Disruptive new biopharmaceutical CDMO Wheeler Bio is aiming to push the boundaries of biomanufacturing, designing a new facility that will advance along the Pharma 4.0 path and potentially set a new paradigm for applying risk-based thinking to introduce new concepts in manufacturing to support their clients. A panel of experts from Wheeler Bio, including Chief Operating Officer Yuk Chiu and Vice President of Quality and Regulatory Affairs Dawn L. Wofford, and from their design–build partner CRB, including Director of Digital Technology Yvonne Duckworth, Bioprocess Engineering Subject Matter Expert Steve Attig, and Project Manager Patricia Robbins, discuss the Pharma 4.0 model and their collaboration to advance it to build a transformative new facility, in conversation with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.
David Alvaro (DA): To begin, can you tell me about the evolution of the Industry 4.0 and Pharma 4.0TM models and their goals?
Yvonne Duckworth (YD): I’ve been an automation engineer in the pharmaceutical industry for over 30 years, and a considerable amount of my time recently has been invested in the Pharma 4.0 initiative. Pharma 4.0 was specifically created by the International Society for Pharmaceutical Engineering (ISPE) in 2017, and I became involved in some working groups associated with that Pharma 4.0 community a few years ago. Today, I am co-chair of their rebranding as the Holistic Digital Enablement team, as well as a recently appointed chairperson on the overall ISPE Pharma 4.0 leadership team. I’m actually the first person from the United States on that leadership team, which is exciting given that we’re trying to internalize this more to the United States.
Pharma 4.0 emerged from the concept of Industry 4.0, which was basically the fourth industrial revolution. The first industrial revolution was centered around steam and waterpower, while the second revolution introduced mass production and electricity. The third industrial revolution built on all of that with computers and electronics, essentially IT-based systems. Today, we have entered into the fourth industrial revolution — “Industry 4.0” — which is centered around cyber physical systems, the industrial Internet of things (IIoT), and the concepts of smart manufacturing, facilities of the future, and the importance of having a high level of connectivity in your system.
Industry 4.0 is not just implementing a few new technologies. Connectivity and integration are two of the key factors under this technology umbrella, but it also includes a range of other technologies, including AI, cyber security, the cloud, robotics, vertical and horizontal system integration, IIoT, RFID, and AI/predictive analytics. There’s a whole host of different applications that fall under Industry 4.0, but the integration of all these technologies is critical.
The pharmaceutical industry, being more reserved and heavily regulated, has not been as quick to adopt these new technologies compared with other industries.
To address that, ISPE created the Pharma 4.0 group to provide guidance to enable the pharma industry to incorporate these technologies in a holistic way and from a holistic perspective. By “holistic,” I mean the need to consider all of the impacts in a broader sense. For example, a key question is how moving toward Pharma 4.0 would affect a company’s workforce. Introducing robots might lead to a workforce reduction, but collecting and analyzing more data creates the need to hire data scientists. Depending on what you’re considering, your workforce may be adjusted either up or down. Another major change is a significant reduction in the use of paper, which generally requires a significant mind shift that typically must be led from the top down. There will clearly be changes in the cultural aspects and the overall mindset of the company.
DA: How would you characterize the adoption of Pharma 4.0TM ideas across the industry to date?
YD: Electronic batch records have been out there for a while, as have robots and the use of manufacturing execution systems (MES) tied to process control systems and sending signals back and forth. But now we’re bringing those activities under the Pharma 4.0TM umbrella. The connectivity and the system integration is happening more frequently, but it comes with capital investment cost, as well as validation considerations. It’s definitely recommended to include those topics upfront, because it’s harder to implement within an existing facility.
DA: Can you discuss the foundational vision for Wheeler Bio and why the Pharma 4.0 paradigm is so important to the company?
Yuk Chiu (YC): Our industry has been focusing on risk management and risk-based decisions for many years, which means that companies are expected to develop deeper understanding of their processes and operations: Do we know what we are doing and why we are doing it? How can the processes be more consistent? What is the basis for continuous improvement? All of this knowledge needs to be supported by data.
In the past, this required substantial amount of paper records or data files from individual pieces of equipment. The lack of integration made it very difficult to extract meaningful information about the entire end-to-end process. It became increasingly clear that it was critical to integrate the systems and develop useful statistical models to identify process criticalities and allow early process faults detection.
The benefits of this approach are considerable. It enables more accurate data-driven decision-making processes, which can lead to reduction in deviations and investigations during manufacturing. As such, the overall consistency of the processes, product quality and product lead time can be improved. Ultimately, that means faster access to therapeutics for patients. At the end of day, Wheeler is driven by a focus on customers and on patients.
DA: How did the Pharma 4.0 model shape some of the early priorities Wheeler had for your facilities?
YC: Wheeler is applying the model to two phases. The first phase focuses on our existing facility: our priorities are to establish the foundation for Pharm 4.0, which includes hiring the right team and building the culture of Lean, risk-based decisions and continuous improvement. Additionally, we are developing our technology platforms, expanding our process knowledge, and building the subsequent control strategies. Our facility, equipment, information systems, and other data infrastructures are designed to be highly flexible and can accommodate over a variety of therapeutic modalities while maintaining a high level of data integrity.
