Bio/pharmaceutical manufacturing harnesses the benefits of digital transformation.
The benefits of digital maturity in pharmaceutical manufacturing were made evident by the COVID-19 pandemic during 2020 and 2021, as the sudden need to develop, manufacture, and distribute treatments and vaccines intersected with travel restrictions, social distancing, and supply chain interruptions. Digital technologies that could meet these new challenges and aid manufacturing scale-up and speed to market, such as automated digital data collection and augmented and virtual reality (AR/VR) remote collaboration tools, were already available and had been adopted by some, but the new demand spurred greater adoption. The need to solve manufacturing challenges gave more companies the incentive to initiate or make further progress on their digital transformation journeys.
“These events directly showed the payoff of information technology (IT)/operational technology (OT) integration achieved over the last several years, but also revealed that we have an opportunity to do much more,” says Dan UpDyke, strategic marketing manager at Rockwell Automation. “The ability for the industry to pivot and quickly bring new therapies to market highlighted the need for flexible, saleable, and connected manufacturing systems. We have already seen an increase in integrating data and recipe management through a manufacturing execution system (MES) and flexible distributed control systems (DCS),” says UpDyke. “These are technologies that enable faster time to market by reducing the efforts to shift to new products.”
“As an industry, we’ve seen we need to be more efficient and we need to be able to monitor and manage processes remotely from a centralized location. People are focused on process intensification and how to better digitize and automate their processes,” says Merrilee Whitney, head of the BioContinuum Platform at MilliporeSigma, the US and Canada life science business of Merck KGaA.
The pandemic created a higher awareness of the need for digitalization, adds Dirk Wollaert, Vertical Market Pharma at Siemens headquarters in Belgium. Digital technologies were key to the success of the rapid development and rollout of the COVID-19 vaccines, facilitating cross-company collaborations even across national borders. “Globalization and industry standardization to facilitate smoother transition from one production plant to another became more important,” he explains.
Another change that accelerated in the past two years was a transition to the cloud for software solutions and data storage, adds Pamela Docherty, Life Sciences Industry manager at Siemens USA. “The ability to push data from the manufacturing floor to the cloud creates a backbone for digitalization,” she says.
In bio/pharmaceutical manufacturing, the application of “Industry 4.0” techologies, such as digitalization, must be aligned with regulatory requirements, including good manufacturing practices (GMPs). The International Society for Pharmaceutical Engineering (ISPE) has trademarked their initiative as Pharma 4.0, also dubbed the “Smart Factory,” and has developed an operating model, which the Pharma 4.0 special interest group notes goes beyond IT to organizational, process, and resource aspects (1).
“There is a cultural aspect to digitalization because it’s a significant investment that results in changes to the operational structure of a facility; it is beneficial when the digitalization comes from the top,” explains Yvonne Duckworth, automation engineer and Industry 4.0 subject matter expert at the CRB Group, a life sciences engineering and construction company. “We are seeing more often that management is driving the adoption of digitalization in new facilities. It is becoming a standard and expected part of facility design.”
In the past five years, pharma manufacturers have been moving toward digital maturity. Assessed using the BioPhorum Group’s Digital Plant Maturity Model (2), some manufacturers are at level 1 (predigital); some are at level 2 (digital silos and islands of automation); many are at level 3 (connected plants) on their way to level 4 (predictive plant with real-time predictive analysis), and others want to adopt some aspects of level 5 (autonomous, adaptive plant), says Duckworth.
Although in past years, digitalization primarily meant moving away from paper-based systems to digital reports that were then printed to electronic or physical paper, a new paradigm enables a jump from Pharma 2.0 paper-based systems to the Pharma 4.0 operator-centric connected plant, said Gilad Langer, industry practice lead at Tulip, which supplies a cloud-based front-line operations platform (3). “This paradigm shift changes the culture and the processes, but doesn’t significantly change the operator’s workflow. Instead, digital apps are built to bring the physical world to the digital world with sensors and cameras, with digital output as the evidence. Data from equipment and human activities are collected via the industrial Internet of things (IIoT),” explained Langer.
From data to digital twins
Digital tools depend first on good data collection. Having equipment that is set up for data collection and data analytics is becoming increasingly important, says Duckworth. Machine sensors and process analytical technology (PAT) instruments can communicate directly with data collection systems using the IIoT. These large quantities of data are needed for machine learning (ML), including artificial intelligence (AI) systems and digital twins, which are representations of the physical world in the digital world.
Visualizing data in ways that scientists and engineers can use to improve understanding and to optimize processes is also important. Technologies can enable an “end-to-end digital thread of information,” says UpDyke. “Multi-site manufacturing in different markets is pushing the industry towards more connectivity, improved visibility across sites and organizations, and increased knowledge and information sharing that will enable expedited recipe development.”
New England Controls, Inc. (NECI), which partners with Emerson, has developed and deployed new digital tools in the past year that enable access to data sources and aggregation into analytical tools to link the “physical plant” to the “digital plant,” says Michael Cody, director of digital and clinical manufacturing at NECI. Access to data with operational context is crucial for pharma manufacturing facilities, says Cody. “The need to aggregate and analyze data from a variety of data sources is pushing equipment and technology providers to be able to interface and communicate with those digital tools in a meaningful way,” he explains.
