What prompts over 100

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1 B i o P r o c e s s EXECUTIVE BioPhorum Operations Group Technology Roadmap, Part 1 Four Trends Shaping the Future of the Industry Steve Jones What prompts over 100 biopharmaceutical manufacturers, leading academics, supply partner R&D heads, regulators, and worldwide regional hubs to get involved in a major project? It s when that project identifies the future technology needs of the biopharmaceutical manufacturing industry and accelerates its collective innovation. In February 2015, the BioPhorum Operations Group (BPOG) Technology Roadmapping steering committee met in Washington DC to create the first technology roadmap for the biopharmaceutical manufacturing industry. The biopharmaceutical market has been experiencing dramatic changes: explosive growth coupled with increasing pressures to reduce costs while producing effective drug products. Such changes have forced manufacturers to change their legacy processes. At the same time, innovation Product Focus: All Biologics Process Focus: Product development, manufacturing Who Should Read: Product development and manufacturing, managers, research and technology Keywords: Cost of goods, risk management, operations, product approval, innovation Level: Intermediate Figure 1: The number of cell culture-based products is growing. Cumulative Number of Approved Biopharmaceuticals Synthetic Tissue or cell Stem cell Recombinant (transgenic) Recombinant Virus Microbiologic Biologic has been slow in the bioprocess industry, with biomanufacturers developing technology in isolation and suppliers unclear on what biomanufacturers really want or need. According to Rajesh Beri (technical director of research and technology at Lonza and a member of the 18-member steering committee), The biologics industry has been slow to innovate in the biomanufacturing area. Most companies are still doing the same manual procedures that were performed since our industry started 35 years ago. Acknowledging that issue, senior executives from BPOG s member companies recognized that they needed Biopharmaceuticals Needing Cell Culture for Manufacturing Vaccines (viral production) Recombinant proteins (e.g., monoclonal antibodies, receptor analogues, enzyme replacement therapies) Tissue culture (tissue grafts) Cell therapies (autologous and allogeneic) Stem cell and regenerative medicine a professionally facilitated industry collaboration to reduce the risk and uncertainty of tackling the roadmap project alone. With collaboration extending beyond the BPOG member companies, industry suppliers R&D heads and academia are able to comprehend fully the industry s needs and invest in research and development work with confidence. To establish an effective roadmapping process, the steering committee needed to create a shared vision of the future of biopharmaceutical manufacturing. That had to be followed by the more difficult task of determining how those goals could be accomplished. REPRINT WITH PERMISSION ONLY BioProcess International 14(11) December 2016

2 Identifying key enabling technologies of the bioprocess industry will be the key to progress. Once you have a common goal, reaching that goal can t be achieved by just wishing your way to it, said Beri. Not all avenues will lead to success. To get there, you need enabling technologies. The steering committee s second event (held November 2015 in Washington, DC) was the platform for identifying key inputs needed to create the first biopharmaceutical manufacturing technology roadmap. Such inputs included recognizing those market trends that would be most influential in shaping the industry s future. According to Bert Frohlich (director of bioengineering at Shire), The industry as a whole is facing increased complexity.... In the face of rising costs and cost pressures, we can get stuck in our old paradigm. Frohlich presented four main trends currently shaping the industry (described below). Those trends helped crystallize the vision for future manufacturing scenarios, and they will ultimately lead to identifying necessary future technologies. Four Biopharmaceutical Industry Trends Introduction of New Product Classes: Over the past 30 years, the number of emerging product classes such cell, gene, and tissue therapies has increased (Figure 1). A defining feature of many of these new therapies is that they target smaller specific patient populations. An autologous cell therpay is even personalized to a single patient. Thus many of these emerging products won t necessarily be produced in bulk but rather in small batches as product variants. As the number of specialized therapies increases, such products will be targeted for smaller populations or even individuals. Continued Growth of the Biopharmaceutical Market: According to Frohlich, The biopharmaceutical market is growing fast, and there doesn t seem to be an end in sight. Judging from the number of products in various phases of clinical development, this growth will be dramatic. The fast-track routes that Figure 2: Decision on design capacity is influenced by projected demand and uncertainty. Frequency (Number of Products Produced) Speed of Construction!!? Delay of capital expenditure Scale out? No scaleup required Loss of potential revenue and/or market share Underbuild were introduced by regulators recently will accelerate speed to market and contribute to rapid market growth. Pressure to Reduce Costs: Frohlich notes that the rate at which costs are rising is unsustainably high. He says the pressure from healthcare payers for value, and the evidence that biosimilars will arrive faster than anticipated (reducing barriers to market entry) will force biopharmaceutical drug-innovator companies to be increasingly effective and efficient with operating expenses, including manufacturing. Biomanufacturers are feeling the added pressures from having failures in their product pipelines as well as the high cost of human clinical trials. Uncertainty in Approval and Sales of New Products: As profit margins decrease and costs rise, the margin for error shrinks. Consequently, biopharmaceutical manufacturers face more difficulties in market forecasting and determining whether to scale-up to manufacturing. This trend highlights a dilemma for biomanufacturers: Should they overbuild to ensure that demand is covered or