Design Considerations for Live Biotherapeutic Product Facilities Working with Spore-Forming Bacteria

In this article, we will discuss the engineering concepts and considerations for a live biotherapeutic products (LBPs) manufacturing facility, along with the challenges associated with a novel facility of this nature. Among the unique challenges that must be addressed in a multiproduct facility manufacturing LBPs is that some species are spore-forming bacteria, which require particularly stringent containment to avoid cross-contamination. To complement these discussions, the article will also provide background information on spore-forming bacteria and their role in LBPs. 

Bringing New Products to the Market

The microbiome is vast, and LBPs range from a single strain to a consortium of microorganisms to fecal matter transplants (full spectrum–based LBPs). LBPs create a truly exciting new therapeutic platform with a novel approach to disease treatment and significant potential to improve patient lives. At both DPS Group and Arranta Bio, we are thrilled to be in a position to help advance the field and bring these important new products to the market.

Arranta’s Watertown, Massachusetts facility is configured to allow for expansion to larger-scale production as demand increases. The current maximum fermentation capacity is 2 x 2000 L, with a total of 13 suites across two segregated GMP spaces. A third (future) GMP space, initially intended for warehouse space, has the potential for inclusion of an additional three suites, including the necessary expanded utilities. The Arranta Bio facility design allows for agility in process configurations: incorporating single-use equipment, strategically located utility panels, and a centralized vaporized hydrogen peroxide system (VHP) routed to each room to allow for decontamination as needed.

The Nature of Spore-Forming Bacteria and Their Benefit to Humans

Endospores are widespread in nature. They are found in the soil and water sources and are associated with insects, plants, and animals. Most spore-forming bacteria belong to two genera of the phylum Firmicutes: the aerobic or facultative anaerobic Bacilli and the strictly anaerobic Clostridia, both of which are present in the human gut.  

Nonpathogenic spore formers have received growing attention as ingredients in probiotic foods and supplements, and more recently as potential live biotherapeutics for the treatment of a number of diseases and disorders. Evidence suggests that using spore-forming Bacillus and Clostridium strains in the food industry is more effective than employing lactic acid bacteria, because bacterial spores are able to survive passage through the acidic stomach and better withstand processing and storage conditions. In addition, spore-based probiotic products often include bacterial species that humans no longer ingest because fruits and vegetables are routinely washed, peeled, and/or cooked.1

Targeted therapeutic benefits of spore formers have recently become evident. Spores of B. subtilis have also been investigated as drug delivery vehicles. Several strains of Clostridium, meanwhile, have been shown to selectively colonize solid tumors, creating interest in their use for selective tumor targeting and destruction.2 Another recent example of a spore-based microbiome therapeutic is one based on Firmicutes spores for the treatment of ulcerative colitis.3 Other LBPs are being developed based on spore-forming Clostridiumbacteria for targeted delivery to the colon.

Manufacturing Challenges with LBPs and Spore Formers

Since LBP manufacturing processes typically include some combination of upstream fermentation, harvest separation, downstream purification, lyophilization, solids milling, and capsule filling, a suitable contract manufacturer must be knowledgeable and skilled with this specialized GMP equipment.

Additional capabilities for maintaining anerobic/low-moisture conditions during the entire production process, from upstream fermentation through encapsulation, are also needed. The process must be designed and controlled to maintain the viability of the live bacteria, not only in upstream operations, but also throughout the downstream processing.

Approximately 10–20% of the bacterial strains being developed as LBPs are spore-forming bacteria. As these therapeutic candidates advance through the clinic, the need for manufacturing facilities designed to safely handle spore formers has increased. This presents a challenge for developers of spore-forming LBPs, as most contract manufacturers do not produce spore-forming bacteria in their facilities due to the challenges associated with eradication of this particular type of microorganism.  The endospore can withstand harsh environments and is far more difficult to kill then vegetative bacteria, which presents a challenge for cleaning and disinfection. Working with spore formers is particularly challenging in facilities with re-usable product contact surfaces and equipment, such as stainless-steel fermenters.  Not only are spore-forming organisms harder to kill with traditional clean-in-place (CIP) and sterilization-in-place (SIP) cycles for cleaning of a bioreactor, but the ability to validate the cleaning and sterilization process is that much more difficult, because the spore-forming organism is an anaerobe, which presents recovery challenges. 

