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Biopharmaceutical Manufacturing Conference Embracing Technology and Innovation

by Louise Uí Fhatharta, Pharmalex

A biomanufacturing facility, a gowned technician about to pour liquid into a stainless steel sterile vat[Author’s note: The contents of this article are solely the opinion of the author and do not represent the opinions of PharmaLex or its parent Cencora. PharmaLex and Cencora strongly encourage readers to review the references provided with this article and all available information related to the topics mentioned herein and to rely on their own experience and expertise in making decisions related thereto.]

The PDA Ireland Chapter hosted an event to discuss how innovation and technology are embraced in the biopharmaceutical manufacturing industry. The event occurred on Thursday, the 26th of September 2024, and was led by industry leaders, experts, regulators and technology company representatives. Attended by professionals from across Ireland and overseas, it led to interactive discussions during the event that centered on the new technology and innovations available for the biopharmaceutical industry. Points of discussion also included the industry's potential challenges during inspections as the industry and regulators navigate to use these new technologies.

Common Deficiencies in Implementing New Technology and Innovation in Aseptic and Low Bioburden Processes

The Medicines and Healthcare products Regulatory Agency (MHRA) inspector’s presentation highlighted the importance of knowledge management as it is often overlooked and is required by ICH Quality Guidelines Q8(R2): Pharmaceutical Development (1) as part of new technology and innovation. It was stressed that regulatory inspectors are looking to see how knowledge gained is being documented and if a site has clear procedures in place for knowledge reproducibility. The expectation is that what is contained within a dossier needs to be very clear so it can be fully understood by regulators.

The ICH Quality Guideline Q9(R1): Quality Risk Management (2) highlights the connection between risk management and knowledge management, emphasizing the importance of handling and building on existing knowledge. The severity, frequency and detection of risks are often determined by the knowledge available at a given site. Similarly, ICH Quality Guideline Q10: Pharmaceutical Quality System (3) applies to systems supporting the production of drug substances and products, including biotechnology and biological products, throughout their lifecycle. It also underscores the critical role of knowledge management.

When introducing new technologies, the knowledge of processes and equipment is initially limited due to the lack of historical data, leading to high uncertainty. Consequently, the overall risk associated with new technology is classified as high. Over time, as technology evolves and more knowledge is acquired, uncertainty decreases, and the technology can eventually be reclassified as low risk.

Key Takeaways From This Event

Technology is evolving with innovations designed to ensure compliance with current regulations, such as Annex 1, to help reduce contamination risk. In addition, data integrity is fundamental and essential and is applicable everywhere in the manufacturing facility, not just in the laboratory. Lastly, regulations are not changing; however, regulator’s expectations are. Multiple parties need to be involved to stay informed about the development of new technologies and their potential applications. This includes end users, manufacturers and regulatory bodies.

The MHRA inspector shared some common deficiencies from the U.S Food and Drug Administration (FDA) Forum (2018-2024). Below is a summary of deficiencies that were presented:

  • Dossier to onsite process – The process viewed at site did not match the process as described in the dossier.
  • Pharmaceutical Quality System (PQS) – Change control process associated with the manufacturing process or facility were not deemed effective as either the change control document was not sufficient or was not there at all to support the change. Change controls failed to assess product impact.
  • New technologies – Incomplete assessment regarding the impact on environmental monitoring, data integrity (computerized systems), aseptic process controls, equipment cleaning and contamination control. The take home from this presentation is that implementing and making changes to new technology and innovation should be treated the same as any other change being managed by your PQS.

Empowering Shop Floor Operators

A large biotech company delivered a presentation on operator engagement, emphasizing that shop floor operators are at the heart of the critical path and must be empowered to share ideas with their line managers. The presenter outlined an empowering culture that promotes resources, leadership and real-time feedback.

In this program, line managers and supervisors are encouraged to provide immediate feedback to operators who bring forward ideas. Action tracking is facilitated through an idea board, which ensures visibility and fosters a safe, collaborative environment rooted in a "we win as one team" mentality.

The company highlighted that for an idea to be embraced and implemented, it requires sponsorship from site leaders. The operator behind the idea must be given time, access to subject matter experts, vendor support and a budget allocation. Importantly, no idea should be dismissed outright; even a "bad idea" can often be reinterpreted as the wrong solution to an actual problem, making constructive feedback essential.

For companies aiming to tap into the knowledge pool of their operators, it is crucial to ensure that leveraging this knowledge not only makes their work safer and easier but also empowers them to drive meaningful change.

Operator training and consistency in procedures are important aspects in the manufacture of a safe product that meets its quality requirements. A company providing training solutions presented their Automated Process Design and Risk Assessment Solution which aims to cut production risks and time-to-market while ensuring quality and compliance. This tool aims to remove subjectivity from the quality risk management process, reducing time and errors. It was presented that this technology has the capability to generate standard operating procedures and uses artificial intelligence (AI) to translate the process frames as captured into usable work instructions. This allows for consistent language across procedures and associated work instructions.

Digital Twins in Manufacturing and Ensuring Robust Data Systems

An aseptic manufacturing company presented on their use of digital twins and showcased how they were using digital twins to aid with reducing product development and engineering runs, cycle development time, line downtime and aid with operator training and safety. It was encouraged that the industry embraces these new technologies to avoid falling behind with these advancements.

Data integrity has always been, and continues to be, a significant focus during regulatory inspections. With the increasing use of digital applications, the volume of data requiring processing has grown substantially. A very thorough and informative presentation on data integrity and its role in the adoption of new technologies and innovations was discussed. The presenter highlighted the need for robust systems supporting digitalization and robotics, ensuring that companies fully understand the origins of their data through comprehensive audit trails.

