Envisioning the Biomanufacturing Facility of the Future

Merrilee Whitney , Head of the BioContinuum Platform, MilliporeSigma

The length of time, complexity, and cost involved in advancing biologics from lead identification to patient delivery is immense. The synergy of process intensification and digital technologies that facilitate process control, connectivity, data collection, analysis, and collaboration will enable more timely and cost-effective production of biologics and increase patient accessibility. This convergent transformation will lead us toward biopharma manufacturing facilities of future.

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, legacy approaches remain highly manual. As we consider methods to expedite manufacturing and increase accessibility to therapeutics on a global scale, modernization will be required. Undoubtedly, the “facility of the future” will be characterized by intensified, continuous, predictive, and autonomous operations.

Borrowing from the term ‘Industry 4.0’, which represents the fourth evolution that has occurred in manufacturing, “Bioprocessing 4.0” describes the digitization and automation that will serve as the cornerstone for the biopharmaceutical facility of the future. Looking ahead, there is a clear industry movement to leave behind paper-based bioprocessing, data silos, manual process control, and equipment that cannot communicate with each other.  In its place will be a manufacturing ecosystem, seamlessly connected via uninterrupted data acquisition and analysis and characterized by information transparency and decentralized decision making. Drug manufacturers will be able to control and understand every aspect of their operation and leverage real-time data to boost productivity, increase operational efficiency and drive growth more effectively and efficiently.

Because of their remarkable potential to help bring new medicines to market faster, intensified, connected or continuous processing, and automation and digitization have been identified by influential industry organizations, such as the BioPhorum Operations Group, as key elements of the roadmap to transform Biopharma manufacturing. In addition to accelerating time to market, this transformation will help position drug manufacturers for success as they face increasingly complex regulatory requirements, intense cost pressures, high development costs and opportunities to expand into a growing number of new product classes.

This evolution will increase flexibility, reduce the manufacturing footprint, and shorten the lead time to adapt and establish manufacturing assets. Manufacturers will be able to significantly mitigate the risk of uncertainty created by changes in capacity requirements. Process intensification will also decrease the cycle time to produce and release product, facilitating an on-demand supply chain.

Next Generation Technologies are the Linchpin
For some in the industry, Bioprocessing 4.0 means a completely single-use manufacturing facility; others envision it as a fully connected and fully continuous process. From my perspective, the goal is the latter; but the true definition of next generation bioprocessing are the technologies that will get us there. I consider “next generation” to be any technology, expendable, or system which significantly changes the existing biopharmaceutical manufacturing template to deliver higher productivity, increased manufacturing flexibility, increased speed, and reduced risk. The fact is, we need more flexible approaches to biopharma production and the evolution is already underway with the intensification of specific unit operations.

Undoubtedly, this evolution has been accelerated by the global pandemic. The speed at which we’ve seen COVID 19 vaccines developed and manufactured is remarkable and a testament to both innovative, agile thinking and the new technologies being applied to address this global challenge. The industry is rapidly conceptualizing and implementing next generation bioprocessing technologies to accelerate the discovery and production of safe and effective lifesaving and life-enhancing medicines.

The Bio4C™ Software Suite
Our Bio4C™ Software Suite, which was introduced in 2020, is an example of a digital ecosystem of products designed to empower biomanufacturers to achieve greater speed, flexibility, and quality while reducing risks and costs. Our Bio4C™ Software Suite is comprised of several seamlessly compatible software products that enable a user remote access and the ability to look across the entire manufacturing process, versus individual unit operations, delivering enhanced process control and insights through a single integrated platform.

The first software product we introduced is Bio4C™ ProcessPad. This web-based software allows users to automatically collect data from disparate sources into a single, unified dashboard to better understand, improve and ultimately optimize the way biotherapeutics are made. It is a browser-based platform for data acquisition, aggregation, management, visualization, and analysis, that provides the user the ability to manage the velocity and volume of complex, various electronic and batch record data sources more effectively.  Instead of manually gathering all data, data is automatically collected, making reporting and analysis less time- and labor-intensive.

