April 20, 2018
Cook Pharmica’s flexible filling line in Bloomington, IN, won the 2017 ISPE Facility-of-the-Year award for equipment innovation. (WWW.BUSINESSWIRE.COM)
Today’s biomanufacturers need to be able to add capacity and capability quickly; provide increased supply service to customers on demand; and streamline the flows of personnel, traffic, utilities, and materials throughout bioprocess facilities. And companies need to be flexible enough to subtract capacity and retool quickly to produce new or different products. Many future facilities will be automated to some extent and use robotics in manufacturing. With personalized medicine on the rise, bioprocessors can benefit from colocation with academic research centers, laboratories, and clinics. Working in partnership, they could improve process development, scale-up, and adaptable clinical and commercial-scale manufacturing. Future facilities should be designed to affect the environment as minimally as possible. And they would do well to be built with employees’ comfort in mind and serve as good neighbors in their local communities.
Flexibility is Key
In a January podcast for the International Society for Pharmaceutical Engineering (ISPE), James Breen, Jr. (vice president of worldwide engineering-technical operations for Johnson & Johnson) discussed changes in building new facilities over the next 5–10 years (1). He stressed that drug manufacturing facilities should address patient needs rapidly, should be flexible and agile and globally focused, and should have the ability to incorporate new technologies as they become available (1). Speed will be of the essence overall, and manufacturers will need to be flexible enough to add or subtract capacity and/or retool quickly to produce new or different drugs. The BioPhorum Operations Group (BPOG) has identified flexibility, speed, quality, and cost as future business drivers in bioprocessing (2). Many ISPE facility award winners for 2017 are good examples of what future facilities will look like.
In a 2015 BPI article, Thomas Aeby and Morten Munk defined flexibility from an engineering viewpoint as the “flexible use of manufacturing suites by design to seamlessly and rapidly adapt to changes in a manufacturing process (e.g., multiple products) and the ability to handle varying volumes of production” (3). Such a facility must have both suite-level and operational-level flexibility. The authors also suggest using an open-architecture design to improve core facility space use and facilitate change-over of processes and production volumes. Continued development of closed processing systems should improve the flexibility of open-architecture designs and allow for smaller and simpler facility configurations than ever before (3).
Bristol-Myers Squibb (BMS) won a 2017 ISPE Facility of the Year (FoYA) award for facility integration when it added new buildings for biologics development and clinical manufacturing to an already operational campus in Devens, MA. One construction manager worked to integrate the two buildings, each designed by a different architect, into existing operations with minimum disruption. Both buildings were designed to accommodate future expansions. The goal was “to ensure that each phase will create the most efficient and streamlined flow of personnel, vehicular traffic, utilities, and materials, with the aim to craft a harmonious, healthy, and happy workplace that integrates facilities and processes at all levels and adds benefit to the community” (4).
Eli Lilly & Company won the ISPE Facility of the Future and Process Innovation Award for replicated sites in Carolina, Puerto Rico, and Indianapolis, IN. Operating the same facility in different locations eases technical transfers from development to manufacturing. The company managed to compress both schedules and budgets for swift commercialization and delivery of projects while saving millions of dollars in costs. Both facilities were designed to allow for rapid reconfiguration accommodating future projects without requiring significant requalification. Design features such as process analytical technology (PAT), advanced automation, and simplified process scale-ups reduce system complexity, increase startup speed, facilitate maintenance, and improve ergonomics for personnel (4).
Single-use technologies (SUTs) are certain to play a role in future biomanufacturing projects. Disposables are known to eliminate the need for cleaning and sterilization needed with stainless steel, so production lines need not be halted for cleaning, and overall water use is reduced. Using disposables also reduces the risk of product contamination (5). Well-designed use of SUTs will help companies achieve flexibility by making it possible to rapidly reconfigure processes and then scale them up, out, or even down (3). Because most single-use equipment has wheels, system mobility allows for suite reconfiguration, unlike traditional systems with stainless steel reactors hard-piped in place (6). One example of a rapid change in scale for SUTs is to consider that the footprint of a 4,000-L single-use bioreactor is not much different from that of a 500-L one, so by reserving space to add extra bioreactors on site, a manufacturer can expand its capacity considerably (3).
