Go strategic with single-use technologies FEBRUARY 2017

Transcription

1 Go strategic with single-use technologies FEBRUARY 2017

2 NEW PHARMA REALITY The world of pharmaceutical manufacturing is changing dramatically The pharma and biotech industry is booming with large and diverse pipelines. The need to bring products to market at high speed and low cost combined with globalisation, increasing GMP requirements and price pressure result in crucial challenges regarding flexibility and timeto-market on a day-to-day operational level. Single-use technology an engineered process equipment solution, providing a clean, disposable product contacting surface and most commonly made of plastic components, which together create a system or unit operation designed for one-time use. The new pharma reality After decades of business as usual, the pharmaceutical industry is facing changes that will mean new expectations of success for pharmaceutical companies. Most importantly, manufacturing sites need to be much more flexible and agile, considering the pace at which the pharmaceutical industry is changing and the uncertainty involved. Many pharmaceutical companies are in the midst of a transformation and this affects their success criteria for manufacturing. The shared perspective of pharmaceutical companies is that of a new pharma reality. As such, it is essential to understand what this new reality of site agility means for pharmaceutical production and site operations. The questions every company should ask itself Companies are forced to adapt by changing R&D strategies, defining new business models, cutting costs and bringing novel drug categories to the market faster and in smaller volumes. Faced with this challenging and dynamic reality, the pharmaceutical companies we meet are asking themselves the following questions: How can we build more flexible production facilities? How can we minimise production downtime? How can we bring our products to market faster? How can we optimise our global quality procedures in smarter ways? How can we minimise the risk of implementing new technologies? Our response At NNE, we don t see ourselves as external advisors, but as partners who share the challenges and successes of our customers. And we are committed to solving our customers most complex problems in this new pharma reality. One key objective is to deliver solutions that will ensure that our customers achieve agile and flexible operations. In this newspaper, we will address the flexibility and agility challenge in more depth - and introduce some of the solutions we provide to help our customers meet the challenge. Focus has shifted High-value products in smaller volumes Potential patient groups for today s products are generally much smaller than seen 5 years ago due to progress of personalised medicine. But there are many more indications and associated products. The new challenge becomes to add flexibility to an efficient manufacturing network. OLD Focus on manufacturing speed NEW Focus on change-over speed Where does flexibility really matter? Process-level flexibility Suite configuration flexibility By now, everyone working with pharmaceutical production has seen the writing on the wall: agility and flexibility are the keywords to a successful biopharmaceutical production site. Because products in this new pharma reality are produced in much smaller scale than before, you have to be able to introduce new products to your facilities much more frequently and be able to produce several different products on the same site. But designing a truly agile and flexible facility requires more than just introducing flexibility through, for example, single-use technology. At NNE we have designed more than 20 flexible facilities for different pharmaceutical companies all over the world since 2011 and that experience has given us a unique understanding of the best approach to integrate flexibility as part of strategic needs. Here, we introduce some of the most important elements to consider. Single-use technology Whether the facility was for monoclonal antibodies or ADCs (antibody drug conjugate) or it included fill-finish capability, the starting point for all of these projects has been Bio on demand, our standard facility for biotech manufacturing based on single-use technology. We see single-use solutions as an important part of achieving flexible manufacturing facilities for biopharmaceuticals. It has become a mature technology and many pharmaceutical and biotech companies around the world have now build significant experience in both API manufacturing, upstream as well as downstream, as for the fill-finish part for drug substance or drug product. Hybrid solutions We often found that a hybrid solution is more operational and cost-efficient, because it maximises efficiency and utilisation. A hybrid of single-use and stainless steel is typically the right solution, but finding the right balance can be tricky especially if the planning is done directly at supplier level, because each supplier may have limited experience with other technologies than what they are supplying. Proper planning and design of a single-use facility or a hybrid facility with a mix of technologies are key. Operations flexibility Site and integration flexibility Investment flexibility Layout and operational design From these projects, one of the most important findings for us is that the challenge is not the construction method itself it is actually an overspecification to specify the building method from early on unless dictated by extremely difficult site conditions. Much more important is the layout, the process understanding, operational design of flexibility, operational knowledge, adaptability and configurability for your changing production demands. Continuous manufacturing Some of the facilities were designed to include continuous manufacturing and it is indeed an important biotech trend. The projects considered perfusion-mode upstream processes in combination with batch-mode downstream operations. A few projects also included considerations for continuous downstream processes. In both cases, the Bio on demand base concept required limited configuration to adapt to these production modes. Designing to operate Each technology has its advantages and disadvantages and a hybrid solution is often the most cost-effective. In fact, the right mixture of the two technologies is part of the solution to combine agile and flexible manufacturing with cost-effectiveness.