underbuild to save on capital costs? Overbuilding can lead to a capacity surplus when a drug product finally is commercialized, burdening the product with higher depreciation costs. Underbuilding will lead to a capacity shortfall, and a company will be unable to meet product demands, Overbuild Which is worse? Nominal Bioreactor Capacity Requirement for Product ,000 2,000 5,000 10,000 20,000 40,000 Capacity Shortfall Add capacity before demand exceeds? Capacity Surplus Fill with other products? Idle Capacity! Flexibility!!? Lower cost of goods (CoG) due to economy of sale Direct impact on CoG (as %depreciation) Capital tied up resulting in large opportunity costs that can quickly outweigh the overcapacity alternative (Figure 2). Against this background of rapid market growth, increased pressure on costs, and new individually tailored drug products, BPOG facilitated a process in which industry experts agreed on biomanufacturing scenarios of the future and the key enabling technologies for those future processes. The next step for the Technology Roadmapping team was to consider the context in which the emerging technology will be used. To do that, they had to identify the manufacturing scenarios that are most likely to form the backdrop to tomorrow s technology. Once accomplished, this clear vision of the future allowed the team to list key technologies that would play a significant role. Part 2 of this BPOG article will focus on that shared vision. And we will discuss how six teams were tasked with developing long-term visions for six technology topics identified by the Technology Roadmap committee. Steve Jones is director of the BioPhorum Operations Group (BPOG); steve@ biophorum.com; category/resources/technologyroadmapping-resources. For reprints, contact Rhonda Brown of Foster Printing Service, rhondab@fosterprinting.com, x194. December (11) BioProcess International 13

3 FOCUS ON... BUSINESS BioPhorum Operations Group Technology Roadmapping, Part 2 Efficiency, Modularity, and Flexibility As Hallmarks for Future Key Technologies Steve Jones For a complex biopharmaceutical industry, setting out to forecast future technologies must involve considering how such technologies will be used. In the first article (1), I discussed why there was a need to develop a technology roadmap for the biopharmaceutical industry and the trends shaping its future: namely, the introduction of new product classes, the continued growth of the biopharmaceutical market, pressure to reduce costs, and uncertainty in approval and sales of new products. Herein I discuss the technology roadmap s objective, the approach taken to develop it, business driver metrics, and (most important) the scenarios that consider how technology might be used in the future. I will also introduce the six teams looking at key technologies and enablers. Background and Objective Over 150 individuals participated in designing and constructing the technology roadmap. They include representatives from more than 17 biopharmaceutical manufacturers, 12 suppliers to the biopharmaceutical industry, eight academic or government institutions involved in biotechnology research and/or training activities, and four engineering consultancy firms. The overarching objective of the technology roadmapping team is Figure 1: Roadmap development and structure Industry Trends Business Drivers (Why) Biomanufacturing Scenarios (What) Enabling Technologies (How) Payer pressure on cost Process technologies ultimately to streamline delivery of drug products to patients. Setting the direction to achieve that requires establishing a common set of assumptions to frame business drivers and industry needs. The intention is to serve as a guide for the biomanufacturing industry by projecting 10-year targets, assessing technology needs and challenges to be resolved to meet those targets, and recommending potential solutions and areas of innovation that the industry can implement. The goal of the first edition of the roadmap is to reach an audience far wider than that represented by just the original member companies. That will Diversification of product groups In-region manufacturing Speed Cost Flexibility Quality Large-scale stainless steel 2,000-L scale single-use continuous upstream process 2,000-L scale single-use batch upstream process <500-L scale, continuous process Very low volume product, customized to patient Modular and mobile Personalized medicine In-line monitoring and realtime release Automated Knowledge Supplier facility management partnerships allow more people to comment, review, and update subsequent editions as well as contribute to implementation planning. The roadmap is designed to be a starting point for future discussions and activities. It acts as a guide, so it is up to individual manufacturers, suppliers, regulators, and others to make their own resource investment and implementation decisions. Choosing a subset of biological therapies to focus on in terms of developing the view of future technology was an important decision. Because of their current and shortterm future dominance, monoclonal antibodies (MAbs) produced by REPRINT WITH PERMISSION ONLY 14 BioProcess International 15(2) February 2017

4 Figure 2: Expert teams delivering roadmaps for the six key enabling technologies Roadmap Team Process technology In-line monitoring and real-time release Modular and mobile Fully automated facility Supplier management Knowledge management Vision Process intensification: intensifying production through highly concentrated reactants and products and combining unit operations into single units Continuous processing: new separation and media technologies, coupled with advanced automation and process control Process control and assurance of product quality through advanced monitoring devices, in direct or multiattribute sensors, and process analytical technologies (PAT) Global regulatory testing standards, advanced process control strategies, and raw-material characterization Manufacturing systems that are quick to configure and assemble using plug-and-play standard designs Scale-up from development to manufacturing, with a focus on automation, equipment, and biology, results in a fully automated facility Suppliers become technology development partners for our industry, collaborating to solve problems Integrated knowledge of product and process technology