A modular facility design uses a set of standardized parts as building blocks for efficient and flexible construction and operations. Compared with traditional, nonmodular setups, a site using modules can be assembled in a fraction of the time. They can be attached or detached easily and all fit together the same way. Global expansions thus can happen quickly by shipping prefabricated modules in containers and then replicating an original facility exactly at another site. That is especially advantageous for markets where construction would be difficult, time-consuming, and/or expensive. And less expensive buildings can lower manufacturing costs and potentially drug prices as well. In the unfortunate case of an unsuccessful drug candidate, a modular design would allow a biofacility to be converted quickly for manufacturing another product — or to be dismantled. When a modular design is combined with SUTs, traditional infrastructure would not be needed, so biomanufacturing processes could be set up differently or even built vertically to increase capacity (5).
Process analytical technology (PAT) will be an important component in future bioprocess facilities because it can anchor a progressive control scheme and facilitate the use of automation (4). The Food and Drug Administration (FDA) describes PAT as a “system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality” (7). In this context, analysis includes chemical, physical, microbiological, mathematical, and risk all integrated together with a goal of consistently ensuring a predefined level of quality at the end of a biomanufacturing process (7).
Automation and robotics will play a greater role than ever before. Future facilities will leverage automation in biomanufacturing strategically to reduce costs and manufacturing time lines. Robotic systems are programmed to perform specific functions using multiple axes of motion. The benefits of automated bioprocesses include increasing process efficiency and reproducibility, freeing workers from performing repetitive tasks and protecting them from hazardous environments, eliminating the chances of human error and contaminations, and saving labor costs (8).
The world’s largest blow–fill–seal (BFS) manufacturing company is Nephron Pharmaceuticals Corporation, a manufacturer of generic inhalation solutions. Nephron received an ISPE honorable mention in 2017 for its new site in West Columbia, SC. The facility is a good example of implemented automation using technologies such as laser-guided vehicles, automated warehousing, robotics to eliminate the need for human intervention, and track-and-trace technology. The company’s goal was to achieve a paperless environment by implementing a customized professional inventory management system (PIMS), laboratory information management system (LIMS), and environmental monitoring (4).
Community Minded
Many biopharmaceutical companies are making commitments to being responsible citizens of the world, investing in equipment and practices to minimize their environmental impacts. In November 2015, five major manufacturers (Patheon, Biogen, Johnson & Johnson, Genentech/Roche, and Novartis) all signed the American Business Act on Climate Pledge with stated goals that include reducing carbon and greenhouse gas emissions, water use, and waste to landfill while increasing the use of renewable energy (9). New facility designs reflect those ideas. One way that biofacility designers can achieve those goals is by using a life-cycle assessment (LCA) to understand all environmental impacts a facility will have (10). Biomanufacturers and facility designers then can follow recommendations from groups such as the US Green Building Council’s Leadership in Energy and Environmental Design (LEED) and have their facilities certified (10).
Green manufacturing programs focus on reducing waste, energy consumption, and water use (9). Companies can do that by investing in methods of cleaner energy generation, renewable energy, and/or using waste materials to produce power. At the same time biomanufacturers should strive to reduce hazardous and nonhazardous waste (9). Some facilities — e.g., the Nephron plant — set a goal of going paperless through the use of automated inventory systems (4).
Around the globe, fresh water is predicted to become a limited resource for human consumption, irrigation, and manufacturing needs — and it already is a limited resource in some locations (11). Companies need to do everything that they can to conserve water and limit its use. One strategy is to repurpose discharge water from manufacturing processes for use in cooling towers or sanitation systems (10). Implementing single-use technologies instead of traditional stainless steel equipment will cut down on water use by eliminating the need for cleaning and sterilization (5).
Biofacilities must release clean water to the environment after making use of it. Effluent water should be free of pollutants, of course, but it also needs to return to its source at its original temperature to protect heat-sensitive fish (12). Another consideration when releasing water is to ensure that it has been treated so that chemicals that could cause antimicrobial resistance are not released into the environment (10).
Amgen has strived to conserve water both for itself and for the benefit of the communities where its facilities are located. In 2015, sites in both California and Puerto Rico were experiencing extreme drought conditions. The company put in place new short- and long-term strategies to conserve water at all its facilities in those locations. As a whole, Amgen conserved 106,000 m3 of water that year (9).