Digital twins are a tool being increasingly used in a wide range of scenarios, from engineering optimization of individual pieces of equipment to analysis of full manufacturing systems. Examples from the past year, says Docherty, include digital twins for process development with an innovative mixing application, a representation of a new skid to enable faster fabrication, an offline training system for a continuous direct compression line, and an alerting system to ensure that people were keeping proper distance on the manufacturing floor.
Siemens also collaborated with GlaxoSmithKline (GSK) on a digital twin pilot project that modeled and controlled the adjuvant particle manufacturing process. The project proved the concept that digital twins could be used in vaccine process development and transferred to manufacturing (4).
As biopharmaceutical facilities shift to modular, multi-product facilities, digitalization enables efficient automation. A DCS can be used to connect the components, even as the process flow changes depending on how the different production modules are combined, says Docherty. Siemens and Sartorius, for example, demonstrated a modular production system using the Siemens DCS with Sartorius’ Biostat bioreactor system. The companies set up an agreement to build standard interfaces between the Sartorius unit operations and the Siemens control system for closer integration (5). This system would allow the option of a fully paperless manufacturing facility.
AR digital tools are finding a wide range of uses in pharma manufacturing. Prior to 2020, AR was being developed for training and as an aid for technicians following standard operating procedures, for example, and it was being used for remote equipment maintenance and troubleshooting. When the pandemic suddenly made being on site impossible, AR/VR suppliers, such as Apprentice IO, stepped up with kits that included smart glasses and the technology to connect remotely (6) and pharma manufacturers and their suppliers began using them for tasks such as remote factory acceptance testing (FAT) and installations. The efficiency of these tools is expected to drive continued use. For example, reports Duckworth, using AR for FAT has now become an accepted practice.
Manufacturers also began using AR/VR tools for remote inspections, audits, and facility tours. Suppliers such as Avatour offers cloud-based communication platforms with 360-degree video capabilities so that viewers can control what they are seeing. “By combining [this communication] with sensor data and geo-location stamps, these platforms provide independent third-party validation of what exactly transpired during each site visit,” asserts Devon Copley, cofounder and CEO of Avatour.
Regulatory agencies also used these tools for what FDA calls Remote Interactive Evaluations of facilities. Although such tools will not replace physical inspections, their use is expected to continue (7).
Efficient development and tech transfer for mRNA vaccine manufacturing
The data analysis and clear communication allowed by digital tools has demonstrated its benefits for process development and technical transfer, making time to market faster. Digital manufacturing technologies were successful in helping vaccine manufacturers, such as Moderna and Pfizer, accelerate their technology transfer and manufacturing process.
“The capability to perform technology transfer from Moderna to their contract manufacturing partner, Lonza, was enabled by the digital technologies deployed in their respective facilities,” says Cody. “Both Moderna and Lonza utilize DeltaV as their process automation system and Syncade as their manufacturing execution system. NECI teams partnered with Moderna and Lonza teams to transfer equipment automation strategies and electronic batch records from company to company, accelerating the manufacturing capacity and establishing supply chain capability as the Moderna COVID-19 vaccine was completing clinical trials and FDA emergency use approval.”
The availability of digital tools and the collaboration of implementing them in a refurbished facility was key to the speed of bringing BioNTech’s mRNA vaccine to commercial production in Europe, adds Wollaert. The process was brought online in under six months, while under normal circumstances it would have taken at least one year, he observed.
Siemens, a long-time partner of BioNTech, assisted the company in converting a facility in Marburg, Germany to mRNA vaccine production using end-to-end digitalization of production. Siemens Opcenter Excecution Pharma was chosen as the new MES, and the digital system enabled conversion to paperless documentation of production with electronic batch records. Although the process has a number of manual work steps, operators are guided through these with the software’s workflow management component. The Siemens Simatic PCS 7 distributed control system was used to automate processes (8).
FDA recognizes the role of digitalization and is working with industry suppliers to better understand these technologies. “The pandemic created significant opportunities for education and experimentation of digitalization with FDA,” says Jason Spiegler, senior director of Life Sciences Strategic Initiatives, Siemens Digital Industries. Although initial projects looking at digital twins took place within FDA’s Center for Devices and Radiological Health (CDRH) (9), the understanding developed in device manufacturing can be applied to other FDA branches, suggests Spiegler. Spiegler also co-leads a joint FDA and industry computer software assurance (CSA) team that is focused on educating and promoting the adoption of risk-based CSA best practices for the life sciences industry. “CSA is foundational for unleashing the potential of digitalization on the shop floor,” says Spiegler.
Although paper-based systems are still prevalent in the industry, the benefits of digital and automated systems were made more clear by the upheaval over the past two years, and the industry can expect more digitalization of manufacturing equipment and processes in the coming year.
“There is more of an acceptance that digital transformation is necessary and worth the investment in a regulated industry. This new awareness will help drive digital transformation and move the industry significantly forward,” predicts UpDyke.