In a presentation made at AVEVA World San Francisco 2022, Pfizer’s executives explained how taking a data-centric approach to operations enabled the pharma giant to innovate at “lightspeed” and deliver the world’s first mRNA vaccine in record time, saving billions of lives.

Like Pfizer, countless pharma and biotech firms today are rapidly adopting cutting-edge digital tools and technologies to transform medicine manufacturing.

Digitalization is an important component of Pharma 4.0—the International Society for Pharmaceutical Engineering (ISPE)’s trademarked name for Industry 4.0 for pharmaceutical manufacturing—to provide faster therapeutic innovations and improved production processes.

Digitalization, cites the mission statement by ISPE providing practical guidance to accelerate Pharma 4.0 transformations, will connect everything, creating new levels of transparency and adaptivity for a “smart” plant floor. This will enable faster decision-making and provide in-line and on-time control over business, operations, quality, and regulatory compliance.

Long a technological laggard, pharma and biotech firms are now racing to embrace digitalization considering it a priority as expectations for increased speed to market are higher than ever.

“Despite lagging in adoption of 4.0 technologies, it is encouraging to see that the overall appetite to embrace it is increasing as the industry sees more evidence of success in being a data-driven organization,” says Thomas McCarthy, industry principal – life sciences at AVEVA. Headquartered in Cambridge, UK, AVEVA is a global provider of industrial software.

Reports show that various pharma and biotech manufacturers, including contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs), are at different stages of their digitalization journey.

While many manufacturers are at a pre-digital stage, some see digital silos and islands of automation, many are on their way to predictive plants with real-time analysis with connected plants and others look to adopting some aspects of autonomous, adaptive plants.

“Samsung Biologics has completed the digital connectivity phase, which has enabled the CDMO to provide their biopharma partners with an advanced level of AI-based service,” comments Hyeokgeon Kwon, director of information strategy at Samsung Biologics, a global, fully integrated, end-to-end CDMO, headquartered in Incheon, S. Korea.

As the world’s largest CDMO by production capacity, Samsung Biologics offers customized CMC solutions from gene to IND for a range of biotherapeutics including mAbs, bispecific antibodies, fusion proteins, and mRNAs. The CDMO partners with over 100 global clients, according to the company website.

Deployment of Pharma 4.0 technologies across biomanufacturing infrastructure, however, is still in its inception, given much of the data work is yet done by hand, says Jason Yu, director of manufacturing execution system at Samsung Biologics.

Yu adds that the growing complexity of modalities in the global spotlight, such as bispecific antibodies and antibody-drug conjugates, may further pressure the biopharmaceutical industry to expedite the transition from hands-based to data-based information gathering and analysis. Having completed the digital transition has become imperative for drug makers to enhance the data integrity of their development and manufacturing process, a fundamental prerequisite for on-time delivery of drugs to those in need without compromising quality.

From factory floor to the cloud

The industry is also witnessing an accelerated transition to the cloud for software solutions and data storage.

In Pharma 4.0, all digitalization software will use the cloud. Industry surveys show that 87% of manufacturers are already using the cloud.

Digital experts say that the ability to push data from the manufacturing floor to the cloud creates a backbone for digitalization. A cloud-first policy has already been adopted by several large or newer life sciences organizations. All programs will reside in the cloud, and people will use devices on the edge to interact with a cloud-hosted data hub from which they can run analytics. Traceability in the cloud is far more advanced than on-prem.

“In fact, all production data can be shared [via the cloud] to take advantage of analytical services including AI, and we expect this data ecosystem to mature through partnerships with original equipment manufacturers (OEMs), development organizations, etc.,” says McCarthy of AVEVA, which offers industrial cloud platform Connect.

According to him, since license holders are legally accountable for quality and they cannot delegate quality to the CMO, the relevant quality information can be shared upon lot completion via the cloud.

Shared computing resources via the cloud certainly make it easier, but some of the data infrastructure still requires investments at the edge or on-premises. What constrains the rate of adoption, observes McCarthy, is often about designing new ways of working and economic viability, rather than technology viability.

McCarthy cites Biosana Pharma, which specializes in the production of mAb biologics, as a case study on how successfully a biotech SME leverages the cloud to consolidate and analyze process and analytical data in real-time from multiple global sites to enhance the development of an end-to-end continuous biotech manufacturing process for biosimilars.

By combining multicycle counter-current operation in culturing, centrifugation, and chromatography, Biosana’s technology platform can cut the costs of mAb production by 90%. The process is end-to-end continuous and operates under cGMP, says the company.

Real-time insights, automated processes

“Embracing Pharma 4.0 technologies propels productivity to new heights, delivering marked improvements in both operational efficiency and financial performance,” says Kristian Byrialsen, director, regulatory affairs, Fujifilm Diosynth Biotechnologies, a CDMO for biologics, vaccines, advanced therapies and oncolytic viruses.

This shift ushers in a dynamic environment where key data are instantly available anywhere, anytime, and at any device, fostering swift and informed responses directly to the customers.

