Biopharmaceutical manufacturers continue to weather the sea change associated with industry 4.0. Although “smart” capabilities seemed urgent to develop during the COVID-19 pandemic, results from BPI’s Platform issue survey indicate that few companies have made headway in doing so. Respondents agreed that smart technologies can enhance operational speed and flexibility. But many companies are shifting resources to address different priorities, while other companies are reluctant to sail further into the digital-manufacturing environs.

Early in 2024, I corresponded with Yvonne Duckworth (a fellow in digital technology at CRB) and Ryan Thompson (a senior specialist in industry 4.0 at CRB) about their experiences with establishing industry 4.0 capabilities. Duckworth and Thompson identified reasons for reluctance among biomanufacturers and emphasized the need for additional use cases and regulatory resources. Such information will help companies to establish corporate cultures that foster digital transformation.

Duckworth is a registered automation engineer with 30 years of technical-design and project-leadership experience in the pharmaceutical and biotechnology industries. In the International Society for Pharmaceutical Engineers (ISPE), she serves as a chairperson for the Pharma 4.0 Leadership Team and as cochair for the Pharma 4.0 Holistic Digital Enablement Working Group. She also is lead author for a chapter in the ISPE Baseline Guide: Pharma 4.0 (1). Duckworth holds an MBA from Rider University and a BS in electrical engineering from Widener University.

Thompson has more than 17 years of experience in leading digitalization projects in the pharmaceutical, food-and-beverage, and consumer–packaged-goods industries. He is a six-sigma green belt and Google Cloud digital leader, and he holds a BASc in mechanical engineering from the University of Toronto.

Setting the Scene

How is industry 4.0 advancing within the biopharmaceutical industry?

Thompson: Industry 4.0 seeks to increase efficiency, quality, flexibility, and speed. Biopharmaceutical companies want to exploit such advantages as much as other manufacturing-oriented companies do, and over the past decade, the life-sciences sector has worked to reduce barriers to adoption. Groups such as the ISPE Pharma 4.0 Community of Practice were formed to provide guidance on how to implement 4.0 principles.

Duckworth: As that committee’s chairperson, it has been rewarding to witness our efforts to advance 4.0 principles in the pharmaceutical industry. ISPE’s Pharma 4.0 framework provides a holistic approach to incorporating digital technologies while accounting for impacts on a company’s culture, people, and processes.

What biopharmaceutical-industry segments have shown the most uptake of industry 4.0?

Thompson: Digital technologies quickly are becoming a requirement as opposed to a differentiator for contract development and manufacturing organizations (CDMOs). Paper-based operations are often a nonstarter when contract manufacturers are competing for work. Many reasons account for that trend. For example, digital operations can expedite technology transfer (to a CDMO and back to a sponsor), improve process characterization, and provide real-time access to data.

Duckworth: Integrating industry 4.0 into operations could transform partnerships between drug sponsors and manufacturers. Digital technologies will enable new forms of collaboration, enhancing manufacturing productivity, quality, speed, and flexibility.

How far along are most companies on their 4.0 journeys?

Thompson: All biotechnology companies have started on their 4.0 journeys, but implementation has been uneven. Large companies tend to have formal strategies at the corporate level, but those policies have yet to reach the factory floor. It is a big lift to digitize existing infrastructure and change business processes to support such efforts. But for greenfield facilities, digital-first is the plan. Some small companies are pushing the boundaries of digitalization — e.g., by setting up minimal onsite infrastructure and instead building business in the cloud.

Duckworth: Implementation of fully integrated systems remains challenging for many companies. The transition from manual to automated operations is a complex process that involves not only technological upgrades, but also a cultural shift within an organization. Achieving the connectivity necessary for 4.0 requires a strategic approach that focuses on data integrity, real-time monitoring, and use of advanced analytics for decision-making. However, the industry is gaining momentum from companies that are starting or continuing their digital-transformation journeys — e.g., by improving system integration and connectivity in their facilities.

Building a Business Case

What constraints are holding the industry back from full digitalization?

Thompson: A lot of hesitancy remains because manufacturers are unsure about what benefits they specifically will realize. Respondents to CRB’s 2023 Life Sciences survey cited such uncertainty as the top reason for holding back on digitalization (2). As an industry, we must identify tactical use cases and report about their costs and benefits.

Duckworth: The ISPE Pharma 4.0 Community of Practice conducted a similar survey. In 2023, the top three challenges were an inadequately supportive company culture, high costs, and a lack of expertise and resources.

The cultural aspect is a significant difficulty for many companies. They must have strong support from leadership to make the changes required for industry 4.0 implementation. Building a business case remains a key challenge. Companies also recognize that digital technologies will have an impact on resources and the workforce. New skills might be required, so companies might find themselves upskilling current employees or hiring additional staff.

Where can manufacturers find use cases and examples of successful digital transformation?

Duckworth: ISPE Baseline Guide: Pharma 4.0 was published in December 2023 (1). It provides advice about embracing emerging technologies, adopting an end-to-end approach for products and processes, and engaging personnel in innovative ways to prepare the future workforce. The document includes structured frameworks with strategies based on organizational size, risk tolerance, flexibility, and maturity level. The publication also contains 35 use cases, providing real-world examples of approaches taken, procedures established, and technologies implemented — and of the benefits reaped, challenges encountered, and lessons learned. I believe that such examples will bring much-needed guidance to our industry. ISPE will continue collecting use cases to that end.

What is the most compelling use case for industry 4.0 adoption that you have encountered?

Duckworth: I know of a few use cases that are changing operations already. One involves use of virtual reality (VR) for cleanroom-operator training. I know of one pharmaceutical company that is applying such training on a global scale, providing operators with an engaging, customizable, and safe environment for practice without risks to operations.

