Pharma 4.0 is the term coined by the International Society for Pharmaceutical Engineering (ISPE) that describes the Industry 4.0 shift towards advanced technology. It includes artificial intelligence (AI) and machine learning (ML), cloud computing, and the Internet of Things (IoT). At the peak of Pharma 4.0, ISPE envisions organizations using the full power of digital technology to provide safe, fast, and effective solutions for the problems we are facing today. Three years ago, CHEManager International published an interview with members of ISPE’s Pharma 4.0 Special Interest Group (SIG) on the idea behind ISPE’s Pharma 4.0 initiative and the challenges on the way to realize the digital transformation of the pharmaceutical industry. In December last year, ISPE published its Pharma 4.0 Baseline Guide which addresses the evolving Pharma 4.0 landscape and the integration of new technologies. In this follow-up interview, industry experts Michelangelo Canzoneri, Josef Trapl, Wolfgang Winter, Christian Woelbeling, and Thomas Zimmer—all members of ISPE’s Pharma 4.0 guide core team—explain the transformational challenges and critical success factors of the digital Pharma 4.0 journey.

CHEManager: Can you briefly summarize what Pharma 4.0 is all about?

Thomas Zimmer: Digitalization opens up the possibility of processing extremely large volumes of data in the shortest possible time. This presents users with major challenges in terms of preparedness for digitalized applications. That is why Pharma 4.0 is NOT an IT project, but an ‘industrial approach’ that encompasses all areas of a company or user. The magic word is ‘holistic view’ of all elements and enablers, as shown in the so-called ‘Operating Model Pharma 4.0’. This concerns resources, organization and processes, information technology and—very importantly—corporate culture. Enablers are digital maturity and data integrity by design.

Originating historically from Industry 4.0 approaches, Pharma 4.0 aims to transfer the principles of Industry 4.0 to the pharmaceutical industry, in particular to the codes and terms typical of the industry and the strict regulation of processes, products and technical standards that are unique to this industry.

Pharma 4.0 therefore describes the prerequisites for a successful digital transformation, regardless of size and area of application.

Christian Wölbeling: Pharma 4.0 addresses holistically all stakeholders in the pharma industry and this includes also the regulatory bodies like EMA and FDA based on the international guidelines of International Council of Harmonization (ICH). The Pharmaceutical Quality System Guideline ICH Q10 is building the basis for the link to the Industry 4.0 basic elements.

 

   Josef Trapl, Memo3

“A science- and knowledge-driven holistic control strategy drives true quality at all levels.”

 

So, what key needs guide companies on the way to Pharma 4.0?

Wolfgang Winter: Many organizations are realizing that they struggle to unlock the potential of their data assets and that their approaches for solving problems across the business are not scaling – they find that the different silos are disjointed. This creates unexpected failures and bottlenecks in drug and process development, scale-up, manufacturing and the supply chain. Companies are desperate to drastically increase their operational excellence. The holistic control strategy approach of Pharma 4.0 addresses this.

Michelangelo Canzoneri: The journey towards Pharma 4.0 is driven by several business needs and pain points that pharmaceutical companies face in today's rapidly evolving landscape. These drivers push companies to adopt digital technologies and transform their operations to remain competitive, efficient, and compliant. Below are some of the key business needs and pain points that propel pharmaceutical companies toward embracing Pharma 4.0:

Business needs are the following:

• Operational efficiency and cost reduction, including automation and digitalization as well as waste reduction
• Faster time-to-market through agility in R&D and manufacturing and accelerated clinical trials
• Quality and compliance, which comprises regulatory requirements as well as data integrity and traceability
• Patient-centricity and personalized medicine, that is, customization of treatments anhanced patient outcomes
• Sustainability and environmental responsibility, including/through green manufacturing and regulatory pressure

The pain points are:

• Legacy systems and infrastructure, which includes outdated technology and high cost of upgrading
• Regulatory complexity through stringent and evolving regulations as well as validation of digital processes
• Data management challenges like data silos and data security
• Workforce skills gap, that is, lack of digital expertise and cultural resistance
• Supply chain complexity, including globalization and complexity of supply chains as well as risk management

By addressing these business needs and pain points, pharmaceutical companies can position themselves to succeed in the Pharma 4.0 era, improving their operational efficiency, compliance, and ability to innovate in a highly competitive and regulated market.