The U.S. FDA has generated the guidance Manufacturing Biological Intermediates and Biological Drug Substances Using Spore-Forming Microorganisms to define the minimum set of requirements to enable a multi-product facility to handle these types of microorganisms. Additionally, using single-use product contact surfaces and closed processing, which is standard practice in biologics manufacturing, throughout the process is extremely important for product quality. 

Architect/Engineering Firm Partner Selection and Facility Design Process

Designing and building a facility that incorporates a complex manufacturing process with unique regulatory requirements requires aligning with an architecture and engineering firm that brings knowledge and experience to the project. Selecting a firm that specializes in the life sciences is helpful but finding one that is specifically experienced in novel therapies manufacturing is ideal.

For new facilities involving next-generation products and newer technologies, the challenges can be even greater. In these cases, a collaborative approach becomes even more important. The process begins by holding workshops with the client to learn the process, identify all the key features that will impact the design, and achieve consensus on the user requirements of the facility.

It is critical to engage a team of architects and engineers that have experience in working with the segregation and process equipment needs of novel therapeutic manufacturing facilities. Material and personnel flows, as well as air-handling solutions, are specifically designed to address working with LBPs. Well-conceived flow diagrams that depict these movements are essential to developing a design that limits the risk of contamination associated with spore formers.

As an ISO 9000 company with more than 45 years of experience, DPS has developed a highly structured approach to design projects, including those for LBP facilities. DPS has experience with clients at all levels of capital project execution maturity, phases in company growth and product development, and project driver motivations. DPS is also experienced in designing novel therapeutic manufacturing facilities for a variety of technologies, leading to a thorough understanding of the specific design and regulatory differences and requirements.

Early collaboration, process needs identification, governing systems philosophy creation, and facility operational requirements (FOR) development are key to the success of any biotech buildout project. This foundation will drive the decisions of the later phases of design. 

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All design projects have design reviews at key milestones for deliverables. These reviews check cross-discipline alignment and adherence to the project’s governing philosophies. They are also a time to perform risk assessmentsn such as process hazards analysis (PHA). With LBPs, these design reviews are also a point to conduct a contamination risk assessment. Evaluating the risk and determining a mitigation to any identified high-risk item builds a safety factor into the design.

Designing a safe manufacturing facility for spore-forming LBPs offers a unique engineering challenge. By partnering with an experienced engineering firm, taking a methodical approach to the design, and assessing risk at each phase, a successful and contamination-free LBP manufacturing plant is achievable.

About the Contributors

DPS is a global architectural engineering, consulting, and project management company, serving high-tech industries around the world. DPS designs biopharmaceutical facilities from the first generation of recombinant proteins through monoclonal antibodies (mAbs) and modern-day novel therapies, such as gene and cell therapy, viral vectors, RNA, oligonucleotides, microbiome, and exosome. DPS’s teams also embrace technology advances, such as continuous manufacturing (perfusion and continuous downstream processing), advanced process analytical technology, improved single-use systems, and modular and podular designs. 

Arranta Bio is a visionary contract development and manufacturing organization (CDMO) that strategically partners with leading microbiome innovators to provide manufacturing, scientific, and regulatory expertise. Arranta’s dedicated team, state-of-the-art facilities, and unparalleled resources are crucial for advancing live biotherapeutic products (LBP) from development to commercial launch. Arranta Bio has experience with aerobic, anaerobic, spore-forming, and genetically modified organisms for both single-strain and consortium products.  Built specifically for LBP drug substance and drug product manufacturing, Arranta’s facilities continue to expand capacity across multiple sites in order to meet the evolving demands of their clients and partners.

