Key Insights From a Journey Through the Pharma 4.0™ Baseline® Guide: Pharma 4.0™ Guide Charts Bold New Course for Digital Transformation

Background

The concept of Pharma 4.0™ was partially developed from Industry 4.0,1 which refers to the intelligent networking of machines and processes in industry through information and communication technology. The journey began in 2004 with the formation of an ISPE Special Interest Group (SIG) for Process Analytic Technology (PAT) in the Germany–Austria–Switzerland (DACH) region. The PAT SIG eventually led to the formation of a much broader Community of Practice (CoP) for Pharma 4.0™ in 2017. Such is the level of interest in Pharma 4.0™ that today the CoP is fast approaching 3,000 members.

I first met Christian in April 2022 at the ISPE Europe Annual Conference in Madrid, Spain, just as ISPE was resuming its conferences after the COVID-19 pandemic. Given how long Pharma 4.0™ had been established within the pharmaceutical industry, I was curious as to why it had taken so long to begin developing a Baseline^® Guide. The answer: the industry simply wasn’t ready at that time. Relevant use cases didn’t begin to emerge until 2022. As a result, work on the Pharma 4.0™ Baseline^® Guide began in July 2022, ultimately incorporating 35 use cases.

With the proliferation of emerging technologies—among them machine learning and artificial intelligence—the industry is clearly poised to apply Pharma 4.0™ principles and begin realizing their many benefits.

The four main objectives of Pharma 4.0™ are:

1. To understand the interdependencies among technologies, processes, people, and regulations necessary for a successful digital business transformation—based on global principles from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)2—starting with an operating model, followed by maturity assessments for all elements and enablers.
2. To explain the principle of a holistic view and transformation specific to the pharmaceutical industry.
3. To orchestrate the interdisciplinary ISPE knowledge spaces, such as GAMP,3 Product Quality Lifecycle Implementation (PQLI),4 Advancing Pharmaceutical Quality (APQ),5 and Pharma 4.0™.
4. To develop the necessary organizational culture for success, as outlined in the ISPE APQ Guide: Cultural Excellence.6

The new Baseline® Guide is intended to help shape the digital transformation of the pharmaceutical industry. It will require a high level of management awareness and a clearly defined stakeholder structure. The principles and process-based approach are outlined in the ISPE Pharma 4.0™ Operating Model (see Figure 1). A roadmap is essential, with clearly identified benefits supported by use cases.

Furthermore, as the Baseline® Guide has the character of a textbook, it represents a second generation of Good Practice Guides in development—akin to a ‘cookbook’—providing more detailed guidance on how to implement a successful digital transformation. Use cases will also illustrate the roadmaps for implementation.

Understanding Pharma 4.0™

Explaining the purpose of digital transformation is essential, as it supports a more holistic approach and enables the generation of usable data to inform decision-making and drive improvements in operations, cost efficiency, and regulatory compliance. Enhancements in regulatory compliance are achieved by bridging automation with regulations and ICH Quality Guidelines.2 This can only be accomplished through clearly defined roles and responsibilities for digitalization, along with a shared understanding between industry and regulators when adopting innovative technologies.

In many organizations, parts of the operation remain isolated—or siloed. One of the key objectives of Pharma 4.0™ is to break down silos and foster a common understanding across departments. For example, Pharma 4.0™ can link departments such as product development, commercial manufacturing, engineering, automation, information technology (IT), and supply chain stakeholders. This integration facilitates innovation, technology transfer, and the maintenance of equipment and systems.

Similarly, in the context of stakeholder management, Pharma 4.0™ can connect regulators—such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and national competent authorities—with industry and healthcare providers. Strengthening these connections can lead to further benefits, including the adoption of innovative technologies, enhanced patient protection, and improved product delivery.

In 2017, the Pharma 4.0™ Community of Practice (CoP) summarized its key objective as follows: “We provide practical guidance, embedding regulatory best practices, to accelerate Pharma 4.0™ transformations. Our objective is to enable organizations involved in the product life cycle to leverage the full potential of digitalization to provide faster innovations for the benefit of the patients.”

The ISPE Baseline^® Guide Vol. 8: Pharma 4.0™ outlines the foundational principles of Pharma 4.0™ and its potential for holistic transformation. Authored by 30 qualified industry professionals, the guide spans 250 pages and includes 35 use cases. Figure 2 illustrates the guide structure.

At the core of Pharma 4.0™, there is strong alignment with Industry 4.0. For example, Industry 5.07 emphasizes the promotion of talent, diversity, and empowerment. Within Pharma 4.0™, this is reflected in the concept of cultural excellence, as described in the ISPE APQ Guide: Process Performance and Product Quality Monitoring System (PPQMS),5 as well as in the ISPE Engage program. Figure 3 illustrates how Pharma 4.0™ incorporates pharmaceutical industry-specific elements to the broader principles of Industry 4.0 and 5.0.

Holistic Control Strategy

Implementing a holistic control strategy for the end-to-end management of manufacturing supply chains is key to realizing the benefits of Pharma 4.0™. All manufacturing steps—from the supply of raw materials to the storage and distribution of products to patients—must be mapped and integrated into an overarching quality framework. This framework can then be evaluated and enhanced through the application of Pharma 4.0™ principles.

It is important to assess the current level of digitalization and define the desired level by creating a roadmap for implementation. Identifying pain points during the mapping of the end-to-end manufacturing supply chain is also a critical step.