The design of open ballroom production suites, digital system integrations, and the use of single-use technologies together with a proper risk management program will allow our operations to be in a consistent state of control, while we can anticipate significant increase in production throughput compared with our competitors.
This approach carries over into phase two for the new facility, which will be dedicated to large-scale late-phase or commercial manufacturing. We will apply all lessons learned during phase 1 to further enable our innovations and technology development in the Pharma 4.0 or even 5.0 journey, ensuring improvements in the overall efficiency and customer satisfaction.
DA: Can you elaborate on the decision to partner with CRB for these projects?
YC: I have had a great working relationship with CRB since 2002, which was around the same time that Steve and I were colleagues at Amgen, before he moved to CRB. Beyond that, CRB consistently partners both with the industry and with regulatory agencies to move the industry forward. The direct association with the Pharma 4.0 initiative is also a real plus. CRB’s experience — with processes, facilities, automation, and project execution — will really help us to bring our manufacturing into the future.
Steve Attig (SA): Everything Yuk mentioned is what drew me in to CRB myself, and it also aligns with what makes Wheeler Bio such a great partner for CRB. Wheeler also has a vision of enriching the culture in Oklahoma City and transforming pharma manufacturing itself.
Many of these concepts — ballrooms, risk assessments, closed processing — aren’t exactly new; we’ve been discussing them in this industry for a really long time, going back to ISPE’s first publications. But that truly forward-looking, holistic vision is rare. Wheeler is building that vision to the design of this new facility, and CRB is helping with their risk management and building the foundation to launch into the next phase.
This design will additionally provide their employees with a huge learning opportunity — instead of being siloed into little rooms and spaces, they have the whole process together, with the team on the floor learning together, talking, and teaching. It’s just a really innovative company and a really exciting opportunity that we’re glad to be a part of.
When you’re working on a project that really pushes the envelope toward what you see as the next step, it’s much easier to bring more enthusiasm and more creative juices to the project. We definitely view this as a harbinger of where the industry is headed.
ISPE and other industry trade groups have been talking about ballrooms and connectivity for some time. New facilities are being designed, but companies tend to be cautious about shifting to new paradigms, instead continuing to take a conservative approach. Wheeler believes in and lives the science, and they have an expert leadership team that knows this industry in and out and is following the FDA in terms of guidelines and feedback. Wheeler and CRB are walking hand-in-hand together through this.
Twenty years from now, most facilities will look like this, and we’ll be going back and saying: “Remember what the Wheeler facility looked like and what they developed?” They have real belief in the science and the risk-based compliance approaches, and we’re right along with them, because we’re also comfortable with that vision.
YC: Things clicked quickly between these two teams. In the past, when I’ve worked with other engineering firms, they have these set rules dictating how things must be done. But with CRB, it’s about understanding the real risks and figuring out how to mitigate them — everything comes down from that level. Discussions have been more open and enjoyable. Neither company is going by the book — we are both introducing new ideas and evaluating them on the basis of science, data, and risk, not industry inertia and the way things have always been done.
Patricia Robbins (PR): Wheeler has been a fantastic client for us to work for because of their willingness to be involved, their openness to our ideas, and the level of information sharing and collaboration. We’ve been really lucky to have such a great client who is willing to work with us like that and not put up roadblocks. They’re willing to look past the conventions so we can work together to follow the science.
DA: For CRB, do projects like this allow you to prove some approaches that you believed in but other clients have questioned so you can help move the whole industry forward?
SA: What Wheeler’s doing here is helping the entire industry. The overall impact of being able to show it off can move everything forward. Many CMOs are very conservative and still see too much risk in designing a facility as a ballroom with closed processing as the foundation. In this case, Wheeler believes in this philosophy and asked us to show them that this philosophy can be made real.
YD: The real focus in the decision to incorporate these technologies should be asking yourself what problems exist at your current facility, what problems can be fixed with technology, and what value you can create by incorporating new technology.
Once you decide on what those technologies are, it’s very important to consider the impact on design. While some technologies have little impact, others will require more significant considerations. Robotics applications will affect the facility layout, predictive analytics will affect equipment vendor specifications, and more robust wireless infrastructure will transform the overall IT network infrastructure. These considerations have to be accommodated for and built into the design, even if the technologies are added later in a phased approach, which works well for companies that have a speed-to-market drive or are limited on funds.
There is some good guidance out there for companies. The FDA has a program called the Emerging Technology Program that was implemented a couple years ago. In February, I presented at the ISPE Facilities of the Future Conference in Maryland, and I had never seen so many FDA speakers at a conference. That change reflects the collaboration between pharma and the FDA during the COVID situation and the mutual desire to continue that momentum and work together more closely. I made some great contacts at the FDA, and they are in the process of revamping their Emerging Technology Program to make it more user-friendly and to take advantage of this opportunity to help in this process of working with the pharma industry to assist them with implementation of new technology.