SUTs bring both advantages and disadvantages when it comes to environmental impact. Their use saves on water use, but disposables are made from a combination of nonrecyclable plastics, and single-use operations result in a great deal of waste. One way to manage that is by incinerating or melting down the waste and converting it into usable energy (5). Some investigations have found that waste was not the biggest contributor to the carbon footprint of SUTs; the larger contributor came from transportation of SUT components to user facilities. One potential solution to that would be for suppliers and end users to be located close to one another (10).
Not only is reducing energy consumption good for the environment, but it also lowers manufacturing costs. Heating, ventilation, and air conditioning (HVAC) consume more energy than any other system in a biofacility (10). Related energy use can be lowered by minimizing the quantity of air used and by turning systems off when they are not needed. Set-point ranges for temperature and humidity can be widened. HVAC equipment such as motors and fans should be high-efficiency models. Finally, regular maintenance helps keep everything running as efficiently as possible. Automation can come into play here as well, with systems that measure air quality and adjust the air change rate, temperature, and humidity (10).
Many companies building new facilities are working toward environmental goals. One example is AstraZeneca’s solid-dose facility in Taizhou, China, a 2015 winner of the ISPE FoYA Award. The site has a lean design that minimizes energy use and optimizes processes. The HVAC system reduces air changes during nonoperational times. The company strives to lessen the amount of transport needed and material wastes there, as well. To prevent release of hazardous molecules into the environment, it has implemented an innovative electrooxidation process to pretreat wastewater before conventional biological treatment is done (9).
In another example, Amgen has been using next-generation biomanufacturing technologies that provide greater productivity in a smaller facility footprint than traditional equipment requires. The company used such an approach commercially for the first time at its new manufacturing center in Singapore. Compared with a larger conventional facility, this next-generation plant reduces carbon emissions, energy consumption, water use, and solid waste output (13). Also, Amgen points out that advanced technologies and process improvements can be combined with classical biomanufacturing to create conservation gains in addition to improving efficiency and saving financial resources (13).
Finally, the BMS Devens site was awarded LEED gold certification for its laboratory/administration building and LEED silver certification for its cell culture manufacturing facility. Such certification is based on project designs that take site development, environmental impact, water and energy use, construction impact, and architectural and building materials all into consideration. For that project, the company received an innovation award from the Massachusetts Toxic Use Reduction Institute (TURI) for recycling 5.6 million gallons of clean and flush water associated with facility startup.
Local Focus: At Devens, BMS adopted the Blanding’s turtle (Emydoidea blandingii), which is listed as “threatened” under the Massachusetts Endangered Species Act. Under the company’s sustainability goals, each facility and business is encouraged to help protect endangered species and habitats. Devens employees have partnered with the state’s department of fish and game, the US Fish and Wildlife service, and local conservation groups to preserve breeding areas for these turtles. One activity employees have assisted with is removing invasive plants from local streams and ponds (14).
Facilities of the future can help the communities where they reside in other ways as well. Nephron, for example, pledges to hire employees from nearby universities and trade schools. The company makes an effort to be open to its community and to encourage students of all ages to pursue careers in pharmaceutical manufacturing. The new facility in West Columbia was designed with viewing areas and access for visitors to see manufacturing processes in action (4).
Employees at BMS in Devens are partnering with MassBioEd’s job-shadowing program by introducing local high school students to the biopharmaceutical industry. They participate in a local public school system’s science program. Employees also support their local community by contributing to a shelter for women with children that runs a housing facility, donating their time at a food pantry, and conducting clothing drives to aid homeless US military veterans (14).
Putting It All Together
Kalbio Global Medika (KALBE) in Jakarta, Indonesia received an honorable mention in the ISPE 2017 FoYA awards for its new facility built to manufacture biosimilar and biobetter products (4). The young project team — average age 24 — used new technologies and tools to create a forward-looking facility. For example, they approached vender validation by pairing detailed early planning and risk assessments that reduced costs and accelerated equipment qualification. Other flexible and cost-effective strategies included implementing single-use manufacturing systems, continuous processing (bioreactors equipped with perfusion technology), and robotic automation. Energy and resource conservation strategies were incorporated into the building design. One example is the novel application of ozone sterilization used in both the purified water (PW) and water-for-injection (WFI) systems (4). KALBE supports local community development, environmental conservation, and fair employment practices (16).