Leveraging advanced data analytics enables Fujifilm Diosynth Biotechnologies to meticulously monitor biomanufacturing processes in real-time, promptly addressing any irregularities.

In addition, advanced data analytics and AI can process vast amounts of data from manufacturing processes to identify patterns, and trends and optimize conditions, leading to higher yields as well as faster and more reliable production times for biologics and other therapeutics. AI-powered, machine learning (ML) algorithms can enhance quality control by continuously analyzing data from manufacturing processes to ensure that the products meet the required standards, which is crucial for patient safety and regulatory compliance.

Developing predictive models will be Fujifilm Diosynth Bio’s next endeavor going forward in the digital journey, adds Byrialsen. “This proactive approach is geared toward uncovering issues before they manifest, thereby preempting potential problems and ensuring a smoother manufacturing process.”

To prevent errors Samsung Biologics has been operating an electronic master batch record system, explains Jason Yu. “The system enables mutual checks and balances with Samsung Bio’s biopharma partners to prevent any could-occur errors and thus enhance data integrity.” 

Leveraging digital technologies, such as automated monitoring processes, predictive analytics, and fault detection, companies can manage processes, avoid deviations, and ideally prevent problems before they occur, endorses Kai Vogt, senior vice president corporate development, legal, corporate compliance, IT, Vetter Pharma-Fertigung GmbH & Co. KG.

Vetter, a CDMO that specializes in the aseptic filling of syringes, cartridges, and vials, offers comprehensive fill and finish services from clinical development to global market launch. With over 6,300 employees Vetter’s sales crossed one billion euros in 2023 registering a 12% rise compared to that of a year ago.

“Robotic process automation (RPA) optimizes repetitive, manual tasks and reduces errors,” notes Vogt.

Vetter has installed collaborative two-arm robots in their secondary packaging unit to improve coherence within processes. Robots like “YuMi” are trained by employees and then autonomously perform the tasks they learn, demonstrating the potential of human-robot collaboration. The focus isn’t just on increasing outputs, he explains, but on improving quality by standardizing processes and freeing workers from routine tasks.

Additionally, ML will be implemented in areas such as predictive maintenance, data analytics, and intelligent factory systems, shaping the cleanrooms of the future. AI and ML can also help increase control over the manufacturing processes, Vogt states.

Complex drugs, unique challenges

Integration of digitalization, however, is not always a smooth process. It can be more challenging when it comes to personalized therapeutic products like CGTs.

CGTs and biologics are currently, the fastest-growing revenue generators. This explosive growth has increased demand for technologically advanced manufacturing support from CDMOs.

Biologics and personalized medicines can be unpredictable and complicated to manufacture. Personalized medicines, in many cases, are designed and developed for small patient populations. To handle these therapies, manufacturing plants of the future must accommodate a variety of product formulation processes, streamline inventory, and shorten timelines.

For CDMOs, these difficulties will be paired with the ongoing evolution of drug developers’ service needs, as drug portfolios continue their shift from single blockbuster products to a co-existence of blockbuster and smaller-batch-size products, indicate studies.

“The integration of digitalization processes for highly personalized and precision therapies, such as CGTs, presents a unique set of challenges, primarily due to the complexity and individualized nature of these treatments,” observes Byrialsen. Fujifilm Diosynth Bio offers CGT services as well.

He notes that CGTs involve intricate and highly specialized production processes that can be difficult to standardize. Digitization must accommodate these complexities and allow for flexibility in manufacturing. Thus, decisions must be made if the digitalization efforts will positively impact the value for the customer. Digitalization needs to support the customization inherent in personalized therapies while also allowing for scalability. This can be particularly challenging when transitioning from clinical trials to commercial-scale production.

Another key challenge, adds Byrialsen, is maintaining a detailed and secure chain of custody for each patient’s therapy. Digitalization solutions must ensure that all materials and products can be traced throughout the entire process to guarantee integrity and patient safety. The integration of digitalization must prioritize the protection of sensitive patient information in accordance with health data privacy regulations like the Health Insurance Portability and Accountability Act (HIPAA) or General Data Protection Regulation (GDPR). 
 
In addition, the cost of implementing state-of-the-art digital solutions can be significant, and it must be balanced against the need to keep therapies affordable for patients and healthcare systems.

According to him, a robust IT infrastructure is essential along with advanced analytics, and secure data management systems, to successfully integrate digitalization into the manufacturing of CGTs.

Digitalization vs flexibility?

Digitalization, as it covers a vast expanse of technologies, can be all-encompassing in the pharmaceutical industry. As it stands, many CDMO industry leaders hold the view that innovation that a CDMO pursues “should always be one that will add value.”

These leaders say it is pointless implementing technology for the sake of technology, and favor implementing innovation that drives business value.

“Forward-thinking CDMOs,” comments Kai Vogt of Vetter, “prioritize quality and efficiency initiatives, for example, replacing manual data entry books with tablets at visual inspection workstations streamlines processes and improves efficiency. While these initiatives are underway, CDMOs can identify projects that may require more effort. Completely redesigning a previously paper-based, manual data transfer system, for example, is far more complex.”