The transition to Pharma 4.0™ is unlikely to occur without incremental steps. It begins with conducting maturity assessments across all elements and enablers of the Operating Model. The ISPE Quality Management Maturity Program5 and ICH Q102 are useful references for conducting these assessments and benchmarking efforts, in addition to the maturity grids shown in the Guide’s attachments. These assessments, based on the Operating Model, take a holistic approach to evaluating digital business maturity and can be further detailed as follows:

• Resources: Team organization; digital skills/Workforce 4.0; resource management; automation and technical capabilities; engineering and construction
• Organization and Processes: Business strategy; quality management; performance management; control strategy; knowledge management
• Information Systems: IT strategy; IT operational governance; IT components; architecture integration; cybersecurity
• Culture: Value-based mission and vision; patient orientation; sense of urgency; activation and empowerment; relationships with authorities

A quality management maturity rating from 1 to 5 has been defined by the FDA.6 The overall Pharma 4.0™ Digital Maturity Score would be an average of these ratings and includes an assessment of data integrity.

Maturity Level 5: Optimized (Best in Class)

1. Policies, standards, processes, and procedures are clearly defined and integrated across the supply chain.
2. Feedback loops are implemented for continual improvement.
3. A high degree of data-based decisions are established.

Maturity Level 4: Managed

1. Policies, standards, processes, and procedures are aligned with current industry standards.
2. Quantitative goals for processes and products are well-defined and measured.
3. Full global integration is achieved.
4. Data are interoperable and contextualized.

Maturity Level 3: Defined (Enhanced Pharmaceutical Quality System)

• Policies, standards, technical and business processes, and procedures (SOPs) are defined on a global level.
• A high level of global (i.e., organization-wide) integration is achieved.
• Data management is clearly defined across all functions and organizational levels.

Maturity Level 2: Developmental (Enhanced Pharmaceutical Quality System)

• Policies, standards, and written procedures (SOPs) are at least defined at the local level.
• There is little to no integration between different entities.
• A master data management framework is available.

Maturity Level 1: Initial (Minimally Compliant)

• Regulatory requirements are fulfilled.
• Only minimal compliance is achieved.
• Operations are highly dependent on individuals; knowledge is lost when individuals are unavailable.
• Processes exhibit high variability and rely on reactive control.
• Numerous deviations and corrective and preventive actions are required.
• Data management exists without a structured framework.

Data Integrity

Once the required level of quality management maturity is established, the next step is to begin digitization by focusing on data integrity by design and achieving a level of digital maturity that enables the principles of Pharma 4.0™. These principles are based on the Operating Model shown in Figure 1, which incorporates a holistic control strategy that drives both digital transformation and a digitalization strategy. Only then can the full benefits and value of Pharma 4.0™ be realized.

The Pharma 4.0™ journey is expected to push the boundaries of innovative technologies and in doing so, it is important to maintain a strong connection with the regulatory authorities. In the United States, this can be achieved through programs such as the FDA Emerging Technologies Program (ETP)8 and the FDA Digital Health Advisory Committee.9 In Europe, similar support may be obtained through the EMA Quality Innovation Group (QIG). 10 I have found the FDA ETP and the EMA QIG to be particularly effective when applied to innovations.

Conclusion

The Pharma 4.0™ journey requires a clearly defined set of business goals and a comprehensive business strategy. Business processes, corresponding process data flows, and data lifecycle must all be clearly outlined. Achieving this vision will require the formation of interdisciplinary teams tasked with enabling the necessary level of quality management maturity—for example, APQ Level 3.5

The final prerequisite is to establish infrastructure connectivity that supports interconnectivity and plug-and-produce integration, based on the International Society of Automation’s ISA-95 Model21 and the Industry 4.0 Structured Network Model.1

When developing business strategies, it is imperative to highlight the many benefits of applying the Pharma 4.0 Operating Model. Some of the key benefits are listed in Figure 4.

The many opportunities presented by digitization include the transition from paper-based or analog records to digital formats. Once digitized, processes can be further integrated through digitalization and enhanced by data analysis. Transitioning from manual to more robust, automated steps—such as those enabled by robotics—will support the modernization of existing operations. A key challenge is to become more proactive, responsive, and efficient through digitalization, IT applications, and infrastructure, especially when compared to traditional approaches to validation and other asset life cycle activities.

Digital transformation is a strategic business initiative—not merely an IT project. It can only be executed by management, who must take full responsibility for the transformation, as outlined in the “ICH Q10 Pharmaceutical Quality System,2” The ISPE Pharma 4.0™ Baseline^® Guide introduces the basic concepts and principles of Pharma 4.0™, aiming to establish a shared understanding among all stakeholders. Additional practical guidance will be provided in future ISPE guidance documents.

Exactly two years after meeting Christian Wölbeling, I saw him again in April 2024 at the ISPE Europe Annual Conference in Lisbon, Portugal. By that time, the ISPE Pharma 4.0™ Baseline^® Guide had been published, and I had already read it. I found it compelling in terms of the opportunities it presented. Given the many emerging technologies and the drive toward digitization, it seemed clear that the industry was ready for Pharma 4.0™.

I’m not sure if the industry fully realizes the extent of the transformation we are about to experience. What I do know is that now is the time to embrace Pharma 4.0™

We appear to be on the cusp of a new era—a paradigm shift that could transform the pharmaceutical industry in ways that are difficult to fully imagine. When I shared my thoughts with Christian, he responded, “Yes, we will be spending the next 20 years implementing Pharma 4.0™.”

I’m not sure the industry fully realizes the extent of the transformation we are about to experience. What I do know is that now is the time to embrace Pharma 4.0™—and the best place to start is by reading the ISPE Pharma 4.0™ Baseline® Guide. After reading it, I can guarantee that the phrase “To boldly go where no one has gone before” will take on a whole new meaning.