3 In the new pharma reality, BIO flexibility ON DEMAND is a strategic advantage Since 2011, NNE has designed more than 20 Bio on demand facilities for top players in the pharma industry. These projects show that flexibility and open architecture provide a robust basis for meeting diverse demands in line with the trend towards smaller batch manufacturing. From idea to first GMP batches in 18 months At NNE, we address the need for fast project completion through an aggressive approach to fast-track work. Our goal is to execute any project within months from project approval after basic design to finalising the operational qualification. Go strategic with single-use technologies Whether your challenge is speed to market, flexibility, product quality or operator safety, single-use technology may be your optimal solution. The advantages of single-use technology are many, with reductions in investment and variable costs the most commonly cited benefits. However, they represent only one aspect of a strategically important decision in production technology. Single-use technology presents a new set of front-end considerations. These include process compatibility, leachables/extractables, film selection, back-up supplier and waste management. In addition, your quality assurance system needs to be extended to cover not only raw materials, but also production technology. At NNE, we employ a stage-gate model to enable you to capture these critical aspects of single-use technology at the right level. In turn, this will benefit your entire facility and all the business processes involved in your manufacturing operations. LINKING TECHNOLOGY WITH STRATEGY Successful implementation of single-use technology starts with a structured and in-depth evaluation of technologies and their implications for your production processes and costs. Based on our modular design approach, we can quickly assess the cost advantages that single-use technology can bring you. By evaluating process designs in terms of cost as a function of the percentage of process equipment that is installed as single-use technology we develop trend curves for cost advantages of single-use technology in a typical bioprocess scope. You can then use the trend curves to quickly forecast the savings for alternative configurations. We will aid you in evaluating your single-use implementation by: Forecasting the savings for alternative single-use technology configurations 360 evaluation of single-use technology s impact on your facility area, HVAC, process equipment, utilities and automation costs Workshops to take you through and evaluate all the technology/supplier combinations Evaluation in a pilot plant scale

4 Reduce investment cost and increase flexibility with single-use technology The Bio on demand concept is based on configuration with single-use technology process equipment to reduce investment cost and provide strategic flexibility. Other advantages include faster scalability and tech transfer and lower contamination risk. Continuous processing enables cost-effective processes and high productivity Continuous biomanufacturing with single-use technology promises a combination of high productivity and low cost that no other technologies can provide. Maintaining the process in balanced continuos mode drastically reduces consumption of expensive single-use components like bioreactors and depth filters. At the same time, it becomes possible to reduce equipment size due to the increased productivity and better utilisation of upstream equipment. Investment costs 350L bioreactor Flexible pilot facility with a 350L stainless steel bioreactor and a 1,000L single-use bioreactor. 1000L single-use bioreactor The million dollar question: Stainless steel or single-use? Investment costs are probably the biggest and most obvious source of the cost advantages of single-use components over fixed steel systems. The difference arises mainly because single-use systems require less instrumentation and fewer utilities. Because sterilisation and cleaning processes are eliminated, installation and support systems are reduced. This advantage clearly allows a manufacturer to purchase more capacity for a limited startup budget, but also has an effect on the variable costs because a much lower investment sum has to be amortized, compared with stainless steel. In fact, it is the low up-front investment cost, which lowers variable costs, that typically tips the scales in favour of single-use systems. NNE calculated the projected investment cost savings that single-use process modules would provide, compared with 100% stainless process equipment, for an up-stream biopharmaceutical operation. The figure shows that investment cost savings of about 30% can be expected with single-use technologies, depending on the extent of their use, compared with a full stainless steel setup. The 30% point is actually an overestimation because microbial fermentation and centrifugation were included in these considerations, although single-use technologies are not readily available for these applications. Cost of manufacturing depends heavily on the frequency of use of single-use technology assemblies. Actual costs depend on a number of site specific assumptions, especially process titers and solubility of protein. The estimate is based on combined single-use technology consumables costs of 150,000 Euros and above per 2000L single-use technology bioreactor batch of monoclonal antibody product. Single-use technology performs best at low