By strategically balancing quick wins with long-term transformational projects, CDMOs can continually improve their operational effectiveness and competitiveness in the industry, explains Vogt. At the same time, a responsible manufacturer cannot afford to experiment by applying trial-and-error principles.

“Digitalization serves but one purpose for us—to further increase the quality and safety of our processes. That is why we only use digitalization when and where it actually adds value,” he asserts.

Technologies such as the Internet of Things (IoT), virtual reality (VR), and autonomous, collaborative robots are among the tools driving digital transformation within the pharmaceutical contract manufacturing industry.

While the implementation of these technologies promises more efficiency and speed, Vogt maintains, it also brings targeted and traceable quality improvements that only increase over time.

At the same time, some CDMOs, while underscoring the significant potential of technologies such as in ML, AI, blockchain, and big data, look to emphasize the point that adopting them purely for the sake of innovation can turn out to be a costly mistake.

Smart CDMOs must also need to stay flexible. For, these service providers must fulfill individual customer needs while maintaining process standardization which is a necessity for digitalization in the pharmaceutical industry.

Since digitalization is no guarantee of flexibility, this quality must be a key consideration in the design of the systems CDMOs create to manage their processes, they argue.

Resilient supply chains

Digital transformation is being accelerated by the need for more supply chain agility, and the increase in remote work.

Post-COVID-19 pandemic, pharma companies seem to be more reliant on multiple-sourcing strategies to fulfill their commitment to on-time delivery. Adopting such strategies requires an optimized supply chain management system, where Pharma 4.0 technologies may help establish and execute such a system, remarks Dongweon Yi, director of process innovation at Samsung Biologics.

“At Samsung Biologics, we operate a robust supply chain management system that enables us to help our global pharma partners untangle multi-layered supply chain issues and ultimately help them deliver their drugs to wherever needed without delay,” Yi says.

Fujifilm Diosynth Bio’s approach to expanding manufacturing capacity—replicating facility design, the pharmaceutical quality system (PQS) and processes with up to 98% equivalence— has the potential of accelerating process performance qualifications, says Byrialsen. “This strategy enhances same product manufacturing several places within the CDMO’s network, mitigating supply chain risks for its partners.”

This has the prospect of generating, analyzing, and reporting large amounts of data to provide the regulators certainty of identical products being manufactured across several lines or even plants.

Looking at CMOs versus internal manufacturing, data is as important as the final product. When a contracted supplier ships the product, it is imperative also to share the data associated with the product—the data that can be used to fine-tune the manufacturing process after receiving the material, along with a certificate of quality.

Automation and robotics are driving significant advances in supply chain productivity. With prolonged pandemic and geopolitical uncertainty, technologies like these are expected to see increasing investment.

Barriers to tech adoption

CDMOs have been slow in adopting Pharma 4.0 technologies owing to various reasons like misinterpretation of regulations, lack of process understanding, and unwillingness to overcome cultural inertia.

The primary challenge is the need for significant investment in advanced technologies. Cost can be a restraining factor for smaller pharma companies or those with limited resources.

Contract manufacturers appear to be lagging in the adoption of 4.0 technology maturity, says McCarthy of AVEVA. The explanation may be due to a combination of risk aversion and cost pressure. “It isn’t uncommon to have the license holder subsidize the investment to implement the requisite technology on their line—assuming the capacity is dedicated to the license holder,” he remarks.

Given the risk-averse mindset of the industry, it is not enough to just show the value of the technology. “These are complex processes with historically long implementation times,” reminds McCarthy. Hence, finding ways to “de-risk” the adoption journey is equally important.

Another significant challenge is ensuring compliance of advanced systems and software involved in the Pharma 4.0 technologies with regulatory requirements. Experts, however, aver that technology is the factor regulators require companies to continue to pursue as they move to the next phase of growth.

The regulatory agencies are increasingly supportive, and there is a collaborative spirit to working together to remove the hurdles and design new ways of working, observes McCarthy.

CDMOs must, however, overcome greater complexity than their pharmaceutical industry counterparts that rapid technology adoption can have a direct impact on the workforce. Hence organizations must focus on building a culture to make the personnel comfortable with digital innovation.

The transition from paper-based systems towards automated connected plants is a paradigm shift requiring changes in culture and processes.

Offering a perspective in this context, Vogt of Vetter avers that the implementation of new technologies opens up additional bandwidth for human employees to engage in strategic works. “While people will never be replaceable, substituting some processes with emerging technologies can free up resources and allow for people to be readily available for human-driven tasks.”

Integration of legacy systems, data privacy and security, protection of IP and attracting and retaining top talent are among other challenges that come with Pharma 4.0. 

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Soman Harachand is a pharmaceutical journalist based in Mumbai and a regular contributor to Contract Pharma. He can be reached at harachand@gmail.com.