DA: What are some of the other challenges you have ahead of you?
YC: One challenge we are facing is the skill sets that are available locally. Pharma 4.0 puts demands on certain skill sets, like data science, automation, and process analytical technologies. To narrow this gap, we can always reach out to our board professional network, previous colleagues, and industry partners. However, it is even more critical to collaborate with the faculties and students from local universities, as there are many ongoing and relevant research projects that fit our needs. By developing long-term relationships with the local institutions, we can leverage their technical expertise, as well as develop a sustainable local biotech workforce in Oklahoma.
Another challenge — coming from the industry’s perception — is that more conservative stakeholders may see our approach as a risk simply because they haven’t had much experience with such facilities or operations. While part of our business is to develop technology platforms and provide great CDMO services to our customers, we are also building long-lasting relationships that allow us to educate them on our approach and the risk modeling that supports it.
Dawn Wofford (DW): This perception of quality and risk presents a bit of a stumbling block. However, the International Council for Harmonisation (ICH) guidelines have sought to push the boundaries and has recommended changes that expand perspectives to include the entire product’s life cycle. That aligns well with the holistic philosophy of Pharma 4.0. Risk management and applying knowledge management supports a holistic view of the product life cycle. I think that will ultimately change the perception of quality and regulatory and help them embrace the change.
There really have been a lot of groundbreaking changes within regulations and guidelines; we are just among the first to follow those to their logical conclusions. Ultimately, we are using a risk-based approach with our process knowledge and providing the appropriate mitigations, to be fully in compliance.
DA: Can you share any details about the timelines for the new facility?
YC: For our existing facility, we began the detailed design in July of 2021, and it has been completed. We are targeted to start construction in early Q3 2022, which should take about four to five months to finish. For the large-scale manufacturing facility, we are targeting the engineering design to start in Q4 2024, and we anticipate the facility to be completed by early 2026.
SA: The current construction is occurring in an existing building, so we don’t need to begin from the ground up. The core and the shell are there, and we’re fitting it out in a different way, which allows us to move quickly on this project. Equipment deliveries are huge issues now, but fortunately we aren’t faced with long lead times, because a lot of this equipment, since it is single-use, is available off the shelf. It’s simply a case of getting into the queue rather than having to design something and customize it to the nth degree. We’re leveraging the power of the vendors and their standard designs to make things happen fast for Wheeler.
DA: I understand that there is already some interest in submitting the design for consideration for ISPE’s Facility of the Year (FOYA) awards.
YC: Each year, ISPE recognizes state-of-the-art projects across our industry for utilizing innovative technologies to improve product quality, to improve the efficiency of producing medicines, and to demonstrate advances in project delivery. We are currently working with CRB to explore several FOYA categories and will submit for one when our facility is up and running.
SA: At CRB, we take great pride in supporting our clients if they want to pursue these kinds of recognition. We take great pride in Facility of the Year nominations, and we can help clients navigate the pathways that they have to go through. We think that there will ultimately be great interest from the industry to tour this facility and see what Wheeler and CRB will have done.
DA: To close on something even more forward looking: do you have any insight into further innovations on the horizon for the industry, even a sense of what the fifth industrial revolution will involve?
YD: CRB generates a survey report that we call the Horizons Report, which explores strategic areas for which we would really benefit from our clients’ input. In last year’s Horizons Report, one of the topics we explored was Pharma 4.0, and we got over 500 results back from the pharma industry. One of the questions was: Where do you see yourself from a digital perspective? What do you want to target going forward, and how long do you think it’s going to take for you to get there?
The Digital Plant Maturity Model is an assessment tool that was created by the BioPhorum group. It establishes five levels of digital maturity, starting with completely paper-based, digitally siloed, and fully manual operations (level 1) to islands of automation and some level of connectivity (level 2). Level 3 involves more extensive connectivity, level 4 is predictive, and level 5 is autonomous. Right now, there are no level 5 facilities. The majority of our clients — whether they are CMOs, biotechs, or cell and gene therapy companies — are either at the border of levels 2 and 3 or at level 3 but aiming to get to level 4, with perhaps a bit of level 5 autonomy sprinkled in.
I think that predictive analytics allowing companies to solve problems before they happen and create downtime will really have a significant role in taking the industry forward. This not only impacts workforce decisions, but it challenges equipment vendors to make sure that their equipment includes technology needed for predictive analytics, such as vibration and high-temperature sensors. Every vendor is different, but I think that they are being challenged enough to realize that they need to keep up with this.
The level 5, fully autonomous facilities, including automated storage and retrieval systems, are very exciting, but they require a high level of throughput to be economically feasible.
DA: Any other closing notes from the team?
SA: What Wheeler’s doing here is helping the entire industry. The overall impact of being able to show off their success can move everything forward.
YC: Ultimately, that means faster access to high-quality medications for patients, which is the real goal of Pharma 4.0 and Wheeler Bio. It is also what drives us; our focus is on our customers and on patients; that’s why we are in this business and why we are wholly invested in digitalization and striving to reach the highest level of digital maturity that is possible today.