across the development, manufacturing, and commercial value streams Benefit Reduction in facility size, reduced capital investment, speed to market Flexibility for smaller patient populations, speed, reduced cost Tighter product and process control reduces cost of quality and enables real-time release Eliminate billions of dollars of inventory, release product 1 2 days after manufacture, reduce quality costs Scalable capacity, manufacturing process available in weeks rather than in years Consistent high-quality product, reliable supply, reduced time to market Innovative supply partners, industry needs delivered faster and better Speed to market, cross-product learning, efficiency throughout product lifecycle A quantitative UNDERSTANDING of business drivers and of their related metrics is particularly important because they help manufacturers determine the relative value of technology options and solutions. mammalian cell cultivation are the key focus. Because recombinant proteins represent the largest class of biological drugs by far today for both therapeutics and vaccines, the roadmap emphasizes opportunities for improvement of such important products and MAbs in particular. Roadmapping Methodology Having established the framework for the collaboration, the team next created the process for developing the roadmap. According to Rajesh Beri (technical director at Lonza and a member of the steering committee), Projecting the enabling technologies of the next 10 years is not an easy or a simple task not in an industry as complex as biopharma. Luckily, other complex industries already have pioneered technology roadmapping with great success, yielding case studies and best practices. To create a method for developing the roadmap, the team chose a process that had been pioneered at the University of Cambridge (Figure 1). This method started with identifying industry trends and business drivers (the why) and progressed through to the next stage of identifying the commercial biomanufacturing scenarios (the what). That provided a clear vision for six enabling-technology teams cataloging the required capabilities and enablers (the how). Business Drivers and Metrics Understanding the connection between market demands and a company s business reality will be key to its success by providing direction in decision making and ability to respond to changes. A quantitative understanding of these drivers and of their related metrics is particularly important because they help manufacturers determine the relative value of technology options and solutions. The roadmapping team identified four major business drivers: flexibility, speed, quality, and cost. The relative importance of those drivers depends on the business model and circumstances of an enterprise. Based on the market trends and business needs, targets were set for each metric s five- and 10-year horizons. For instance, a key flexibility metric is the titer range in upstream processes, which are directly accommodated by downstream facility fit. A key speed metric is the time to release product (end-to-end speed). A key cost metric is reducing the total cost to supply by 50%. In a few cases, targets were set considering only MAbs. Those metrics aligned with demands of identified trends and drivers that require significant innovation to leap forward and supplement existing focus on incremental improvements to support current operations. Visualizing Future Biomanufacturing Facilities The technology roadmap steering committee reviewed numerous scenarios for biomanufacturing that could exist in 10 years. Selection was based on the realization that there will be very different facility requirements depending on product portfolio, volumes required, emerging market requirements, and need to fully use existing capacity. Given the complexity of the biopharmaceutical industry and an increasing diversity in drug products and companies, the committee selected five high-level scenarios to cover a full spectrum of process and facility types. Each scenario or facility type is associated with a representative 16 BioProcess International 15(2) February 2017

5 Table 1: Main facility-type scenarios with typical associated product types and business drivers Scenario Facility Type and Base-Case Process Typical Products and Product Classes Typical Business Scenario and Key Drivers 1 Traditional large-scale stainless-steel facility: fed-batch upstream process, stainless-steel Low-complexity proteins (e.g., MAbs, MAb fusions, and other recombinant Very high-volume product: demand range = 100s to 1,000s kg/yr, relatively high certainty bioreactors >10,000 L, high (relative) cell culture proteins with low degrees of of approval and market acceptance, little to expression rate ( 3 g/l), batch downstream process, high (relative) purification recoveries glycosylation) no requirement for regional manufacturing, desire to maximize use of existing assets or to build new (greenfield), single or few products, low to moderate need for fast launch 2 Large- to intermediate-scale facility with singleuse technology and perfusion cell culture: perfusion upstream processing with 2,000-L single-use bioreactors, batch downstream processing 3 Intermediate-scale and/or multiproduct facility with single-use technology using batch-mode cell culture: batch upstream and downstream processing 4 Small-scale portable facility: typically uses single-use technology using batch-mode cell culture, continuous upstream and downstream processing, portable process desired for regional manufacturing or designed for rapid facility change out 5 Parallel processing facility for personalized medicine: isolated, patient-specific preparation of therapeutic protein or biological therapy, typically manual cell culture or cell preparation, batch downstream processing, highly portable but limited set of unit operations for possible bed-side deployment or centralized parallel processing MAbs and/or more complex proteins (non MAb) such as therapeutic enzymes Higher complexity proteins: bispecifics or multicomponent biologics, conjugates Potentially highly complex biologic such as vaccine or allogeneic cell therapy Potentially highly complex biologic such as autologous vaccine or gene or cell therapy High- to medium-volume product: demand range = 100 kg/yr (range ), moderate certainty market acceptance and/or peak