References

  1. “Spore-based probiotics provide bacteria species we rarely ingest anymore, due to washing, peeling and cooking our vegetables.” Emerson Ecologics. 16 Aug. 2019. Web.
  2. Umer, Brittany, David Good, Jozef Anné, Wei Duan and Ming Q. Wei. “Clostridial Spores for Cancer Therapy: Targeting Solid Tumour Microenvironment.” Journal of Toxicology. 2012: 862764 (2012).
  3. Henn, Matthew R. et al. “A Phase 1b safety study of SER-287, a spore-based microbiome therapeutic, for active mild to moderate ulcerative colitis.” Gastroenterology. 4 Aug. 2020. Web.
  4. Tetz, George and Victor Tetz. “Introducing the sporobiota and sporobiome,” Gut Pathogens 9: 38 (2017).
  5. Guidance for Industry Manufacturing Biological Intermediates and Biological Drug Substances Using Spore-Forming Microorganisms.S. Food and Drug Administration. 2007. Web.

Originally published on PharmasAlmanac.com on June 25, 2021.

Remaining Nimble in Biopharma Construction and Engineering

Genesis AEC, a consulting, architecture, engineering, construction management, and CQV (commissioning, qualification, and verification) firm, can help pharma clients tackle whatever new challenges they face, thanks to their embedded flexibility, active approach to training and education, and adoption of innovative trends, such as 3D printing and augmented reality (AR) technology. Meryl Towarnicki, Executive VP of AE Services, spoke with David Alvaro, Ph.D., Scientific Editor in Chief of Pharma’s Almanac, about staying competitive, how to address the pressing talent shortage, and the future of “lab in a box” building.

David Alvaro (DA): What can you tell me about how Genesis AEC is positioned among your peers and competitors in the market?

Meryl Towarnicki (MT): We’ve recently put a lot of effort into making sure that the market understands who we are as a firm. We have evolved rapidly over the last ten years, adding subject matter experts (SMEs) and services, such as process architecture and engineering, to fit our clients’ changing needs. As such, we’ve been on a campaign to reeducate our existing clients and the industry about our full-service capabilities. We’re ranked fifth in Pharmaceutical Design by Engineering News-Record (ENR); and within our sector we can compete with firms much larger in size. In fact, we bid on the same RFPs as some of our larger competitors. Although we’re a smaller, nimble, quality-focused AEC firm, we’re as equipped as the bigger players.

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DA: Genesis AEC does a lot of work with biotech startups. Do you think those kinds of companies are an ideal organizational fit for the firm?

MT: Startups are often looking as much for guidance as design/build services, as they haven’t been down the path of creating a facility before. We’re a good fit for these companies because we can deliver an economical turnkey facility. For these young companies, they can struggle to get the attention that they need from larger firms. We’re quite in tune with helping startups develop their business plan for their facility, and, when we begin to dig into the details of their project, we are adept at demonstrating that to them. For example, we have a client who needed to add on new operations and thought that they would have to lease the adjacent space to accommodate the expansion. After one meeting, it was clear that we could provide consolidated lab space, an area for pilot scale functions, and a cGMP suite all in their existing location. They used this information in a board meeting to secure funding, and it demonstrated our skill in helping with their business plans beyond just the design and construction project.

But that’s not all — Genesis has clients from small startups to Big Pharma, CDMOs, and CMOs; with our size and skillsets, we can play in every arena. We’ve gained a lot of experience with various project sizes all along the drug development process, and we’re open to all types of clients. Of course, larger companies come with different standards, as well as a little more bureaucracy, which we are nimble enough to navigate. We can also right-size our services for smaller clients that prefer to be more independent and require a more economical fit-for-purpose project.

DA: What was the impact of the COVID-19 pandemic on Genesis AEC and your operations?

MT: We weathered the pandemic well from several perspectives. Right before COVID hit, we moved our headquarters into a brand-new office in Blue Bell, PA. We also opened offices in Philadelphia and Boston and two offices in California. At that time, we had invested in a Zoom-based platform called RingCentral, which allowed our team to collaborate easier between offices. It proved to be a seamless way for us to continue operating during the beginning of the pandemic, and we were fortunate to have had it in place in advance.