utilisation and with flexible production schedules because the technology does not load the production economy with financial costs and insurance related to more expensive stainless steel equipment. At higher production volumes and increased facility utilisation, the increased use of expensive single-use technology assemblies becomes a burden and costs will soon exceed those of stainless steel. Payback times for the stainless steel solution at full utilisation have been estimated at between three and seven years depending on case - the key assumption being that the facility is fully utilised from day one. COGM ($/gram) Cost reduction compared with traditional equipment (%) CAPACITY AND COST OF GOODS MANUFACTURED Capacity Installed capacity vs. COGM (at 90 % capacity utilisation) Single-use process modules (%) Area impact In reality, the important issue is not stainless steel or single-use technology, but rather how technologies can be combined to provide the most productive and cost-effective process in a fast and predictable way. Choosing one or the other technology concept or a hybrid of the two depends on both strategic considerations and feasibility studies of each individual case. The future will change biopharmaceutical manufacturing paradigms from stainless steel to hybrid combinations of single-use and stainless steel and complete single-use facilities. Today, new biopharma manufacturing facilities have to be smaller and more flexible, efficient and cost-effective, and able to adapt quickly to changes in market demand. Past and current processes From large-scale stainless steel to single-use, continuous processing and hybrid. The last decade has changed the manufacturing landscape for biopharmaceuticals due to the rapid development of single-use technology. From being an experimental technology, it has become a mainstream technology that plays an important role in bioprocessing both upstream and downstream. Single-use technology is more and more broadly chosen to be a reliable and cost-effective alternative to the stainless steel-based equipment that has historically been mainstream in biopharmaceutical manufacturing. Experience tells us that the challenge not only lies in making the right choice and ensuring a good implementation, but more so using a structured and scientific approach to find the right balance between single-use and stainless steel technology. Each technology has its advantages and disadvantages and a hybrid solution is often the most cost effective. In fact, the right mixture of the two technologies is part of the solution to combine agile and flexible manufacturing with cost-effectiveness. ADVANTAGES Risk mitigation Improved flexibility Improved utilisation Faster changeover for multi-products Closed system integrity Smaller footprint Improved segregation strategy Reduced manufacturing foot print Single-use systems have fewer utility requirements and they can be stacked or moved in certain volume ranges. These systems occupy a small footprint because of their improved designs and mobility as well as their decreased demand for piping, valves, instrumentation and the related maintenance space required. Single-use systems do require room for manipulation, transport and waste removal, but even with these space requirements, they occupy less space than fixed systems. To manipulate or maintain the equipment which already occupies less space it is possible to push equipment aside to allow access. In this way, the process modules can share footprints to a certain degree. We have calculated the reduction in equipment footprint that could be achieved if single-use systems were installed as process modules instead of 100% stainless steel for the same upstream area. The figure shows that it is possible to save about 25% of the space that a similar stainless steel installation takes, based on the extent to which single-use technology is employed. These reductions come from flexibility for future applications or investment-cost savings that result from smaller building costs. Typical cleanroom cost ratios range from USD 3,000 to USD 5,000 per m 2. Therefore, single-use equipment also can lower buildings fixed costs when used in cleanroom areas. Cost reduction compared with traditional equipment (%) Single-use process modules (%)

5 Strategic use of single-use technology: Rise of the hybrids Parameter* Buffer prep: Single use Single-use technology provides flexibility in terms of reduced capital expense, phased investments and reconfiguration possibilities. The optimal solution for market supply of monoclonal antibodies is often a hybrid solution between single-use technology and stainless steel. The strategic use of single-use technology allows for interesting phased approaches, where variations in capacity demand between clinical and market supply phases are considered. The result could be a facility lifecycle strategy where the facility undergoes a transformation from a clinical/launch facility based entirely on single-use technology to a hybrid technology market supply facility as demand increases. 