market demand, relatively small product mix (one to several products) with limited need for campaign changeovers, and possible requirement for regional manufacturing Medium- to low-volume product: lowvolume product for a specific patient population, demand range = 10 kg/yr (range 5 50), multiple products to be manufactured at same site because of changing product mix and/or possibility of regional manufacturing required per product but several products possible, clinical-scale manufacturing and/or lower certainty of approval and market acceptance Low-volume products: low-volume product, 1 kg/yr (range 0.5 5), relatively low certainty of approval or market acceptance, requirement for regional manufacturing highly likely, high need for rapid deployment and/or into regional markets Very low-volume or personalized product customized to patient, base case = 1 kg/yr (range ) Essentially, there won t be one SCENARIO that fits all the demands. set of business conditions that reflect a typical mix of key drivers. Each business scenario was selected with a distinct set of business dimensions, including capacity requirements and business drivers (e.g., facility flexibility, speed to clinic and to market, quality, and cost of manufacturing). Paul McCormac (director in Pfizer s Biomanufacturing Sciences Group) has a unique understanding of the biomanufacturing landscape and played an integral role in identifying the roadmap s future manufacturing scenarios. The scenarios are a vision of what the multiple manufacturing footprints will look like in the future to support biotech products in development. Essentially, there won t be one scenario that fits all the demands. Some probably will be very large in scale, some will be 2,000-L disposable with continuous operations. Other scenarios will be very small scale for newer, exciting therapies. The range of those potential requirements has proved to be quite considerable. Production outputs can vary from metric tons of a recombinant protein (as has been the case for some blockbuster MAbs) to very small quantities of a drug or preparation intended for a single patient. Table 1 summarizes the five main scenarios. It includes a list of typical products and facility features that are characteristic of each scenario and describes the general facility type and manufacturing process. Projections on Innovation Efforts Six expert teams projected where the industry will be investing its innovation efforts over the coming decade. Process technology, including advanced automation, concentrated reactants, and continuous processing, which would evolve from current standards and manufacturing processes In-line monitoring and real-time release, including quality control technologies for eliminating lag time between manufacturing and distribution-enabling businesses to be more agile and reduce cost of holding inventory Modular and mobile manufacturing systems that are quick to configure and assemble using plugand-play, standard design Automated facilities and improving automation and equipment 18 BioProcess International 15(2) February 2017

6 to make the transition from development to manufacturing more seamless Supply partner management such that suppliers become technology development partners for industry, collaborating to solve problems Knowledge management, including integrating the knowledge of product and process technology across development, manufacturing, and commercial value streams. The six teams created individual roadmaps for their areas, describing the vision for the future and the benefits that would accrue to the industry. The combination portrays a future landscape describing where the bioindustry will be investing resources over the next decade. Subject-matter experts were engaged for each team to visually roadmap details of needs, challenges, and potential solutions. Strategy Development The technology roadmapping process started at a macro level by defining market and industry trends. Such trends include reducing costs, meeting the demands of smaller populations of patients, and improving the speed of products to clinics. At a lower level, such needs are translated into business drivers (cost, speed, flexibility, and quality) and then broken down into further granularity (e.g., describing how in 10 years time there will be a 10-fold reduction in the cost of a classic MAb product). The committee has created scenarios for the future of manufacturing and the types of facilities that will be needed. By doing so, experts can step into the actual manufacturing value stream to work out how the future bioindustry wants to operate and the technologies required to achieve those targets. The final article in this series will be timed to coincide with the launch of the technology roadmap. It will provide highlights and conclusions from the report, including discussions on where innovation is necessary to achieve the 10-year vision of the future. It will feature who has been involved in the creation of the roadmap, the cross industry input, and how that will shape the future. Part 3 also will present approaches to roadmap implementation for accelerating innovation and describe how the BPOG team is working closely with stakeholders in the industry to communicate the content. Reference 1 BioPhorum Operations Group Technology Roadmap, Part 1: Four Trends Shaping the Future of the Industry. BioProcess Int. 14(11) 2016: Steve Jones is director of the BioPhorum Operations Group (BPOG); steve@ biophorum.com; category/resourcestechnology roadmapping-resources/introduction/. For reprints, contact Rhonda Brown of Foster Printing Service, rhondab@fosterprinting.com, x194.kn All-in-one laboratory chromatography equipment BATCH CONTINUOUS No need to choose, You can have it all! BOTH ADAPTABILITY: Batch, parallel batch, continuous chromatography and continuous process. FLEXIBILITY: From 1 up to 6 columns, with any media, the possibilities are endless! SMART SOFTWARE: BIOSC Predict, a unique optimization software to develop the capture step. GLOBAL SUPPORT: Training, responsive maintenance and rental service. CONTINUOUS SCALE UP: Expertise in designing equipment from lab to pilot scale. Biosc@novasep.com Winner Pharmaceutical Engineering