We were designated as an essential business during the strictest lockdown period and kept up certain design and construction projects, which boosted staff morale and gave us a sense of purpose. Our business is much more than architecture, engineering, and construction — it’s about healthcare and helping patients — which helped to keep the whole company motivated and focused on our responsibilities, especially during a pandemic. We had to find different ways to execute and keep everyone safe on the job site, but many of those ideas were in play even before COVID, such as modular construction, building off-site in a warehouse for a more controlled environment, having fewer workers on-site, reducing risk, and elevating safety levels.

In the early stages of the pandemic, we didn’t know what the impacts would be in terms of procuring products and materials and project timelines. We were always very cautious and transparent with our clients, letting them know that we’re going to work as hard as we can to deliver their project on time.

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DA: What do you see as some of the longer-term impacts or ways that the post-pandemic world is going to be fundamentally different than what came before?

MT: I’ve never been a believer in going backward. It’s clear that the way we work and the expectations of where our employees need to physically be have permanently changed. That added flexibility can help all of us have a better work/life balance. The pandemic has also pushed us to look at design and construction differently. Even pre-pandemic, Genesis was pushing the limits of ready-made construction and bringing more assembled sections to a jobsite. Offsite fabrication is the future for improving quality, safety, and speed. In fact, our clients are the real drivers of change, as they need facilities up and running faster than ever before. Any EPCM must find a way to accommodate to remain competitive.

DA: How does one determine the best approach for a given project on the spectrum of modularity between traditional, fully stick-built construction on one end and a totally prefabricated or “podular” model on the other extreme?

MT: I think the best approach depends on the therapeutic the facility is designed for. Certain therapies can be manufactured in a small space — such as the “podular” concept of a “lab in a box.” While that might be applicable in some cases, other situations require more of a middle ground — some parts of the facility may be modular, while other parts just make more sense to build in a more traditional stick-built method. The approach will always be project specific and what is best for a particular client. Regardless of the approach, clients will always expect projects to be completed as soon as possible. Ultimately, we’re going to have to follow the science — there’s no such thing as a “one size fits all” approach to architecture and engineering, especially for pharma projects. Everything depends on the therapy type and the production requirements; you can make one drug for thousands of people in one type of facility or an autologous therapy that’s specific to one individual that is produced in a hospital setting.

DA: How has the Genesis AEC service offering evolved over the last few years?

MT: As I mentioned, we have added new offices as we’ve grown, which has helped attract more talent. We’ve invested in process architecture and process engineering to support our manufacturing clients, which has allowed us to build our portfolio and experience. In terms of technology, we’ve purchased 3D printers, which are used in traditional ways such as creating site models, but we also use them to create scale models of laboratory and process equipment. These “doll-house” pieces are instrumental during programming meetings for clients to understand the design and contribute to the solution.  We want our clients to achieve the best sense of space, which is why we’ve also introduced AR technology, which allows users to see three-dimensionally and interact with the proposed space. These advancements help the design process and aid in decision-making.

We’re constantly being challenged and pushed by our clients to finish builds faster, which trickles down to the design process happening in parallel with bidding and building a project. I think architects and engineers must become a little bit more comfortable with the shifts in our industry. Pharma (and especially biotech) is pushing us to deliver faster than ever, and we’ve got to innovate to keep up; that’s going to be a key differentiator between firms.

DA: In terms of technological innovation, is there anything on your wish list that you can conceptualize and would make things a lot easier but isn’t yet available?

MT: The way companies manage their own facilities’ data is extremely inefficient — and often inaccurate; one of the first steps for an architect and engineer when they start a new project is to physically survey the existing space, and this happens repeatedly for a client on every single project. I believe that there would be tremendous benefits to a technology that helps clients create building information models of their existing space — more than just laser scans and cloud points — that they can hand to their service providers. Millions of dollars are spent to constantly capture that data. Having inaccurate information of an existing facility is a huge roadblock, and simply can’t be left out of the Industry 4.0 movement. You can’t revolutionize what happens in a facility if the data regarding the facility remains unsophisticated.  

DA: I would imagine that, in order to prepare for trends before they even really manifest, the company needs to always be actively researching these things to develop a good understanding even before customers start asking, so you’ll know how to advise them as to what’s feasible and what’s not or give them new ideas to consider. Can you explain how you stay on top of trends?