2 g/l 5 g/l 10 g/l Buffer prep: Stainless** Buffer prep: Single use The series of process and facility simultations show CAPEX and OPEX outcomes for an all single-use technology 4x2000L SUB facility compared with a hybrid stainless steel/single-use technology 4x2000L SUB facility in which the buffer preparation module is based on stainless steel preparation tanks. Buffer prep: Stainless** Buffer prep: Single use Buffer prep: Stainless** Parameter Production bioreactors SUB size (L) Number of SUBs installed Annual production weeks Turnover time in production SUBs (days) Batch initiation in campaign mode (days) Annual capacity (batches) Purification yield (%) Value SUB Parameter Protein A column diameter (cm) Protein A cycles (per batch) CIEX column diameter (cm) CIEX cycles (per batch) Number of buffers for purification Total buffer volume (L) Maximum buffer volume (L) 2 g/l g/l g/l Relative COGM (excl. CAPEX) Relative consumable cost (per gram) Relative water usage (per batch) Relative buffer requirement (per batch) Relative buffer prep. time (per batch) Relative solid waste (per batch) Number of buffer preparation bags Number of buffer preparation vessels Number of buffer hold bag Number of buffer hold vessels 0, Titer Annual capacity (kg) * Relative to the reference condition (buffer prep: single use; titer: 5 g/l) ** A threshold volume at >1000L is used for going from single use to stainless steel buffer preparation and hold Red numbers in the table are basis for different titers. 2 g/l g/l 10 g/l DETAILED COGM CATEGORIES UNIT OPERATION BREAKDOWN COGM (excl CAPEX) 67% consumables 21% Labour 4% Other PROCESS TIMINGS N-2 seed N-1 seed Production Harvest Clarification Utilities Maintenance Media Insurance & other Buffer Indirect QC tests Quality Resins/MA Process N-2 seed N-1 seed Production Harvest clarification Harvest filtration Protein A Virus inactivation Materials 8% Materials USD/Gram 5 Harvest Filtration Protein A Virus Inactivation Depth Filtration CIEX Bind & Elute AIEX membrane Flow Through Filters Bags Depth filtration CIEX bind and elute AIEX membrane flow through Viral filtration UF/DF Consumables Labour Other TOTAL Viral Filtration UF/DF Bulk Filtration 0 5 days 10 days 15 days 20 days Bulk filtration Materials Consumables Labour

6 Site agility: The key to your continued success In pharma operations, your timelines are shrinking. The only way for you to succeed is to operate with maximum site agility and flexibility. Your facilities need to handle changes in production demands and quality regulations fast, and implement new knowledge and technology faster still. De-risk tech transfer by scaling out instead of scaling up Establishing the right capacity at the right time is crucial, especially for new locations in the manufacturing network. Single-use technology allows easy and low-risk addition of capacity by simply adding more equipment at the same scale. The mobile nature of single-use equipment makes moving a validated process and associated equipment from one facility to another foreign location realistic and so provides for fast and robust tech transfer. KEY DIRECTION-SETTING QUESTIONS New facility Established facility Guided decision process for single-use technology Is the programme for a new facility or to retrofit into an existing facility? Is it for a single product or inteded as multipurpose for unknown future processes? Is it a development (pilot) or launch (commercial) facility? Is it a biotech product or a combination (biotechnology and chemical) product? Is it an innovator company, a contract manufacturer, or biosimilar manufacturer? Multi product Development Biological product CMO Few kg per year Single product Commercial production Chemical product Innovator s facilities Ton of product per year A GUIDELINE MADE IN COOPERATION WITH NNE In October 2014, the PDA guideline PDA TR 66 was released with help from a team consisting of leading drug manufacturers, FDA representatives and equipment suppliers as well as two global technology partners from NNE. The PDA TR 66 discusses single-use systems that are in either direct or indirect contact with raw materials, intermediates, and pharmaceutical drug substances or drug products and is intended to provide the reader with critical concepts or points to consider when implementing a singleuse system strategy in a pharmaceutical manufacturing process. These concepts are intended to be valid both for chemically synthesized small molecules and for bioprocesses that produce large-molecule biopharmaceutical products The document does not intend to discuss disposable items related to laboratory activities, final delivery system to the patient, transfusion bags, packaging, or medical devices. WHY DO WE NEED PDA TR 66? Drug shortage Aging facilities The new pharma reality going from traditional OSD manufacturing to specialty drugs/injectables Aligned quality approach Best practice sharing Base decisions on facts rather than gut feeling Arguments to convince the sceptics Supply chain challenges Common platform for moving forward PATIENT SAFETY CAN NEVER BE COMPROMISED Quality, safety, and efficacy are designed or build into the product. Quality cannot be adequately assured meerely by in-process and finished-product inspection or testing. This guidance supports process improvement and innovation through sound science. Guidence for Industry FDA/CDER 2011 Process validation: General principles and practices Is the required capacity a few kilograms per year or tons of product per year? A growing need for flexible, multipurpose and more cost-effective manufacturing will have a significant impact on the design of the production facilities in the future. Recent increases in cell culture yields have led to significantly reduced bioreactor volume requirements, which again has opened the door for single-use manufacturing technologies such as pre-sterilised assemblies of plastic bags, tubing and