7 FOCUS ON... INNOVATION BioPhorum Operations Group Technology Roadmapping, Part 3 Enabling Technologies and Capabilities Bob Brooks, Jonathan Dakin, Clare Simpson, and Linda Wilson Although great strides have been made over the past 20 years to increase the productivity and robustness of manufacturing processes for biopharmaceuticals, the cost and complexity of their development and manufacturing remain high, especially in comparison with those of smallmolecule pharmaceuticals. Process improvements are required to increase patient access while maintaining the viability of an R&D-driven biopharmaceutical industry. Facility productivity, cost of goods (CoG), and capital investment all have significant margins for improvement. Such goals can be achieved not only through process technologies available to the industry, but also through enhancements to the way in which those technologies are implemented. Automation, analytics, modularity, and knowledge management all have key roles to play in this transformation. In part 3 of this series, we discuss how those factors will shape the industry s future. Thirty-one member companies contributed to this first edition of the roadmap, with additional input from academics and agencies. More than 170 people (both biopharmaceutical manufacturers and suppliers) are now actively involved in the roadmapping process. Figure 1: Process technologies key themes Streamlining unit operations Incremental efficiencies Cultural shifts Future performance targets Approaches Linking upstream and downstream processes Continuous processing High-value hot spots Process modeling Unit operations technology assessment Manufacturer and supplier collaboration Process Technologies: the Backbone of the Roadmap Developments in process technologies are set to increase the productivity and robustness of biomanufacturing. Better technological solutions in manufacturing plants ultimately will lead to safer and more cost-effective drug products. The impact of future process technologies is likely to affect every business driver: cost, quality, speed, and flexibility. Thus the Technology Roadmap expert team has arranged the document as if it were a process map rather than focusing on each business driver or technology type individually. Disruptive technologies Described alongside operational needs Integral to accelerating industry performance Linkages Faster process improvement Regulatory impact assessment Cohesive validation processes Inline monitoring (performance feedback) Automated facility (linking operations) Knowledge management Closed systems and standardization The analysis focused on the most common production scenarios in the industry from an upstream perspective: 2,000-L disposable and 10,000-L stainless steel bioreactor capacities for the commercial production of monoclonal antibodies (MAbs). The process map of a bioprocessing operation includes each unit operation and its drivers, needs, and challenges described in detail. Priorities for each process operation will vary. As an example, for bioreactor design, the team suggests that the biggest driver should be speed to reduce the time for cell growth. For the harvesting and distillation step, the biggest driver will be cost. REPRINT WITH PERMISSION ONLY 20 BioProcess International 15(4) April 2017

8 A focused development effort on a select number of technologies (Figure 1) could have a broad and significant impact in our industry, including process intensification to improve titers, thus reducing volumes and the number of unit operations, increasing the number of streamlined ways of working, and lowering capital cost of facilities richer chemically defined media, feeds, and supplements that enable higher cell densities and titers, simplified media make-up, and longer media stability robust, scalable harvest technologies and cell retention devices that minimize large capital investments and handle increasing cell densities standardized modular claims for robust viral clearance approaches that provide streamlined regulatory processes and ease process development buffer management approaches that reduce operational constraints and space requirements for buffer preparation and hold as well as costefficient inline dilution solutions high-capacity chromatography resins with extended lifetimes to reduce costs single-use technologies to increase flexibility and improve closed systems, decreasing capital cost and total cost of goods over product lifetime. Challenges in Reaching for Increased Process Efficiency The bioprocessing industry faces many challenges in reaching its goals of increased process efficiency and improved economics. Among them are variations in product potency, market requirements, and manufacturing productivity that necessitate a broad range of facility designs. To have maximum impact, new process solutions must be adaptable across a broad range of scales and facility types. As mentioned in a previous article (1), we used data modeling to evaluate the four most common production scenarios and distill the most useful strategies from the huge amount of data. Among our findings were both small or and large changes to Figure 2: In-line monitoring and real-time release Now Raw Material Inputs The Future Raw Material Inputs Constrained Process Adaptable Process Variable Product Quality Attributes Predictable Product Quality Attributes individual unit operations. Although such changes made quite integral differences in small areas of a process, they didn t make huge differences to overall process speed, cost, and capacity. Our conclusion was that the high value and breakthrough improvements will come only from truly disruptive technology that affects a process from end to end and links upstream and downstream. Among the valuable input from supply partner members of the Technology Roadmapping team was the feedback that a lot of the needed technology is already available. But it is not already being used because the first company to implement it will have to bear the brunt of costs associated with validation and regulatory compliance. That company also will have to determine what the validation process would include and what would have to be demonstrated to regulators. It is at this point that the benefits of a collaborative industry approach reap rewards, negating the need for anybody to be the first guinea pig. Regulators also will be able to evaluate new technologies in an open environment, speeding up the approval process. Benefits of Implementing Modular