MT: At Genesis, we are always promoting education and training. Whether it’s through vendor contacts that we turn to for new products in the industry or conferences, seminars, and workshops. We always try and remain current or a little ahead of latest trends.  Many clients can be resistant to change, but we still educate them and bring new ideas to the table.

While the next big thing is definitively elusive, at Genesis, we remain open-minded and nimble. Part of this means always being ready to jump in and support clients with whatever might be needed for their facility. I think that our approach is conducive to aiding clients with what’s next — because they don’t always know either — which is why they’re looking for qualities like flexibility, adaptability, and speed in a partner.

Originally published on PharmasAlmanac.com on September 22, 2021.

Applying an Advanced Pharma 4.0 Perspective to Design the Facility of the Future

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.

Originally published on PharmasAlmanac.com on September 8, 2022

Integrated Design and Engineering: Focused on the End Goal

Rather than a stage-gate process, CRB’s ONEsolution™ approach offers integrated design, engineering, and construction with a focus on the end goal in mind — an operating biopharmaceutical facility. This approach fosters open communication, trust, and effective teamwork. It also enables the use of lean design and construction techniques, leading to dramatically reduced project timelines.

Shift in Focus

The conventional approach to design and construction of biopharmaceutical facilities involves the use of separate and distinct design and construction teams. The design team focuses on design deliverables, while the construction team focuses on the construction of the facility. Neither team, however, is driven by the ultimate deliverable, which is the completion of an operational facility that manufactures new medicines for patients in need.

The Vision
To address this shortcoming, CRB established the ONEsolution approach to change how projects are delivered. With the ONEsolution vision, an integrated team consisting of owners, designers, engineers, subcontractors, and construction professionals are engaged with the project from the outset and focuses on the end goal of opening an operational facility. Everyone on the team is thinking about how the facility will operate and what needs to happen for it to be operational from the start of the project, thus aligning a team of hundreds of people for end-to-end delivery.

CRB’s ONEsolution program is a process that is a genuinely integrated approach that can provide support for any stage of a project, from operations improvement to predesign and preconstruction through procurement and construction. The members of our integrated teams of planners, architects, designers, engineers and constructors work with one another on a daily basis. They are cohesive units with strong collaborative foundations that know how to support clients from the conception of the idea for a facility to startup of operations.

ONEsolution integrates in-house planning, design, and construction into a structured, measurable, and efficient approach to achieve your project objectives. As single, accountable, and collaborative entities, multi-disciplinary teams partner with clients to execute architecture, engineering, procurement, construction, safety, quality, regulatory inspection, commissioning, and management of each project. From concept to completion, our integrated, multidisciplinary process allows for innovation and efficiency in achieving success.

Collaborative Teams

An integrated design and construction provides clients with a single source of responsibility, communication, and streamlined coordination. From the start of a project, planning, design, and construction professionals are aligned with the client’s vision and driven to collectively pursue and achieve the project goals. With everyone on the team embracing an environment of trust, collaboration, shared incentives and common purpose, there is much greater project buy-in than is possible when a project is controlled by a single project manager that sets the schedule and assigns responsibilities.

Frontloading of projects with larger teams from the outset also reduces the need for the handoff of information, thus minimizing risks. Those handoffs that must occur are much more reliable and meet the conditions that satisfy those involved with respect to content, quality, and on-time delivery. When teams get the information they need when they need it and at the quality they are expecting, greater trust is established, leading to further team integration.

A high-performing team with members that trust one another and are focused on the end delivery of an operational facility enables leaner operations. Through our commitment to lean design and construction principles, we can eliminate waste and identify innovative, cost-effective solutions to maximize the value of your project and reduce project timelines. Resources are maximized, schedules are optimized, and redundancies are eliminated, allowing projects to move forward with streamlined consistency.

We challenge these high-performing teams to target 0 RFIs when there is high trust and accountability and reliability of information exchange, and many such integrated projects have reduced project delivery time by more than one-third compared with industry norms.

There is also a financial benefit. Rather than budgeting to the client’s design, the integrated team gains a deep understanding of the facility requirements and then provides a design that meets the client’s budget and needs, minimizing financial risk with an early cost projection and predictable results.