Biofacilities of the future will address patient needs quickly. They will be flexible and agile, globally focused, able to incorporate new technologies, ready to add or subtract capacity, and capable of retooling quickly to produce new and different drugs. Some sites will be colocated with academic researchers, laboratories, and clinics. Future facilities will have to affect the environment as minimally as possible. And they can be built with people in mind, including employees, neighbors, and patients.
References
1 Ebner CG, Breen Jr. JA. Facilities of the Future: Innovating the Future of Manufacturing. ISPE 14 January 2018; www.youtube.com/watch?v=jUCzEYh9HFA.
2 Jones S. BioPhorum Operations Group Technology Roadmapping, Part 4: Efficiency, Modularity, and Flexibility As Hallmarks for Future Key Technologies. BioProcess Int. 15(2) 2017: 14–19.
3 Aeby T, Munk M. Meeting the Demand for a New Generation of Flexible and Agile Manufacturing Facilities: An Engineering Challenge. BioProcess Int. 5(11) 2015: S16–S23.
4 2017 Facility of the Year Award (FoYA) Winners. International Society for Pharmaceutical Engineering: Bethesda, MD, 2017: www.ispe.org/facility-year-awards.
5 Martin J. Modular Facility Design and Single-Use Equipment Considerations for Pharma Manufacturing. Pharm. Online 26 January 2018; www.pharmaceuticalonline.com/doc/modular-facility-design-single-use-equipment-considerations-for-pharma-manufacturing-0001.
6 Craig JL, Jenkins M. Toward Flexible Hybrid Facilities of the Future. BioProcess Int. 10(11) 2012: S34–-S37.
7 CDER/CVM/ORA. Pharmaceutical CGMPs, Guidance for Industry, PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. US Food and Drug Administration: Rockville, MD, September 2004; www.gmp-compliance.org/guidemgr/files/PAT-FDA-6419FNL.PDF.
8 Markarian J. Using Robotics in Pharmaceutical Manufacturing: Robots Are Proving Advantageous in Filling, Inspection, Packaging, Laboratories, and the Manufacture of Personalized Medicine. PharmaTech.com 19 November 2014; www.pharmtech.com/using-robotics-pharmaceutical-manufacturing.
9 Markarian J. Pharmaceutical Manufacturers Go Green. PharmTech.com 20 January 2016; www.pharmtech.com/pharmaceutical-manufacturers-go-green.
10 Markarian J. Designing Sustainable Pharma Facilities: Innovative Methods for Water and Energy Conservation Can Reduce Carbon Footprint. Pharm. Technol. 41(12) 2017: 48–49.
11 McKie R. Why Fresh Water Shortages Will Cause the Next Great Global Crisis. Guardian 7 March 2015; www.theguardian.com/environment/2015/mar/08/how-water-shortages-lead-food-crises-conflicts.
12 Final Recovery Plan for Central California Coast Coho Salmon Evolutionarily Significant Unit. National Marine Fisheries Service, Southwest Region: Santa Rosa, CA, 2012; www.westcoast.fisheries.noaa.gov/protected_species/salmon_steelhead/recovery_planning_and_implementation/north_central_ california_coast/central_california_coast_coho_recovery_plan.html.
13 Martin E, Gould S. The 25 Best Healthcare Companies to Work for in America. Business Insider 20 May 2015; www.businessinsider.com/best-us-healthcare-companies-to-work-for-2015-5.
14 Devens, MA. Bristol-Myers Squibb: New York, NY, 2018; www.bms.com/about-us/our-company/worldwide-facilities/devens-massachusetts.html.
15 Big Pharma Beats Out Google and Disney as the CareerBliss Happiest Companies of 2017. Business Wire 1 December 2016; www.businesswire.com/news-home/20161201006167/en/Big-Pharma-Beats-Google Disney-CareerBliss-Happiest.
16 KALBE; www.kalbe.co.id/id/tanggung-jawab-sosial.
Alison Center is editorial assistant for BioProcess International, PO Box 70, Dexter, OR 97431; [email protected].
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