Development and delivery of lifesaving therapeutics to patients in the most efficient and cost-effective manner possible is the goal of biomanufacturers. While templated processes in biologic manufacturing have served to decrease timelines over the past 20 years, manufacturing processes remain highly manual, legacy processes. As we consider methods to expedite biologics manufacturing and increase accessibility on a global scale, modernization of manufacturing will be required.
While significant strides have been made in the development of biologics, there are still many opportunities to increase efficiencies. In monoclonal antibody (mAb) manufacturing, the dominant production method relies on batch manufacturing, a labor- and resource-intensive process. This widely templated process includes the following major steps, or unit operations: cell line development, fermentation, harvest, chromatography, viral inactivation, polishing steps, viral filtration, ultrafiltration/diafiltration, final formulation, and fill and finish.
These unit operations typically occur in isolation from each other, but optimization, or intensification, can result in higher throughputs in connected and reduced footprints. Different mechanisms of intensification include increasing bioreactor titers, increasing throughput with connected or continuous operation, and integration of multiple purification steps, thereby reducing the number of unique steps required in the overall process. As process efficiency increases, the equipment required is smaller, further enabling single-use and closed system implementation and providing manufacturers an opportunity to reevaluate the classification of their manufacturing space.
Digital technology is a key catalyst in the evolution from intensified to connected and continuous processes. Automation will be a central requirement, but data analytics, when applied to advanced process intensification, can further increase production efficiencies. Also essential to process intensification and continuous manufacturing are Intelligent systems, which communicate with each other using standardized protocols. In essence, the digital technology aims to converge and integrate the four critical “Cs” — to digitally control (the equipment), connect (the layers), collect (the data) and collaborate (with stakeholders) in a facility across all its operational components.
The ultimate goal is a comprehensive digital solution that provides a fully automated biomanufacturing process. The entire process from end-to-end would be seamless, eliminating manual intervention, anticipating process deviations early and eventually errors and contamination associated with operator interventions. Process monitoring would be in real time with feed-forward and feedback loops resulting in optimum steady-state operation for improved and consistent quality. This frees the operator to focus on technical assistance and confirm system operation in a sustainable manner.
There is widespread recognition that the biopharma industry has a lot of opportunities for improvement, and we can learn immensely from other digitally mature industries. Opportunity examples are increasing speed, improving manufacturing flexibility, managing uncertainty, handling new modalities, and cost pressures. Everyone across the supply chain and the entire biopharma ecosystem is working on these dimensions, and each player can contribute to greater efficiency in some shape or form in their respective areas of expertise in the value chain.
Companies can better understand their present state with the BioPhorum’s digital plant maturity model (DPMM), which was designed to enable evaluation of current strengths and weaknesses and transform the manufacturing environment through the application of digital innovations, such as process modeling or predictive analytics. Some biomanufacturers are at level one. Many are at level two, with basic PLC (programmable logic controller) controls, automation, and transcription. A few have moved beyond these initial stages, advancing to level three or early level four. Of course, there is no one solution to address all needs and move up in maturity level.
There are different levels of maturity with respect to digitalization depending on the individual player and supply chain position: equipment vendor, drug manufacturer, business development scientist, or process development lab. Each is at a different stage of evolution.
A digital transformation in biomanufacturing is a critical piece in creating a facility of the future that is truly a convergence of intensified, connected, and continuous processing seamlessly coupled with uninterrupted data acquisition and analysis. Together, these technologies will make real-time lot release and lights-out manufacturing achievable to the ultimate benefit of patients around the globe, expanding access to affordable lifesaving and life-enhancing biotherapeutics.
At MilliporeSigma, we are integrating the efforts around upstream and downstream process intensification and software, automation, and analytics in the BioContinuum™ Platform to converge our vision of the Facility of Future.
Rather than build automated equipment with an analytics layer, MilliporeSigma takes a holistic view, believing that, in facilities of the future, solutions will encompass all layers. We believe that the underlying digital architecture of tomorrow must focus on interoperability, standardization, and modularity, with a special emphasis on end-user experience. Systems and equipment will be supplied by multiple vendors and controlled so that they operate safely in a standard, secure, and compliant manner. From a data perspective, they will be connected seamlessly and operate intelligently with one another to create true efficiencies. Contextual data from all unit operations and the systems underlying and connecting them will be collected and aggregated in one place for end-to-end process analysis. The end users of tomorrow will be digital natives and will expect their interactions to be a lot more intuitive.