and Mobile Processing Biopharmaceuticals and cell and gene therapies currently are produced in fixed facilities that require significant upfront, at-risk capital investment. Modular and mobile concepts offer an opportunity to shift this paradigm away from large, fixed assets toward networks of smaller, standardized manufacturing facilities. They can be built in less than half the time and in a way that defers cost until there is greater certainty about market demand and probability of success. Such manufacturing platform standardization provides an opportunity to accelerate the delivery of therapies to the market, improve supply-chain responsiveness and regulatory review for new products, and simplify the process of adding capacity. One of the greatest challenges to this approach is a need for standardization. Biomanufacturers understand that being able to buy standard parts from multiple suppliers would make the market cheaper and more dynamic. When manufacturers launch their products and write their facility and kit plans, many tend to overcomplicate them. By the time those plans reach a supplier, the kit has become customized and tailored to a manufacturer s specific use. Of course, the supplier is willing to accommodate the customer s needs. A complete culture shift in the industry is required to move toward standardization that manufacturers can use, suppliers will buy into, and regulators will accept. Another challenge to implementing the modular and mobile approach is regulatory validation. Currently validation takes a three-stage approach: First, equipment coming into a factory is validated, then the operation that will be performed using that equipment is validated, and finally the product coming out of that operation is validated. This process can be simplified down to only one episode of validation. For example, if the same standard components are used in the same arrangement in a facility and under the same conditions, then there should be no need to revalidate. Again this is a seismic shift in thinking for the industry that would involve changing the way regulators authorize the production of new products and the change-management processes involved. Eliminating nonvalue activity for both manufacturers and regulators could speed up time to market of new products by 50 80%. 22 BioProcess International 15(4) April 2017

9 The third challenge in implementing a modular and mobile approach is flexibility. In theory, scaling up/down a manufacturing facility should be very easy if it must be moved to a new location. This scenario would be very useful in times of emergency, such as during a pandemic outbreak, when a vaccine production facility could be located where it is most needed and removed when the outbreak is over. In that scenario, production is being moved to the patient population. That reach brings with it a globalization issue: different regulatory standards and approaches in different regions. Global standards would be required so that those facilities could be moved around quickly and easily. In summary, to realize the benefits of a modular and mobile strategy, the industry will need to make progress with the following recommendations. First, develop standard, simple, fit-forpurpose design of facilities and processes packaged in a modular format. Such modules could be fabricated, tested, and delivered much more quickly and at a lower cost than traditional facilities. They could be added or removed as needed without interrupting operations and could be repurposed, allowing for alignment of capacity with demand. Second, industry consensus on standards will be required to define the capabilities and interconnection of a facility, room, process, equipment, automation, and single-use systems (SUS) with a key need to focus on interconnection. That would require collaboration between pharmaceutical manufacturers and suppliers. Third, collaboration with regulators will be required to enable a new regulatory strategy in which the facilities are treated as equipment for purposes of validation and qualification. This would allow faster regulatory licensure of follow-on capacity additions or new products. Fourth, operational robustness, operator safety, product quality, and ultimately patient safety will be improved through standardization and continuous improvement. Robust supply and performance of disposables will need to be supported through improved supply chains. Finally, efficiencies in drug-product operations and supply-chain inventory of drug substances will be improved through design and colocation of drug-substance and drug-product facilities. Drug manufacturers can use the above strategies to successfully respond to the market trends and business drivers. Making Real-Time Release Possible with In-Line Monitoring Using innovative measurement systems such as in-line monitoring will speed up manufacturing to quickly release biopharmaceutical products (Figure 2). In-line monitoring has multiple benefits not only in terms of lead times, but also product quality because in-line monitoring improves measurement systems and because of the knock-on effect on supply chains and capacity. For manufacturers, it provides a cost positive benefit, including drastic reductions in the costs of holding large inventories. The real step change achieved through this approach is in lead times for drug-product release moving from over 20 days to under five days. A manufacturer can decide the fate of a batch in real time rather than having to wait a month for analytical results. Implementing in-line real-time monitoring for bioprocesses brings unique challenges. They include the complexity and variability of raw materials (especially living organisms), the difficulties with moving from stainless-steel to single-use equipment, and the potential shift from batch to continuous processing. One key challenge to achieving real-time release is ensuring that high-level technology demands and systems are met. The industry s future needs will revolve around the development of innovative in-line monitoring systems, associated probes and sensors, and appropriate analytics to make sense of data and give a control point later in each process. The only way that such scientific and technical challenges can be overcome is if the bioprocessing industry has close relationships both with academics (in terms of