 

    Thomas Zimmer, ISPE

“Pharma 4.0 is NOT an IT project, but an ‘industrial approach’ that encompasses all areas of a company or user.”
 

What are the benefits that Pharma 4.0 can offer the pharmaceutical industry?

Josef Trapl: Pharma 4.0 is revolutionizing the pharmaceutical industry by integrating advanced technologies such as the Internet of Things (IoT), Module Type Package (MTP), Asset Administration Shell (AAS)/digital twins, artificial intelligence (AI), and blockchain into drug development, technology transfer, manufacturing and supply chains.

First, it enhances efficiency and productivity by enabling real-time monitoring and automation of processes, reducing human error, and optimizing resource utilization. MTP technology allows for modular and flexible production, enabling rapid adaptation to changing demands and reducing downtime. The use of digital twins, virtual replicas of physical systems, allows for predictive maintenance, process optimization, and simulation of production scenarios, leading to more informed decision-making. AAS further standardizes and integrates digital data, ensuring seamless communication and interoperability across systems.

A science- and knowledge-driven holistic control strategy drives true quality at all levels, leading to improvements in diagnostic and therapy efficacy, process efficiency, and drug availability. As companies progress from a pre-digital state to predictive plants – where complex interactions are anticipated based on real-time analytics – they are moving toward the adaptive plants of the future. These adaptive plants operate in a self-optimizing, autonomous manner, embodying the essence of Pharma 4.0. Additionally, Pharma 4.0 significantly improves product quality and safety, with advanced data analytics allowing for more precise control over manufacturing conditions and better prediction of potential issues. The data-driven approach ensures that decisions are backed by robust evidence, leading to more consistent outcomes and streamlined operations. The integration of track-and-trace systems boosts supply chain transparency and security, effectively combating counterfeiting and ensuring that only genuine products reach the market.

Furthermore, Pharma 4.0 fosters a patient-centric and data driven model, tailoring treatments and therapies to individual needs through personalized medicine, ultimately improving patient outcomes. Finally, it facilitates regulatory compliance by ensuring that all processes are fully documented and traceable, simplifying audits and accelerating the approval process for new drugs. In summary, Pharma 4.0 represents a comprehensive transformation that drives innovation, reduces costs, and enhances patient safety across the pharmaceutical industry.

 

   Wolfgang Winter, Agilent Technologies

“The encouraging news for Pharma 4.0: there are already approved continuous manufacturing sites in many regions of the globe!”

 

M. Canzoneri: A roadmap for the digital transformation of a pharmaceutical company on the journey to Pharma 4.0 typically involves several key stages, each building on the previous one.
This roadmap outlines a strategic approach that balances the adoption of new technologies with the development of a supportive organizational culture and alignment with regulatory requirements.

• Assessment and vision setting (phase 1): business objectives alignment, current state assessment, and define future state vision
• Strategy development (phase 2): digital transformation strategy, technology selection and investment planning, and regulatory and compliance planning
• Pilot programs and early wins (phase 3): select pilot projects, deploy pilot solutions, and measure and communicate success
• Scaling and integration (phase 4): expand successful pilots, end-to-end integration, and workforce transformation
• Continuous improvement and innovation (phase 5): performance monitoring and optimization, sustainability and patient-centric innovations, and stay aligned with regulatory changes
• Future-ready adaptability (phase 6): agility in response to market changes and innovation ecosystem
• Governance and risk management (phase 7): governance framework and risk management

This roadmap provides a structured approach that balances technology adoption with organizational change, ensuring that digital transformation efforts align with business objectives, regulatory requirements, and long-term sustainability goals.

Implementing digital technologies and initiating successful digitalization projects is a challenging process – especially in the pharmaceutical sector. What do you see as the biggest challenge(s)?