filters that are only used once and then disposed of. With a financial investment reduction and simplified installation, single-use technology can be more appealing than stainless steel technology. Combining single-use technology and high-yield processes can further reduce the price tag for comparable facilities by 70-90%. Additionally, as products contacting surface are used only once, single-use technology runs a much lower risk of batch-to-batch contamination, which is of particular importance in multipurpose facilities. A facility based on single-use technology is easy to reconfigure and can therefore be ready for a new product in a matter of days. This flexibility translates to reduced development timelines and thus accelerated time-to-market peak. In an increasingly fragmented market, the need for speed to secure market shares is more important than initial minimal cost of manufacturing. And with markedly increased cell culture yields, the cost contribution from the manufacturing facility is limited compared with development costs. This is where the facility lifecycle enters the picture with single-use technology it becomes possible to optimise facility installations based on anticipated lifecycle stages. For instance, the strategy could be to start with just one single-use bio reactor to get material for clinical trials and then upgrade the facility with additional bio reactors later in anticipation of market supply production while clinical trials are taking place. As the next pipeline product must be developed, the facility can change the lifecycle stage back to clinical production and the extra bioreactors can be moved to a market supply expansion facility. Such a strategy becomes possible because single-use technology is so decoupled from the facility building itself. As an interesting side effect, our environmental impact studies show that single-use technology is perhaps 50% less energy-intensive than stainless steel manufacturing. It may appear counterintuitive, but the emissions from disposing plastics are more than offset by elimination of the cleaning and sterilisation processes required for reusable technology, basically because heating up many tons of water is extremely energy-intensive. Full implementation of high yield processes and single-use technology results in facilities with a markedly reduced carbon footprint per kg product compared to the stainless steel facilities of the 1990s. TRENDS More complex and customised systems Consolidation in the industry Improve deployment decrease operational failures by improved design Improved SUS sensors Particulates CHALLENGES Ensure fully closed systems Closed systems impact on facility design and operation Standardisation of quality requirements and testing procedures Collaboration between industry organisations Install SUS in existing facilities SUS chromatographic columns through continuous systems Better understanding of leachables impact on cell culture growth and product profile A Is SUS technically feasible? Size, pressure temperature limitations Complexity of the system Compatibility B Business case acceptable? Flexibility Facility utilisation and impact Balance of capital and operating costs C Product risk acceptable? Cross contamination Adsorption Extractables/ leachables D Process risk acceptable? System integrity loss Process adjustments Operator safety No SUS may not be applicable E Process cont. strategy acceptable? Process validation Measurement quality Process interaction F Implement strategy acceptable? Regulatory acceptance System reliability Internal change acceptance G Logistic cont. strategy acceptable? Supply Qualification Transportation Yes A SUS is feasible? BEING ON LOCATION TO GET ACCESS TO THE LOCAL MARKET The need for local biopharma manufacturing capacity is increasing in the fast-growing emerging markets as the customer base expands and national initiatives manage the markets. The trend is being amplified by blockbuster patent expiry and the implementation of regulatory legislation for accelerated pathways for biosimilars. For biopharmaceuticals, emerging markets are not about low-cost manufacturing hubs, but about being on location to get access to the local market. Consequently, many big pharmaceutical companies and local manufacturers are investing in new facilities in these countries. Because of the local focus, it s a matter of several local facilities instead of one central facility for global supply. Such facilities must clearly meet local manufacturing regulations, but also increasingly adhere to global Good Manufacturing Practice (GMP) standards. So here we see two new features of the biopharma facilities of the future. They are adaptable to local conditions and yet comply with global regulations as quality requirements are being harmonised. A blueprint facility concept that can be established as interesting markets develop will become an important strategic asset for biopharma players with global aspirations. You can talk of innovative production techniques in the sense that our emerging markets customers are highly innovative and open-minded and therefore capable of leveraging technologies and market dynamics radically. Obviously, the traditional stainless steel production concept may not be the right solution going forward; but while single-use facilities are still regarded as the plants of the future in mature markets, they are fast appearing as a preferred solution to the blooming biopharmaceutical industry in emerging markets.