developing the analytics and using prediction models) and suppliers (to specify equipment that will be needed for real-time monitoring of processes). The industry will need to work collaboratively to ensure that regulators accept and understand these new approaches and that suppliers are brought into processes early to develop a set of common standards for equipment and specifications. In the Technology Roadmapping team, companies and supply partners already are talking together about the needs, the difficulties, and the solutions to be developed and implemented. Part of the collaboration is connecting with regulators and academics and keeping them well briefed on the progress being made as well as being transparent about challenges and options we have for the future. Automated Facilities of the Future Future biopharmaceutical facilities will be fully automated. They will include a critically enabling set of standardized and interoperable technologies and capabilities that will decrease capital and operating costs, reduce time to build and commission facilities, and speed up drug-product launch to market. They will be integrated from development to final drug product, and they will be able to handle variable processes, variable batch sizes, and variable geographies. To meet different market demands, future facilities will be able to quickly ramp capacity up or down and do so with minimal staff, minimal time to change over, maximum safety, and minimum regulatory observations. Benefits provided by an automated facility include full integration across all systems such as manufacturing execution systems (MES), personal communication systems (PCS), and laboratory information manangement systems (LIMS) full integration for quicker and cheaper build times; access to all the data generated with full context; and decreased variation such that full 24 BioProcess International 15(4) April 2017

10 Figure 3: Process technologies key themes Holonic components are the whole and part of the whole. Equipment comes complete with automation, MES, and ERP elements fully established. In effect, the MES or manufacturing ERP system for a facility is built as the components are linked together, rather than by attempting to fit equipment into an existing framework. The concept delivers significant flexibility, but requires a paradigm shift in the way that systems are created: There is no longer a difference between layers, but simply a platform component that delivers functional capabilities. Pervasive connectivity means having small, inexpensive, and robust networked processing devices distributed at all scales to allow for simple connections rather than integrating disparate systems. The facilty of the future will be created dynamically from holonic components with pervasive connectivity to and across the value chain. Operationally, the facility will use real-time quality control for production, be capable of automatically adapting to change, and deliver intelligent insight and decision support based on boundary-free information flow and self learning. Self or machine learning focuses on prediction based on known properties learned from available data. It is supported by data mining, which focuses on discovery of unknown properties of data. The output of this process supports the ability to establish knowledge from those data. Real-time quality control is the logical point at which we move from paramater control (e.g., temperature) to full process control (multiple parameters) actually controlling the quality outputs that we want to achieve. The logical conclusion of this is that we have the correct analytical systems in place so that external quality control becomes no longer necessary. Boundary-free information flow is integrated information securely delivered whenever and wherever it is needed and in the right context for the people or systems who will use that information. integration will lower operating costs and improve quality standardization of underlying processes and unit operations that allows for quick and easy configuration (instead of custom programming) data management, with the extraction and visualization of information out of the data highly available automation systems reduction of manual labor through the use of robotic systems and mechanization (currently, labor costs for biopharmaceutical facilities are among the highest of any industry) new and converging technologies that eliminate errors through paperless operation and guide maintenance and support activities; reduce cost through the use of smart scheduling techniques to maximize use; and enable the move to cloud and virtualized technologies disruptive concepts and technologies such as the convergence of platform technologies to provide a new model for operation, with capability and intelligence distributed at much lower levels in the plant architecture (plug-and-play modules); and the use of large amounts of data and adaptive machine learning to provide decision support and help eliminate delay and errors. Important challenges must be overcome to fully implement an automated facility. The first of these is variation in volumes and batch sizes involved in manufacturing processes and the diverse geographical locations. Attaining the ability to ramp capacity up and down will speed up commercialization. The sooner that is done, the faster the build costs can be met and a company can get into profitability. Achieving standardization across the industry is a huge paradigm shift for achieving best practices as well as standardization of equipment and protocols. Adapting to change and a willingness to collaborate will be the hallmarks of leading companies, both for end users and suppliers. Some people may see that as a battle to determine winners and losers in terms of automation providers, but that type of focus will serve only to delay change and lead to adoption of less technology in the near term while bioprocess companies wait to see what evolves. Suppliers will need to ensure that their supply chains are on board and should realize that it is possible to work within standards and still remain competitive (Figure 3). Knowledge Management: The Heart of a Manufacturing Process Knowledge management as a process of capturing, developing, sharing, and effectively using data is important to drive business by providing patient, product, and