W. Winter: Since the first CHEManager interview on this topic, we witnessed an impressive number of Pharma 4.0 digital transformation projects across the industry. These initiatives began with informal grass-roots activities such as presentations, workshops, hackathons, plug-fests, proof-of-concept projects. Research institutes and universities have been instrumental in pushing the scientific and technical boundaries, exploring areas like process analytical control, mechanistic modeling, robotics, machine learning and more. In the meantime, the regulatory agencies explicitly encourage the industry to rethink traditional approaches to discovery, development pilot scale, and manufacturing. This led to pilot or lighthouse implementations at new manufacturing sites. Some of these projects have even been recognized in prestigious awards like ISPE’s FOYA — Facility of the Year — awards.

However, implementing digital technologies and initiating successful digitalization projects in the pharmaceutical sector remains a challenging process. Despite the progress, getting buy-in at the C-level and overcoming compliance-related concerns are still the biggest roadblocks. Businesses driven by shareholder value often prioritize short-term wins over long-term investments, making it difficult to sustain momentum in digital transformation initiatives. Digital transformation is not a sprint; it is an ultra-marathon, requiring patience, persistence, and a long-term vision.

J. Trapl: Navigating the stringent regulatory environment is another major challenge. Pharmaceuticals are highly regulated, and ensuring that new digital tools comply with rigorous standards set by agencies like the FDA or EMA, while still fostering innovation, is a delicate balance. Additionally, data integration and interoperability pose significant difficulties. The industry relies on vast amounts of data from diverse sources, and integrating this data into cohesive digital systems that allow for real-time analysis and decision-making is complex, particularly when dealing with legacy systems.

Change management and cultural resistance within organizations add another layer of difficulty. The pharmaceutical industry has traditionally been conservative, with a strong emphasis on proven processes and risk aversion. Introducing digital technologies requires a shift in mindset, and achieving this cultural shift can be challenging, especially when there is a lack of digital literacy or fear of job displacement due to automation.

Cybersecurity concerns also loom large as digitalization progresses. Protecting sensitive data, including intellectual property and patient information, from cyber threats is crucial, and implementing robust cybersecurity measures while ensuring seamless digital transformation adds to the complexity.

What could a roadmap for the digital transformation of a company look like?

T. Zimmer: There are several ways to approach digital transformation: pilot projects, so-called ‘light house projects’ or more systematic approaches that cover one or more functional areas or even a cross-functional business process, like product transfer, production/quality or upstream and downstream supply chain. The preparations are important: a clear business objective, a clear idea of the benefits to be achieved, a clear idea of the operational capabilities for data, processes, capable project staff, sustained support from the client and budget owner combined with regular checks on progress including bug-tracking and all performance indicators. There are numerous ISPE guidances, the individual elements of good engineering practice, good project management, advanced pharmaceutical quality, to name but a few, which can be used as support here.

W. Winter: Let me add that a pre-requisite to successful digital transformation is a certain professionalism and maturity in terms of skills, processes and quality system in a company. I do not remember the exact source of the quote, but if you digitalize a bad process, you just have a digitalized bad process that does not advance your digital maturity and operational excellence at all.

 

   Michelangelo Canzoneri, Merck

“Pharma 4.0 offers pharmaceutical companies a wealth of opportunities to innovate and extend the business potential of established products.”

 

How will the new Baseline Guide Pharma 4.0 developed by ISPE support pharmaceutical companies in their digital transformation?

C. Woelbeling: The new Baseline Guide is building a comprehensive repository for approaching the digital business transformational journey for an organization and all of its involved stakeholders. It will be the basis also for new training programs to prepare organizations for the transformation.

W. Winter: This new guide is a helpful compendium for decision makers, stakeholders and professionals on how to approach digital transformation in pharma, understand the ‘why’ and how to approach technology & automation requirements in light of evolving regulatory compliance. The Baseline Guide contains a large reference list of current industry use cases and implementations that already went live. The baseline guide is intended to connect the silos by building common understanding between development, manufacturing, engineering & IT, regulators, suppliers and patients.

