Industry 4.0, a trend toward more comprehensive applications of data, analytics, and automation, is making its influence felt in bioprocessing—hence the rise of Bioprocessing 4.0, or Biopharma 4.0. To see how the 4.0 paradigm is being realized in bioprocessing, GEN spoke to three experts: Jian Dong, senior vice president of global biomanufacturing, WuXi Biologics; Anil Kane, head of scientific and technical affairs, Thermo Fisher Scientific; and Daniel C. Smith, PhD, CSO, Cobra Biologics and industrial professor at the School of Life Sciences at the University of Warwick.
GEN: What kinds of bioprocessing problems are cited by your clients?
Dong: Clients who come to WuXi Biologics have challenges that include aggressive timelines, regulatory uncertainties, and shifts in capacity utilization over product life cycles. Dealing with these shifts requires flexibility in assigning production slots and scaling manufacturing. Other problems may include low productivity, unsatisfactory process performance, or high production costs.
Some clients may have difficulty in finding the right contract development and manufacturing organization (CDMO) to manufacture their products due to the uniqueness of process or product volume. There are also clients (such as virtual startups) who come to us to leverage our expertise in the manufacture of a product from development to commercial manufacturing through our Follow-the-Molecule
Kane: As a leading service provider to the pharmaceutical industry in the space of small- and large-molecule active pharmaceutical ingredients (APIs), drug products, and cell and gene therapeutics, Thermo Fisher Scientific partners with virtual, new, small, and emerging biotech companies; mid-size specialty pharma companies; and large pharma companies.
Our partners present us with unique problems from various stages of drug development and manufacturing. We work closely with our partners to design strategies that encompass diverse tasks (such as route scouting for small-molecule APIs, cell line development, and biologics purification) and span multiple commercialization stages (defining product concept, developing processes, and designing a final market image or concept). We help our partners resolve their problems and bring their products, including cell and gene therapies, to market.
Examples of manufacturing problems could be lower yields, lower biologic titers, stability issues, and quality deviations—problems that reflect an inadequate understanding of the variables of raw materials, process variables and control strategies leading to a non-robust process and product.
Smith: Usually requests concern our service provision for plasmid DNA, microbiota, and/or viral vector production to GMP grade. For plasmid DNA, the main request concerns the potential to increase process productivity, linked to reduction in cost of goods. For microbiota products, it can range from help in transferring a process and scaling up, to full process and analytical development for a novel organism or range of organisms.
Currently, the main request from potential customers concerns viral vector production. The challenge here is to access a scalable, cost-effective platform for their specific vector. This can be challenging due to the maturity of the process. As an industry, we are still challenged when faced with processes that have been run in an academic lab environment and need to be rapidly converted into scalable GMP processes, including those for first-in-human studies.
Another challenge is to rapidly assess the scale of manufacturing required. Variations in nonstandard analytical techniques hinder the prediction of viral vector titers that could be obtained using different systems and performed at different sites.
GEN: Which Biopharma 4.0 methods do you use in your work with clients?
Dong: WuXi Biologics is actively adopting Biopharma 4.0 methods in our service to clients and in the development of our new facilities. For example, we use smart equipment in manufacturing. Our robotic aseptic filling facility became GMP ready in July 2019.
We are developing smart maintenance or predicative maintenance capability to enable us to prevent equipment failure between preventative maintenances. We developed a program which uses artificial intelligence (AI) to monitor the performance of chromatography column in real time. We developed WuXiUP, a continuous manufacturing platform for almost all biologics. It achieved 30–50-g/L titer and enables 1000-L disposable bioreactors to achieve similar productivity as traditional 10,000–20,000-L stainless-steel bioreactors.
Kane: Pharma 4.0 envisions highly efficient automated processes—which could be continuous, batch, or a hybrid of these—driven by an integrated manufacturing control strategy.1 The idea is a transformation from today’s current submission-based control strategy, in which a strategy for commercial manufacturing is transferred or scaled up from the development phase, to a holistic strategy that includes equipment, facility, GMP, and business controls, which includes adaptation throughout the product life cycle as learning is captured.
The primary goal is making pharmaceutical production safer and more efficient along the whole value chain. We do use a number of “elements and enablers,”2 and we certainly utilize the ICH Q10–defined enablers—knowledge management; quality risk management; and monitoring of critical quality attributes (CQAs), critical process parameters (CPPs), and critical material attributes (CMAs)—as key elements of product and design. We are looking into the digitalization of processes and systems.
Thermo Fisher has invested in the development and manufacturing of small-molecule APIs (using continuous flow chemistry) as well as the manufacturing of solid oral drug products (using a continuously maturing technology that is in line with and a component of Pharma 4.0). However, the enabling technologies are accompanied by implementation barriers. These include difficulties in meeting speed expectations (for establishing proof of clinical efficacy) and generating the data and securing the resources required for process modeling and analytics.
Smith: Currently, very few. This is due in part to the rapidly evolving situation for advanced therapy medicinal product development and manufacturing, and to the need to move quickly through the clinical development pathway to commercialization. The approach is also hindered by the lack of a standard platform for viral vector production, as well as the need to satisfy requests for small batches of critical starting plasmids.
An important constraint is the cost and time it takes to implement these methods into the CDMO business model (which is a marginal business and relies on customer funding). Customers do not want to pay for this type of set up, but rather expect CDMOs to have it in place. Time and cost concerns can prevent CDMOs from implementing the approach.
GEN: How could working relationships be optimized?
Dong: Compliance, transparency, and ownership are very important in building a strong relationship with clients. At WuXi Biologics, we value IP protection as our shared lifeline with clients. Data integrity and transparency in the communication of process tech transfer, and in the execution of production batches, helps to build trust, facilitating decision making and helping ensure production success.
We encourage our team members to learn more about clients’ projects and which diseases the projects are meant to address. Our team members need to understand the importance of their work to patients. We also want to foster an ownership culture and a collaborative spirit among our team members.
Kane: At Thermo Fisher Scientific, we believe in transparent, open communication with our clients and partners in discussing their programs, laying out design strategies, understanding stage/phase-specific risks, clarifying go/no decisions, and investing in subsequent phases of drug development and manufacturing. We encourage our partners to have Stage Gate Reviews of their programs and have a thorough alignment with the cross-functional subject matter experts. These practices help establish agreed-upon program deliverables, ensuring the robustness of products. They also facilitate the design of processes that satisfy technical, safety, quality, and regulatory requirements.
We also encourage “Governance and Executive Leadership Steering Committee” review meetings to monitor program progress and address issues and provide a senior-level support/direction to keep the programs on track, that is, on time and on budget.
Smith: The main “best practice” is good communication between parties and upfront agreement to the principles by which the project will be run. All too often, the initial discussions are hampered by mismatched timeline, service, and cost expectations. At Cobra, we strive to maintain a focused but flexible approach for customers. We have a strong and experienced project management team in place that acts as the voice of the customer internally and serves as the single point of contact for that customer.
1. Markarian J. Pharma 4.0. Pharmaceutical Technology 2018; 42(4): 24.
2. Binggeli L, Heesakkers H, Woelbeling C, Zimmer T. Pharma 4.0: Hype or Reality? Pharmaceutical Engineering. Published July/August 2018. Accessed March 11, 2020.