process information. Including dimensions of people, processes, content, and technology (PPCT), it is both a multidisciplinary and cross-functional approach to innovation and continuous improvement. A robust and reliable knowledge management platform integrates product and process information across development, manufacturing, and commercial value streams. It provides near real-time access to information and crossproduct learning. As the industry advances in its maturity and capabilities, the need for knowledge and knowledge-enabled processes becomes essential. The Technology Roadmapping Team s vision of knowledge management for the future is of an organization in which people have access to all knowledge in seconds or minutes (Figure 4). This capability would enable and speed up many tasks: Technology transfer would be efficient and done right the first time. Knowledge would be readily available for risk assessment and development of process designs and control strategies. Investigations would find root causes quickly. Second-generation products and analytical methods would be developed using a foundation of deep and growing institutional knowledge. April (4) BioProcess International 25

11 Figure 4: Knowledge management diagram for people, process, content, and technology (PPCT) Knowledge workers Knowledge managers Formal communities of practice Training and communications Measurement reward systems Knowledge-sharing culture Repositories Document management Common taxonomy Enterprise discoverability and sharing capability Tagged content Shared standards, specifications Content Lessons learned would be built seamlessly back into routine operations. Many organizations have experienced difficulties associated with poor knowledge management not helped by the proliferation of knowledge management solutions that do not deliver on their intended use. Especially within biomanufacturing, content management systems are neither institutionalized nor strongly adopted nor routinely used. A geographically dispersed and mobile workforce presents challenges in knowledge management collaboration. Unclear knowledge management strategies that are not introduced with a business focus will have difficulties attracting attention and gaining momentum. Another major barrier to knowledge management can come from a lack of a systemic approach and no cultural readiness: Although the right technology is important, it is insufficient unless it is incorporates the right people processes. Implementing a knowledge management system requires both a paradigm shift and a cultural transformation that begins from the top of an organization. The bioprocess industry understands that this knowledge management revolution is on its way. Manufacturers must make sure they can not only manage the volume of information, but also ensure People KM Technology Process Forming communities of practice Collaboration process Survey, census, requirements analysis Metrics and reporting Cross-organizational integration Linking to the operating force Workflow and project management Collaboration tools (DCO) Learning Portals Search engines and locators Dashboards, wikis, and blogs Warrior dashboard that it is understood and that best practices are in place. Data privacy is another issue that the industry must address. Doing so will allow manufacturers to share knowledge and store it in the cloud, while making sure that there is privacy for both manufacturers and suppliers. The technology roadmap outlines the industry s needs for knowledge management. Understanding the value in achieving those targets (set for 10 years out) is critical and and can be achieved through collaboration and partnership. The competitive and precompetitive spaces offer many opportunities to look at best practices for early adoption of knowledge management systems. Supply Partnership Management: The Key Ingredient The Technology Roadmapping team recognizes that supply partnerships are an important area of the roadmap. The Supply Partnership Management team focused on its own future goals and on becoming an important element and contributor to all of the other teams. Supply partnerships are a developing way for companies to work, bringing more value to the supplyand-demand side of the industry and accelerating the pace of innovation. The goal is to influence the direction and decision-making of the industry as companies develop new future technologies. The Roadmap s Supply Partnerships team had a different slant than the other teams. It focused specifically on the relationship of biopharmaceutical companies and their supply base rather than just one technology. The team envisions a future biopharmaceutical industry characterized by a few fundamental elements: creating a series of standards for materials, components, specifications, documentation, and more creating new value propositions that focus on delivery and performance in addition to the traditional focus on innovative technology; this allows customers to reward great manufacturers that sustain business and not just the great innovators that get selected early in a development cycle creating more flexibility, agility, and interchangeability that will lead to greater opportunity for suppliers of new and additional applications as well as improve supply chain continuity creating lean and efficient supply chains driven by super integration of business systems between customers and suppliers. Five key enablers that will deliver the industry s vision are openness and trust, standardization, built-in quality, electronic data exchange, and forecasting and demand planning. The main drivers for moving toward this vision are cost, speed, and flexibility. Total cost to supply should be driven down by volume use, improvements in supply chains, and upfront build costs being reduced by implementing more flexible designs. Quality is a key challenge. Companies need to keep raw-material variability low and product availability high. Quality needs to be built in, which means minimizing through automation any opportunities for errors to occur in a design process (e.g., using robots). When it comes to forecasting and inventory planning, the onus is on integration with suppliers and biopharmaceutical manufacturers to work together, sharing information on material use and replenishment timing. 26 BioProcess International 15(4) April 2017