This approach can then be expanded to the entire facility and its users to include key internal and external partners, such as quality control laboratories and contract development and manufacturing organizations, contract research organizations, and raw material suppliers. That results in deeper collaboration and better information sharing across the value chain, and ultimately even greater efficiencies and higher quality.
What connects them all, however, is what is missing: solutions that are built by bioprocess experts specifically for the bioprocess industry.
The key in the biopharma industry is to build solutions from the bioprocess engineering perspective, to anticipate the needs of operators as processes are integrated. Software systems, including the way the software menus are arranged and the order of the process steps, should reflect the way a bioprocess engineer thinks. Solutions developed for other industrial applications, such as the energy industry, and then retrofitted for biopharmaceutical manufacturing are often unintuitive and incomplete rather than holistically designed to solve bioprocess-specific steps.
The Bio4C™ Software Suite is a novel platform combining process control, analytics, and plant-level automation, which enables users to look across the entire manufacturing process versus at individual operational units. Comprising standalone but comaptible software products, the Bio4C™ Suite's development is driven by the need to integrate the four C’s — control, connect, collect, and collaborate — allowing for full control, transparency, and intelligence leading to data-driven decisions on a process and plant level.
The “collect” dimension of the four Cs, Bio4C™ ProcessPad software is a data collection, visualization, and analytics software platform that enables bioprocess monitoring, life cycle management, reporting, investigations, and continued process verification (CPV).
Intelligently combining process data from disparate data sources, such as batch records, quality control results, standard databases, QMS, MES, LIMS, and data historians, into a single, contextual, integrated data source, Bio4C™ ProcessPad ensures that process information is current, complete, and accessible throughout the product life cycle. The out-of-the-box data visualization and analysis tools mean users don’t need to be data scientists to understand, explore, and analyze their data.
The “connect” facet of the Bio4C™ Suite, Bio4C™ Orchestrator connects individual unit operations to a centralized platform for unified visibility and monitoring of regulatory-compliant biomanufacturing systems and processes. Bio4C™ Orchestrator provides remote access to systems, recipes, reports, user accounts, and alarms from a centralized process dashboard.
Bio4C™ Orchestrator is browser-based to extend accessibility and data sharing across the entire organization. No software products need to be installed. The features and user interfaces have been designed by bioprocess engineers, so they are intuitive for both operators on the plant floor and top management.
Built for the biopharma industry from the ground up, Bio4C™ Orchestrator’s scalable, modular architecture grows and adapts as manufacturing and facilities change and evolve. The software also incorporates the important design principle of modularity using open standards. With plug-and-play capability, Bio4C™ Orchestrator is future-ready. The incorporation of National Institute of Standards and Technology (NIST) standards into the code platform also ensures security in a world focused on collaboration.
We envision Bio4C™ Orchestrator displacing traditional thinking in terms of connecting large, distributed control systems. The result will be creation of a niche somewhere in between that is much more lightweight and very purpose-built for meeting the needs of the bioprocess industry.
Every Bio4C™ Suite software product, including Bio4C™ Orchestrator, is backed by expert and comprehensive support. At MilliporeSigma, we invest in the success and support of our software customers. Our Customer Success Team begins by focusing on the problems the customer want to solve. They then recommend a complete solution configured to realize optimum benefits for the customer.
The Customer Success Team is also involved in the installation and continues to engage with customers on an ongoing basis once installations go live. They provide training and revalidate requirements as new software versions are implemented. Because the Customer Success organization and managers are involved from the start, they can apply the knowledge gained from the first installation and ongoing use of the software to the evolving needs of customers as their organizations grow and evolve.
As the biopharma industry continues to expand around the world, we look forward to serving as an innovative partner that can help bring process efficiencies to both new and existing facilities wherever they are located. With our integrated approach that emphasizes control, connectivity, data collection/analysis, and collaboration, we can help manufacturers reduce time to market with solutions that are built-for-purpose and designed to support bioprocess intensification.
The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.
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