Another use case is maintenance reporting through speech recognition and AI. Technicians wear headphones and dictate their actions. Their reports are transcribed and mapped into specific fields in a company’s computerized-maintenance management system (CMMS).

This last use case came about during the pandemic but still adds value to modern practices: 360° cameras can be used to capture facility conditions and provide a dimensionally accurate pictorial tour to remote teams using a web browser. In several facilities, quickly adopting such technology enabled projects to progress despite travel restrictions.

Thompson: AI-facilitated maintenance reporting can enhance regulatory compliance. Technicians can report issues contemporaneously, leading to fewer missed or forgotten actions.

If you are using such a system to determine whether equipment is fit for purpose, then it will need validation. That could be simple. For instance, maintenance activity could be sent by email for confirmation before being recorded officially.

Finding Additional Support

As adoption of industry 4.0 increases, how are security concerns shifting?

Thompson: Conversations with clients have revealed three areas of hesitancy, the first being cybersecurity. It is an insurance requirement to demonstrate implementation of risk reductions, backup and recovery plans, and staff training. A related concern is upcoming enforcement of the EU Network and Information Security 2 (NIS2) Directive, which will place responsibility for some security functions on critical industries (3).

Some discussion surrounds the EU General Data Protection Regulation (GDPR) and how it affects personalized medicines such as cell and gene therapies (CGTs) (4). In that context, biopharmaceutical production has undergone a major paradigm shift, with manufacturers now integrating with healthcare providers and needing to deal with personally identifiable information.

The final concern is a business-related aversion to sharing data with technology companies. Manufacturers worry about how their data are stored, accessed, and used. In general use cases, such as storing data about how a motor functions, there is no concern about proprietary information. The concern likes with detailed data such as those from bioreactor processes, even if such information is abstracted.

How are regulatory agencies responding to industry 4.0?

Thompson: The US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) has instituted a Framework for Regulatory Advanced Manufacturing Evaluation (FRAME), which includes applications of AI (5). The agency also has published guidances and solicited feedback (6, 7). The FDA knows that digital transformation is coming and is trying to get ahead of the curve, encouraging manufacturers to use advanced digital technologies when doing so makes sense and when risks can be addressed adequately.

The European Medicines Agency (EMA) is working on industry 4.0 frameworks as well and has published a reflection paper on the topic, including discussion of AI in the medicinal-product life cycle (8). The EMA takes a similar approach to that of the FDA, ensuring that manufacturers are assessing and mitigating risks appropriately while being supportive of innovation.

Duckworth: Companies can receive agency support in a few ways. One is the FDA’s emerging technology program (ETP), which is designed to promote adoption of innovative approaches such as AI into pharmaceutical manufacturing (8). The ETP enables drug developers to meet with the emerging technology team (ETT), which comprises representatives from different FDA quality-review and inspection programs, to discuss potential technical and regulatory issues before submitting applications (9). The ETP also provides training and guidance to FDA reviewers and facilitates technology integration into the existing regulatory framework. By participating in the ETP, pharmaceutical companies can benefit from early feedback, reduced uncertainty, fast review, and improved product quality and availability.

The EMA also is engaging stakeholders to explore AI in biomanufacturing. One agency initiative is to create quality information groups (QIGs) with experts from different domains to discuss best practices for AI in drug development and regulation (10). The QIGs are meant to foster a common understanding of AI’s opportunities and obstacles and to identify needs for guidances and standards.

References

1 ISPE Baseline Guide: Pharma 4.0. International Society for Pharmaceutical Engineers: Bethesda, MD, 2023; https://ispe.org/publications/guidance-documents/baseline-guide-vol-8-pharma-40-1st-edition.

2 Horizons: Life Sciences Report, 2023. CRB: Cary, NC, 2023; https://go.crbgroup.com/2023-horizons-life-sciences-report.

3 The NIS2 Directive — A High Common Level of Cybersecurity in the EU. European Parliament: Brussels, Belgium, 2023; https://www.europarl.europa.eu/thinktank/en/document/EPRS_BRI(2021)689333.

4 Morrison M, et al. The European General Data Protection Regulation: Challenges and Considerations for iPSC Researchers and Biobanks. Regen. Med. 12(6) 2017: 693–703; https://doi.org/10.2217/rme-2017-0068.

5 CDER. Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) Initiative. US Food and Drug Administration: Silver Spring, MD, 2023; https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/cders-framework-regulatory-advanced-manufacturing-evaluation-frame-initiative.

6 CDER. Using Artificial Intelligence and Machine Learning in the Development of Drug and Biological Products. US Food and Drug Administration: Silver Spring, MD, 2023; https://www.fda.gov/media/167973/download.

7 CDER. Artificial Intelligence in Drug Manufacturing: A Discussion Paper. US Food and Drug Administration: Silver Spring, MD, 2023; https://www.fda.gov/media/165743/download.

8 CHMP/CVMP. Reflection Paper on the Use of Artificial Intelligence in the Lifecycle of Medicines. European Medicines Agency: Brussels, Belgium, 2023; https://www.ema.europa.eu/en/news/reflection-paper-use-artificial-intelligence-lifecycle-medicines.

9 Emerging Technology Program (ETP). US Food and Drug Administration: Silver Spring, MD, 023; https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/emerging-technology-program-etp.

10 Quality Innovation Group. European Medicines Agency: Brussels, Belgium, 2024; https://www.ema.europa.eu/en/committees/working-parties-other-groups/chmp-working-parties-other-groups/quality-innovation-group.

Brian Gazaille, PhD, is managing editor of BioProcess International; [email protected]; 1-212-600-3594; Yvonne Duckworth, PE, is a fellow in digital technology, and Ryan Thompson is a senior specialist in industry 4.0, both at CRB Group; https://www.crbgroup.com.