7 UCB Pharma cgmp biotech plant for drug development and pilot manufacturing As part of its transformation from a chemical company to a global, patient-centric biopharma company. UCB Pharma has built a cgmp biotechnological pilot plant including development laboratories on its site in Braine-l Alleud in Belgium. The overall purpose of the project was to provide clinical manufacturing and development capability for mammalian cell culture-based protein products utilising a template process, which covers most products which are foreseen by UCB s global technical development group. The new facility contains a pilot plant (up to 2,000L bioreactor scale including both upstream and downstream operations), a process development laboratory (for upstream and downstream processing) and a stand-alone utility building. With the facility, UCB Pharma s aims to speed up availability of biotechnological drugs for serious illnesses in the central nervous system and immunological problems, concentrating on pilot projects and delivering products for clinical trial activities. The first stone was laid on 4 June 2010 and final handover took place in February NNE supported UCB under an engineering, procurement, construction management and verification (EPCMV) contract from the detailed design through construction to verification. NNE s architects have been responsible for the redesign of the front-end study project aligning the building with the neighbouring building and clarifying the layout in a logical manner supporting the process flow. The building T2 is situated at the beautiful campus-like UCB Braine l Alleud site, which represents a high landscape quality. Utilising daylight for working space wherever possible has been a top priority in the creation of the building layout. The powder-coated aluminium façade cladding corresponds to the neighbour building and is designed to give a refined simplistic expression. Patient safety first Investing in this new facility is a central part of UCB Pharma s patient-centric approach to business. To safeguard patient-centricity, the project is based on risk and science-based verification principles according to the ASTM E2500 as well as the ICH guidelines Q8, Q9 and Q10. The application of the ASTM E2500 verification approach may seem difficult to handle at first. However, the tools and principles of risk assessments and verification of vendor-prepared tests are well known and easy to implement. As a result of the verification methodology, duplication of tests is avoided and focus is intensified on the areas with the highest risk to patient safety, which is a key element of the verification approach. Furthermore, flexibility in project execution is increased by elimination of the non-value-adding dependencies between installation, operational and performance qualification (IQ, OQ, PQ). At the same time, resources are used more efficiently and the quality risk assessment process ensures that focus is directed towards the real quality issues. The projected savings on quality-related documentation are expected to be reduced by approximately 30% compared to the traditional commissioning and qualification approach, and the projected reduction in quality function manpower is in the range of 50-70%. PROJECT INFORMATION Total investment cost: EUR 65 million Services provided: Conceptual design, basic design, detailed design, engineering, procurement, construction management, verification (according to ASTM E2500)

8 Boehringer Ingelheim Biotech cgmp facility to support Chinese growth plans Boehringer Ingelheim is building its first biotech facility in Asia. The facility s design is based on NNE s Bio on demand concept. Boehringer Ingelheim is one of the leading contract manufacturers of biologics worldwide, with a strong network of sites in Europe and the USA. Now the company is bringing its world-class biopharmaceutical technology to China through the establishment of a new bioscience centre in Shanghai. The new cgmp facility will develop and small-scale manufacture monoclonal antibodies and recombinant proteins. Intended for contract manufacturing, it will provide a full range of development and clinical services to Chinese and multinational customers. SUPPORTING CORPORATE AND NATIONAL GROWTH PLANS The greenfield project represents Boehringer Ingelheim s first biotech venture in Asia and is part of the company s strategy to establish production in China and penetrate the Asian biotech markets. Additionally, the project represents the first market entry of any major multinational company into the Chinese biologics market. And it s precisely this field of technology that has been selected as a strategic emerging industry in China s th five-year plan ( ). RMB billion has been earmarked to fund R&D for new biotech drugs. FULL FLEXIBILITY TO MEET FUTURE PRODUCTION NEEDS Boehringer Ingelheim has chosen NNE to execute the design of the new facility. A key objective for Boehringer Ingelheim was to leverage NNE s experience with designing flexible and lean biotech facilities based on single-use technology. The design can easily accommodate future changes in product portfolio as well as future expansion enabling the company to meet future market demand. The facility concept used for the Boehringer Ingelheim project is designed for flexibility and easy expansion. It is an excellent example of the features embedded in NNE s Bio on demand TM concept. PROJECT INFORMATION Total investment cost: EUR 35 million Services provided: Feasibility study, conceptual design, basic design, detailed design