Is the development of Pharma 4.0 also reflected in regulatory authorities such as the FDA or the EMA?

W. Winter: Absolutely! We would not have started Pharma 4.0 as an initiative without a clear change of the regulators’ mindsets from a culture of compliance – that is doing things to check the boxes — versus holistic control based on science, data and knowledge — that is doing things because they make sense, are effective and efficient. For instance, FDA has been encouraging the idea of advanced medical product manufacturing technologies to improve drug quality, availability of medicines, and faster time-to-market. We are also seeing new regulatory frameworks for advance manufacturing evaluation by the regulators, for instance in the area of AI applications in pharmaceutical manufacturing. On the international level, ICH Q13 published in 2023, is a significant step towards continuous manufacturing of drug substance and drug product. The encouraging news for Pharma 4.0 is that there are already approved continuous manufacturing sites in many regions of the globe!

T. Zimmer: As the digital transformation, framed by Pharma 4.0, will definitely be used in GXP relevant processes and therefore will impact product quality, safety and efficacy — Pharma 4.0 will be directly or indirectly subject to regulation. This depends also on the fact how new technologies will be used for process design and also for decision making processes, for example, product quality or quality risk management.

As new technologies can be used, for example, IoT, AI/ML, predictive analytics, wearable devices, digital twins, virtual reality, various simulation tools and much more.

FDA and EMA are preparing guidelines, whitepapers, position papers in order to prepare themselves for a dialogue with technology providers, manufacturers, industry associations and other stakeholders where experts work on technology and innovation.

It is important to emphasize that the underlying principles of the current regulation for GXP, for documentation, for CSV&C will remain unchanged. It also can be stated that the ultimate responsibility for pharmaceutical operations and products will stay with the owner of the manufacturing and marketing authorization. A computer will never make a quality or compliance relevant decision. Using, for example, AI/ML will create the need to explain transparently and understandable within a GMP inspection, how the way from data to decision is made.

 

   Christian Woelbeling, Körber Pharma Software

“Pharma 4.0 addresses holistically all stakeholders in the pharma industry and this includes also the regulatory bodies like EMA and FDA.”

 

New cell and gene therapies continue to drive up development costs. Does this influence the willingness of companies to invest in digitalization?

W. Winter: From my perspective, clearly yes! The new modalities and their new production facilities that obtain regulatory approval and which we get introduced to in ISPE clearly show that. These new sites are highly modular, connected, well integrated from the sensor to the enterprise in a Pharma 4.0 way.

J. Trapl: The rising development costs associated with new cell and gene therapies certainly add pressure to pharmaceutical companies, but they do not necessarily diminish the willingness to invest in digitalization. In fact, the opposite may be true. As development costs soar, companies are increasingly recognizing that digitalization is not just an option but a necessity to remain competitive and sustainable. Advanced digital technologies, such as automation, artificial intelligence, and data analytics, can significantly streamline research and development processes, optimize manufacturing, and reduce time-to-market. This, in turn, can help offset the high costs associated with these cutting-edge therapies.

Patient-centric requirements are increasingly driving the need for personalized medicine, where treatments are tailored to individual patient profiles. This shift demands robust digital infrastructure and advanced technologies. For example, data analytics and AI are essential for processing large volumes of patient data, including genetic, molecular, and clinical information. These technologies enable the identification of biomarkers and the development of targeted therapies that are more effective and have fewer side effects.

Moreover, digital twins – virtual models of patients – can simulate treatment outcomes, allowing for more precise and personalized treatment plans. Blockchain technology is also being explored to ensure the security and integrity of sensitive patient data, which is critical in personalized medicine. Additionally, wearables and remote monitoring devices provide real-time health data, allowing for continuous monitoring and adjustments to treatment plans based on a patient’s evolving condition.

The integration of these technologies supports a patient-centric approach by ensuring that treatments are tailored to the unique needs of each individual, improving outcomes, and enhancing patient satisfaction. Digital tools also enable more efficient communication between patients and healthcare providers, ensuring that patients are actively involved in their treatment decisions.