The key to a successful design-build approach is integrating teams that are focused on the ultimate deliverable of an operating biopharmaceutical facility.

Key roles on these integrated teams begin at the leadership level with directors, managers, and key build strategy experts from clients, key team members, and trade partners and continue to build throughout the development of the project.

These integrated teams thus provide seamless collaboration between the client and design, construction, and C&Q professionals. By removing the traditional trade boundaries and layers of responsibility, sound judgments can be made that transform the client’s vision into reality. There are no handoffs, priorities lost in translation, or finger pointing, removing inefficiencies and the stress of decision making.

Integration Workshops

Projects that will be completed using this fast-track design and construction approach begin with an integration workshop. Depending on the size of the project, these workshops may last a few hours to a couple of weeks. They provide an opportunity for team members to meet and get to know one another. They also provide the mechanism for building the project strategy, which is codified as a project charter around which the team can rally.

Underlying all of the activity at these integration workshops is the recognition that safety comes first and quality must always be expected. These concepts are pillars that do not move. The team focuses on the elements of a project that can be adjusted — cost and schedule.

Generally, five or six key areas are identified, starting with the purpose of the project, which for biopharmaceutical facilities means getting needed medicines to patients. The team works with the client to establish the essential elements required to meet the minimum needs of the project with regard to safety, basal level of facility functionality, regulatory compliance and operability.

In essence, the charter includes all of the information that is needed to make decisions and provides an order of priority for those decisions whether schedule or cost is the primary driver. It is essential that these issues are established at the initial integration workshop so that it is possible to have solid decision-making capability throughout the entire project without concern that priorities will change.

Project Charter

Even so, the charter is a living document that evolves during the life of the project. The target schedule and cost are generally fixed elements in the form of a commitment to have an operational facility by a certain date for a certain cost. Within those elements, however, there is flexibility to adjust the scope — specifically how those targets will be achieved.

The charter, which describes the key elements of the job, must be made available to everyone on the team. It is used during the onboarding process when additional team members join the project following the initial integration meetings. Having access to this information help these new partners understand why and how decisions are being made and ensures that everyone is on the same page.

In some cases, it is not possible to align all aspects of the project as initially envisioned. Part of being a highly functional team is having the ability to identify when problems occur and address them early on so they will not impact the overall mission. The living nature of the charter helps facilitate this process.

When ONEsolution is the Right Approach

For ONEsolution to be effective, clients need to be seeking a new, innovative project experience and accept that change is needed to achieve maximum project results –– one that delivers an operational facility at their target cost and schedule. They need to have the flexibility to assemble integrated delivery teams committed to their project goals rather than the traditional procurement of a design, then construction, then commissioning and qualification.

Sometimes, this approach is not right for every project. Because it involves establishing an integrated team from the outset that executes planning, design, engineering, and construction work in parallel and is aligned with the project charter, it may not be suitable for projects with owners that have a procurement-driven organization or mindset that expect design completion before bidding out construction activities.

ONEsolution is ideal for projects that desire cost and schedule certainty, because, with this approach, the entire team is engaged early on and are all working toward the same goal.

Often, emerging biopharmaceutical companies that are trying to be first to market with a novel drug product are attracted to the ONEsolution approach, as most of their projects require schedule and cost certainty. Often, these firms typically have smaller, more intimate project teams that can make decisions more quickly than is possible in large, mature organizations with many stakeholders.

ONEsolution execution is also well suited for projects from big pharmaceutical companies that have a nimble mindset and recognize the value offered by an integrated design, engineering, and construction approach.

Positive Feedback

The trust that is created within the collaborative teams that complete these integrated projects has a significant impact on team members working on them. It creates a positive work environment within which people have fun and spend time working to improve, rather than pointing fingers. As a direct result, the overall experience for everyone involved from project team members to client partners to contractors is better overall.

Clients have reported a sense of calm on these projects despite the accelerated timelines. They are amazed that we can set a target completion date 18 months in the future and finish a project on time — or in many cases early. CRB employees always look forward to the opportunity to work on the next ONEsolution project, because it is a genuinely enjoyable experience.

Originally published on PharmasAlmanac.com on March 17, 2020