The ISA-95 Standard: Enterprise-Control System Integration is now more relevant and useful than ever, serving as a foundational data model for modern manufacturing information Technoloy. The presentation also noted that many industries currently operate hybrid systems, combining automated data generation with manual, paper-based processes. Looking to the future, the objective for sites is to advance toward AI-driven processes, digitalization, robotics, continuous environmental monitoring and an enhanced Manufacturing Execution System to stay competitive and leverage technological advancements effectively.

Robotics Systems and Gloveless Technology

Gloveless robotic systems within aseptic filling also emerged as a more frequently seen technology. Options are available for open-isolator settings where automated systems or robots reduce the need for glove handling by automation. A case study was presented on Grade A/B mobile collaborative robots and how they can reduce human interaction and streamline compliance with EU GMP Annex 1: Manufacture of Sterile Medicinal Products Annex 1 (4) requirements. These advancements in robotics have been utilized to change environmental monitoring plates and perform glove integrity testing without human interaction.

In the area of glove integrity, there was also a presentation about innovative gloves using color indicator technology that will highlight any piercing of the gloves that would render them nonintegral. The glove was demonstrated where a normal blue cleanroom under glove could be worn in combination with the glove using the color indicator technology as an over-glove to form a breach indication system. It was presented that the gloves are suitable for use in aseptic and Class 100 (ISO 5) / EU GMP Grade A environments.

As per Annex 1, air visualization studies are also an important aspect when it comes to cleanroom qualification, development of environmental monitoring programs and operator qualifications. New innovations in smoke studies, or smokeless smoke studies, were demonstrated when image-based technology was used. This application uses invisible clean gas, negating the need for smoke or seeding particles, meaning zero contamination in the cleanroom. An illuminated background imaging technique shows the air motion over varying flow scales and rates, giving live real-time feedback of air flows to a computer or tablet. This technology can also be used to assess thermal images from cleanroom personnel and other equipment in the Aseptic Processing Area to assess the impact on air flows. The use of this technology shortens downtime in the production area as no after-treatment is required, and the seeding gas utilized is harmless and clean.

Cell and gene therapies are at the forefront of developing medicinal products and novel technologies. CRISPR is a technology that can be used to edit genes; examples of CRISPR and mRNA therapeutics were showcased. Both of these technologies are open processes within a Grade A and B biological safety cabinet. EudraLex Volume 4: Good Manufacturing Practice Guidelines, specific to Advanced Therapy Medicinal Products (5), describe the GMP requirements that should be applied in the manufacturing of ATMPs. The presenter illustrated an example of in vivo and in vitro processes, highlighting areas where single-use systems and isolator technology are being embraced by the institutions involved in the development and manufacture of ATMPs.

Real-Time Monitoring

Shortening the time to results allows for quicker action on potential issues, and decision-making using real-time monitoring is a key development in pharmaceutical manufacturing. Case studies presented highlighted how industries are using real-time monitoring technology as an early detection tool to alert sites about potential issues in the critical zone, enabling immediate action. Companies reported that using this technology reduced the risk to product quality and potentially saved batches. A second case study demonstrated how real-time monitoring technology was part of an enhanced investigation, helping to determine the root cause of increased microbial counts in a cleanroom. The shift toward real-time monitoring, especially for viable and non-viable particulates, has been driven by Annex 1. This regulation is pushing the industry to explore alternative and rapid methods for monitoring critical processes and reducing the risk of product contamination.

Conclusion

The PDA Ireland Chapter's September 2024 event offered invaluable insights into the evolving landscape of biopharmaceutical manufacturing, emphasizing the critical role of innovation and technology. Discussions highlighted both the potential and challenges of adopting advanced technologies, including the importance of robust knowledge and risk management frameworks, empowered operators and strong regulatory alignment.

From digital twins to robotics and real-time monitoring, the event underscored the necessity for the industry to embrace these advancements to remain competitive while ensuring quality and compliance. Collaborative solutions like AI-driven systems, automated risk assessment tools and innovative environmental monitoring technologies showcased how the industry can proactively address operational inefficiencies and regulatory demands.

References

  1. ICH Q8R2 - Pharmaceutical Development (2017). Accessed through: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use-considerations-ich-guideline-q8-r2-pharmaceutical-development-step-5_en.pdf
  2. ICHQ9(R1) - Quality Risk Management (2023). Accessed through: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use-ich-guideline-q9-r1-quality-risk-management-step-5-revision-1_en.pdf
  3. ICHQ10 – Pharmaceutical quality system (2015). Accessed through: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-guideline-q10-pharmaceutical-quality-system-step-5_en.pdf
  4. EudraLex Volume 4 Good Manufacturing (GMP) Guidelines – Annex 1, Manufacture of Sterile Medicinal products (2022) . Accessed through: https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf
  5. EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 Good Manufacturing Practice Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (2017). Accessed through: https://health.ec.europa.eu/document/download/ad33d9dd-03f0-4bef-af53-21308ce2187d_en?filename=2017_11_22_guidelines_gmp_for_atmps.pdf

About the Author

  • Louise Uí Fhatharta
    Fhatharta is a Manager/Consultant with Pharmalex, bringing over 20 years of experience in microbiology, quality control and quality assurance within the pharmaceutical industry. Her expertise spans sterile fill finish, medical devices and combination products. Fhatharta has led site and laboratory expansion projects from design through method transfer and operational readiness, providing critical oversight in quality, sterility assurance and microbiology. With a strong background in analytical and problem-solving skills, Fhatharta has also developed exceptional leadership abilities. She has successfully managed inspections from several competent authorities, including the FDA, Health Products Regulatory Authority and DEKRA.