With the Bio4C™ ProcessPad, a user can collect data from any supplier’s system or unit operation. This software facilitates the integration of data collected from a wide range of sources, including, manual paper-based systems, and digital systems such as LIMS, QMS, and MES.  Aggregation of manual records, external databases and high-frequency sensor-based machine data enable near real-time insights while facilitating 21 CFR part 11 compliance. Questions related to process investigations or troubleshooting can be answered instantly using statistical methods such as correlations, group comparisons, bivariant and multivariant data analytics techniques.  In addition, the lot genealogy feature allows users to trace batch raw material sources, and their associations with the manufacturing process, in near real-time.  

Our second software product, the Bio4C™ Orchestrator, enables users to centrally, and ideally remotely, connect and integrate bioprocess systems. It allows connection of individual skids in an orchestration layer that provides monitoring, visualization, and centralized execution of manual activities in a browser-based platform that can be viewed in real time. With this connectivity, users can optimize processes, improve quality and compliance, and accelerate time to market.

Bio4C™ Software Suite aims to address the automation needs of drug manufacturers in a holistic manner with solutions for unit operation control automation, equipment connectivity, data collection and collaboration.  Under this guiding principle, we continue to expand our software suite and are building the next generation control platform called Bio4C™ ACE (Application Control Engine) for unit operation automation.

In addition, given the importance of data management and analytics, there is a growing need for process monitoring, control, and detection of deviations. For example, the FDA expects drug manufacturers to have an ongoing program in place to collect and analyze product and process data relating to product quality; including the quality of incoming materials, in-process materials, finished products and relevant process trends. In response to this growing need, later this year we will launch the ProCellics™ Raman Analyzer with Bio4C™ PAT Raman Software which can measure a broad range of bioprocessing parameters simultaneously, providing real-time monitoring and process control.

Ensuring a Smooth Adoption
The adoption of any new technology requires expertise, patience, and a commitment to success. To ensure a smooth adoption for our customers with the Bio4C™ suite, we start with an understanding of the problem the customer needs to solve. With the Bio4C™ ProcessPad for example, we would look to understand how they currently manage their disparate data sources, what kind of challenges they face as they aggregate the information and how their processes are defined manually. We then work with them to design automated data integration from LIMS or ERP systems and create forms for operators to input manual entries or process observations. We also help the customer design dashboards for data visualization and reporting and conduct a “train the trainer” sessions with end-users.

For Bio4C™ Orchestrator, we work with the customer’s automation teams and integrators to plan the implementation and integration of the software. With a detailed implementation strategy and project plan, our implementation manager ensures we work collaboratively through the phases of user requirement specifications, design, implementation, validation, and training, followed by go-live. While our Bio4C™ user portal provides a single web-based interface to track service-related information for the user’s software and systems products.

Taking the First Step Towards Bioprocessing 4.0
The way drugs and vaccines are produced is undergoing an unprecedented transformation enabled by connected, digitized, and automated processes, and fuelled by data and machine learning.

At a fundamental level, the evolution has begun – with flexible, easily-connected intensification blocks that enable a process to meet a particular customer’s needs. Every customer will have different templates and different objectives, so it is incumbent on us as suppliers to have building blocks that can be seamlessly integrated, as well as can operate independently of one another, if needed.

As our collective progress towards the facility of the future concept gains traction, companies are exploring how to link operations - creating fully connected, fully continuous processes. Our advice to biomanufacturers is to have a clear idea of what you’re trying to achieve and define the bottlenecks you are facing. Obtain a good understanding of what connecting processes means at the bench scale first, because addressing the challenges early on will make it easier when moving to larger scale.

Partnerships too will be essential to transition into this new generation of advanced bioprocessing. Suppliers, like my organization, have a central role to play since we are developing solutions to help manufacturers gain the greatest benefit from next generation bioprocesses and help them overcome the challenges that come with this type of change. Each molecule and manufacturer are unique with different processing priorities. Collaborating with a vendor offering a wide portfolio of manufacturing options, coupled with deep technical expertise, enables manufacturers to tailor processes to meet user needs and help them welcome in the era of Bioprocessing 4.0 and the facility of the future most effectively.

Merrilee Whitney

Merrilee is the Head of the BioContinuum™ Platform, driving the strategy and execution of Process Intensification Technologies, Software & Automation, and Analytics to meet the needs of biologics manufacturers. Throughout her 15 years at MilliporeSigma, she managed multiple product lines including clarification, aseptic, virus filtration, and Single Use & Systems.

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