Ultimately, while the high costs of developing new therapies are a challenge, they also serve as a catalyst for greater investment in digitalization. Pharma companies understand that embracing digital technologies is key to optimizing their operations, reducing costs, and delivering innovative, personalized therapies more efficiently.

Can Pharma 4.0 offer new business opportunities for established products?

W. Winter: Based on the Pharma 4.0 use cases evaluated for the first edition of the baseline guide, we see that existing brown-field plants selectively implementing Pharma 4.0 upgrades increase their asset utilization, decrease maintenance cost, optimize inventory and often reduce quality deviations, all leading to incremental productivity overall. These focused projects typically show the general feasibility of the approach, and create appetite for drastically higher outcomes and benefits.

M. Canzoneri: Yes, Pharma 4.0 can offer significant new business opportunities for established products by leveraging digital technologies and advanced data analytics to enhance product value, improve efficiency, and create new revenue streams.
Below some examples on how Pharma 4.0 can unlock new opportunities for established pharmaceutical products:

• Product lifecycle extension: improving manufacturing efficiency and enhanced quality and compliance
• Personalized and targeted therapies: Patient-specific variants and targeted drug delivery systems
• Data-driven innovation and real-world evidence: post-market surveillance and real-world data as well as predictive maintenance and supply chain optimization
• Patient engagement and digital health solutions: connected devices and adherence solutions as well as patient support programs
• Expanded market access and new revenue models: geographic expansion and pay-for-performance models
• Sustainability and corporate responsibility: eco-friendly manufacturing and circular economy initiatives
• Innovation in distribution and supply chain: cold chain and advanced logistics as well as blockchain for traceability
• Regulatory and market differentiation: regulatory innovation and competitive advantage
• Digital twins and simulation for product improvement: product optimization and innovative Formulation Development
• Collaboration with healthcare providers

Pharma 4.0 offers pharmaceutical companies a wealth of opportunities to innovate and extend the business potential of established products. By leveraging digital technologies, companies can improve manufacturing efficiency, enhance product quality, personalize treatments, and create new value-added services. These innovations can not only reinvigorate existing product lines but also open up new revenue streams, improve patient outcomes, and strengthen the company’s position in a competitive and evolving market.

Will Pharma 4.0 become a new industrial revolution?

W. Winter: When you are amidst big changes, you don’t realize a revolution is happening around you. I would ask this question in a different way… Industry 4.0 is an industrial revolution that changed so many things already: Ubiquitous broadband, computing power, data and knowledge changed customer experience, the way we purchase and consume, how we navigate, our preferences, how we interact with our families, colleagues, customers or competitors. To me, the question is: Which corners of the healthcare industry think they can avoid the digital transformation (revolution), why and how long?

C. Woelbeling: The revolution started already with the launch of the “FDA PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance” guideline in 2004. This paradigm shift for process understanding, quality by design and process control is now enabled by the 4.0 technologies. In the early years the analytical and mechanistical process & control models were too expensive to implement and only some business cases showed up. Change management is still the key issue — both in terms of the human element and from the perspective of traditional validation concepts. The ISPE CoP Pharma 4.0 is exactly tackling these obstacles to overcome them.

How long do you think it will take for digitalization to reach the entire pharmaceutical production process? Which hurdles and where in the pharmaceutical value chain still need to be overcome on that journey?

W. Winter: I clearly see that, for the time being, we will live in a hybrid world. Different models will operate concurrently. Manufacturing sites designed, planned, built, validated and put into operation 10 or 15 years ago will continue for years on the basis of that design space. They will make only very focused, gradual investments and upgrades. New modular sites designed in the last three to five years, and which are going into operation now, often embrace Pharma 4.0 concepts at many levels and will continue down that path for the next 15, 20 years. It is not a question of either Pharma 4.0 OR ‘traditional’ Pharma 3.0, we will continue seeing 3.0 AND 4.0 concepts in parallel.

C. Woelbeling: The Pharma 4.0 Operating Model is designed to include continuous improvements, developments and managed changes in the interest of efficiency, cost reduction and at the end to prevent drug shortages and to ensure constant product quality by Digitalization.