methylene blue is widely used as a dye in therapeutic and diagnostic applications, but Provepharm says its Proveblue is the first grade of methylene blue that is compliant with the 

 and International Conference on Harmonization requirements. The product also complies with the European Medicines Agency’s guideline on specification limits for residues of metal catalysts, according to the company. 



(Norwalk, CT) has agreed to purchase and license select lithium products from 

(Charlotte, NC). The lithium products that will now be available through Optima include lithium aluminum hydride and lithium borohydride. 



 (Manchester, UK), a company specializing in pharmaceutical metal catalyst and scavenging technology, has successfully completed scale-up of its nickel EnCat immobilized catalyst in preparation for bulk-scale production of high-volume intermediates and APIs. Nickel EnCat is an immobilized nickel catalyst that traps catalyst species in a porous polymer bead, thereby helping to prevent product and wastestream contamination and facilitating handling and scale-up. 



 (Concord, OH) announced on Feb. 10, 2010 that it has agreed to acquire the discovery and preclinical business of 

, which has facilities in Bothell, Washington; Lyon, France; and Taipei, Taiwan. Ricerca’s  headquarters will remain in Concord, Ohio. The proposed transaction between the two companies is subject to customary regulatory and closing conditions. The transaction is expected to close within the next two months.



 (St. Louis, Mo) provided a roundup of its recent investments in API production. The company has announced investments totaling $90 million in the past two years to expand its API production and biologic products. In 2009, the company announced a $30-million investment at its Madison, Wisconsin, site, to expand capacity for commercial-scale high-potency manufacturing. Completion is scheduled for the end of the first quarter of 2010. The new facility consists of two 100-L CGMP suites, another suite containing two 2000-L, reactors, and a further site containing two 4000-L reactors. SAFC also completed a $4.5-million investment in Madison to increase CGMP pilot-plant and large-scale kilogram laboratory high-potency API capacity. In. St. Louis, Missouri, the company recently commissioned a suite for producing high-potency API conjugates. 

SAFC is also investing $29 million to expand its large-scale production of bacterial and fungal fermentation-derived biologic high-potency APIs. The 50,000-ft

 facility will focus on the production of secondary metabolites, cytoxins, and large-molecule proteins.  The facility is scheduled for completion in the first half of 2010. 

SAFC also recently invested $12 million to expand its viral-product manufacturing facility in Carlsbad, California. The new suites added 8000 ft

 of manufacturing space and enables 100-L batch production in stirred-tank bioreactors and 1000-L batch manufacturing in disposable bioreactors. The expansion also included the addition of an 7000- ft

 (Shan-Hua, Tainan County, Taiwan) is constructing a new plant on a 66,670-m

 site in Changshu, Jiangsu Province, China, for initially producing GMP-grade pharmaceutical intermediates and later will be equipped to handle API production. The plant, which will also include a research and development center, is scheduled to be fully operational by 2011.

Contract Manufacturing

At last month's Informex, exhibitors announced expansions and new partnerships relating to contract manufacturing of active pharmaceuticals and intermediates and fine-chemicals supply.

PTSM: Pharmaceutical Technology Sourcing and Management-03-03-2010

The Opportunities, Challenges, and Trends in Biomanufacturing

A Bio View of Outsourcing

Pfizer Outlines Postacquisition Manufacturing Strategy

Roundup of Informex 2010