9 Bavarian Nordic Meeting the need for vaccines in record time Although the infectious disease smallpox has been eradicated, governments are showing renewed interest in developing and stockpiling smallpox vaccines as a precaution against bioterrorism. In the US, this is being driven by its BioShield initiative. One of the world s safest, multivalent vaccine vectors for the development of vaccines against smallpox is MVA-BN, based on Bavarian Nordic s patented technology. Bavarian Nordic needed to transform an existing pharmaceutical production building into a clean and qualified new facility for the production of its vaccine against smallpox. The facility had to be ready quickly in order to prove that Bavarian Nordic could produce the vaccine for its RFP3 order evaluation for the production of vaccines for emergency use in the US. A FULLY MODERNISED, VALIDATED FACILITY The project included a facility clean-up of the previous pharmaceutical production process. All existing interior walls and surfaces in the production areas were demolished and a cleaning validation was performed before the construction of new process and production areas. NNE helped the customer with all phases of the project from early strategy and site selection to full operation and completed the project in just 11 months from basic design to handover. NNE was also responsible for procuring building and environmental permits and production permits for biological agents. In order to achieve this fast-track project execution, a host of accelerating measures need to be adopted, including: Single-use technology Massively parallel project execution Intensive teambuilding involving users, engineers and contractors ENSURED CAPACITY The result of the project is a state-of-the-art, future-proof facility, which also contains a shell construction area for possible future expansion. With a production capacity increase of a minimum 40 million doses per year, the company has ensured the supply of its current and future vaccines and its ability to meet growing demand. Bavarian Nordic is now an important supplier of smallpox vaccines to several governments, most notably the US. PROJECT INFORMATION Total investment cost: EUR 30+ million Services provided Conceptual, basic and detailed design, contact, preparation and submission of documentation to the authorities, procurement support, construction management, installation management, commissioning supervision, testing

10 Novo Nordisk Creating a flexible biotech facility with single-use technology NNE has helped Novo Nordisk to build its first facility based entirely on single-use technology, resulting in greater flexibility and lower costs. Using plastic bags instead of steel tanks is essentially what single-use technology for pharmaceutical production is all about. The first Novo Nordisk facility to be based entirely on single-use technology is the 1T Extension Pilot Plant in Bagsværd, Denmark, which produces antibodies and NNE has played a major role in making it happen. The project team handed over the project in February It has been an ultra-fast-track project, which means that the schedule has been quite tight, but the end result was very good, says NNE Senior Process Engineer, Kim Vincentz Andersen. Novo Nordisk needed to establish new production capacity that would enable it to meet increased market demand and support new products in the pipeline. The pilot plant also provided the company with extra capacity for supplying clinical trials and small-scale commercial production. The plant will produce monoclonal antibodies (MAbs), which are typically used to treat cancer and inflammatory diseases such as Crohn s, psoriasis and other autoimmune diseases. A RISING TREND Plants for the production of antibodies hold great significance for Novo Nordisk and, as an early cost-benefit analysis from NNE helped to reveal, turning to single-use technology provides many advantages for the company. We see single-use as a good possibility for the future production technology in pilot scale. It provides great flexibility and lower investment costs and most likely also lower maintenance costs, says Project Manager Lotte Vistisen Specht, Novo Nordisk. Of course, Novo Nordisk isn t the only company that is aware of these advantages. Especially within biotech, going from multi-use technology to single-use is a rising trend, according to Senior Technology Partner at NNE, Niels Guldager: It is a good solution for biotech because you are dealing with proteins in quite a safe process without high pressure or high acidity. The main advantage is that you reduce the risk of contamination because you only use the bags once. Installation costs are lower and, once installed, single-use technology frees up a lot of highly skilled manpower. The people previously involved with cleaning can now use their time elsewhere. NO WASTED WATER Using disposable plastic bags rather than steel tanks might sound harsh on the environment, but the environmental reality of single-use technology is more nuanced than that. You have to compare it with what it replaces. The cleaning process with steel tanks requires vast amounts of hot water and is very energy-heavy, both when you heat the water and when you clean the wastewater afterwards. With single-use technology, you don t need any water at all. And plastic actually burns rather cleanly, says Niels Guldager. NNE has a high level of expertise when it comes to single-use technology and our Global Technology Partners have been involved in more than 30 single-use projects over the past five years. PROJECT INFORMATION Total investment cost: EUR.5 million Services provided: Concept brief, conceptual design, basic design, detailed design, engineering, procurement, construction management, commissioning and qualification

11 Ark Therapeutics Oy Customised single-use solution for production of gene-based products Ark Therapeutics Oy needed a BSL-2 cell culture manufacturing plant based on single-use process technology and had a short timeline to realise it, so the company turned to NNE for the solution. Gene-based medicine offers a new biologics platform for difficult-to-treat-medical conditions where the fundamental biology of the disease is too broad for small molecule approaches. Ark Therapeutics Oy is a leader and pioneer within gene-based medicine, focusing on unmet medical needs in vascular disease and cancer two of the largest therapeutic markets in the world. A research and development company, the organisation had little experience with major engineering projects. So when it needed a facility established quickly using a single-use solution, Ark Therapeutics Oy looked for a partner with proven experience in single-use process technology and fast-track engineering. BRINGING EXPERIENCE TO THE TABLE With its expertise in single-use technology and award-winning fast-track solutions, NNE was a perfect fit and was able to provide Ark Therapeutics Oy with a unique, tailored solution to be completed in just 16 months. NNE was given complete responsibility for all site activities, including the design, installation, testing and qualification of cleanrooms, HVAC, media, clean utilities and process equipment for filling and primary packaging. UNIQUE FACILITY FOR BREAKTHROUGH PRODUCTS The biological manufacturing operation now provides process development and manufacturing capabilities for internal Ark programmes and those of third party clients for a variety of stages of therapeutic development. In its new production facility, Ark Therapeutics Oy is able to produce ground-breaking gene-based biopharmaceutical products based on modified viral particle technologies as well as other biopharmaceuticals up to biosafety level 2 (BSL-2). PROJECT INFORMATION Total investment cost: EUR.5 million Services provided: Basic design, detailed design, procurement support, installation management, commissioning supervision, qualification (up to operational qualification) and validation support

12 Jumping hurdles in single-use technology The industry often highights advantages of single-use technology: flexibility, execution speed, investment cost, area need, reduced cleaning, validation and ease of change-over. But the reality is more than a room full of plastic. A well-executed project will also include a decision process to carefully evaluate limitations and concerns of single-use technology. Specialised in biotech and single-use technology Our subject-matter experts are with you all the way from project idea through project execution to ramp-up and beyond. Through focused pharma engineering, we help you obtain and maintain an optimal production setup so you can always deliver on demand. Concerns of single-use technology Risk-based approach in leachables, extractables and product compatibility Tie layer (EVA) Ethylene Vinyl Alcohol - gas barrier layer (EVOH) Air side Linear Low Density PolyEthylene (LLDPE) Leachables Cell Bank Cell Culture Impact to cell culture Leachables impact to operations Purification Purification & impurity removal Formulated Bulk Filling Close to patient Container closures Increasing risk of leachables SUS supply is a complex journey - Raw material attributes - Film design and composition - Critical processing parameters - Critical controls - Testing and verifications - Functional performance - Shelf life - Cost - Dual sourcing strategy - Back up supply storage - Disaster recovery planning Increasing storage time & volume to surface area exposure increases risk Ethylene Vinyl Acetate (EVA) Single-use technology in drug substance Single-use technology - supply chain model Liquid side Component suppliers, distributors Resin suppliers Component suppliers, distributors Filters Film production Media supplier Source: Duncan Low, Amgen, PDA Sensors Bag assembly Sourcing Risks Mixers System assembly Dispensing FILM-RELATED RISKS UNIT OPERATION RISKS OPERATIONS RISKS SUPPLY CHAIN RISKS Single-use technology in drug product Connectors Milling Extractable and Leachables Particles Film integrity Physical strength Labels Connectors Volumes Heating and cooling Mixing Mass transfer Transfer speed Pressure PH Solvents Installation Integrity testing Waste handling Training Safety Environment More manual operations Sensors Supplier delivery assurance Supplier quality agreements Supplier change control Supplier s suppliers Design management of SUS Standardisation Tubing Sterilisation Shipping End user Blending

13 A new world of single-use technology strategies Copenhagen Kalundborg Hillerød Brussels Frankfurt (Bad Homburg) Chartres Paris Lyon Tianjin Basel San Francisco (Emeryville) (TEDA) Montreux Morrisville Shanghai (Research Triangle Park) Bangalore Offices Project references Single-use MAb / biotech projects Discussions initiated NNE Biotech Center NNE S BIOTECH EXPERTS Niels Guldager Global Technology Partner Mobile: ngu@nne.com Morten Munk Global Technology Partner Mobile: mbmn@nne.com Jeffery Odum Global Technology Partner Mobile: ouj@nne.com Hartmut Schaz Global Technology Partner Mobile: hmus@nne.com Rajesh Gupta Director Mobile: rjgu@nne.com Kim Vincentz Andersen Specialist Mobile: kva@nne.com Philipp Eberhardt Specialist Mobile: pppe@nne.com Peggy Sander Project Manager Mobile: pggs@nne.com NNE is an international company specialised in pharma engineering. Through focused pharma engineering we enable our customers to deliver on demand. NNE.com Kang Wei Senior specialist Mobile: wkag@nne.com