One example of this kind of synergy is the transition from offline water testing using the oxidizable substances test to the online total organic carbon (TOC) monitoring we utilize today. When the USP added this test as an alternative method in 1996, no one imagined that just two years later it would become a standard test for purified water systems. Today online TOC monitoring is used for more than continuous water quality testing; it is common in clean-in-place (CIP) systems, as part of cleaning validation, and as a process analytical technology with broad applicability.
These overnight sensations often are years in the making. Technology and operating experience will slowly gain ground until an outside event, like a regulatory change, slingshots the technology to the forefront of modern pharmaceutical engineering. TOC analyzers were invented in 1972, but didn’t breakthrough until twenty-four years later.
Such is the case with the advent of the revised Annex 1 in 2022 and the popularization of real-time airborne viable particle counting. Laser-induced fluorescence (LIF) was invented in 1968, with applications in biological threat assessment being the most prominent application for decades. UV-LIF particle counters grew out of this research and became commercially available in 2012. But it wasn’t until the publication of the revised Annex 1 that the door really opened for this technology… and the technology will pay off for regulators with a potential for big gains in public health through the rapid identification of contamination in aseptic manufacturing environments.
What Changed
When Annex 1 was adopted in August of 2022, it embodied two concepts that are critical for the rapid deployment of UV-LIF viable particle monitoring systems. In Section Two “Principle” it suggests: “… The use of appropriate technologies (e.g. … rapid/alternative methods… should be considered to increase the protection of the product… and assist in the rapid detection of potential contaminants in the environment and the product.” This first statement of principle opens the door to rapid methods that help improve the control of contaminants. These principles also align directly with the Pharma 4.0™ vision, which combines automation, digitalization, and data-driven decision-making to transform pharmaceutical processes.
In Chapter Nine “Environmental and Process Monitoring” the document goes on to state: “9.28 The adoption of suitable alternative monitoring systems such as rapid methods should be considered by manufacturers in order to expedite the detection of microbiological contamination issues and to reduce the risk to product. These rapid and automated microbial monitoring methods may be adopted after validation has demonstrated their equivalency or superiority to the established methods.” This statement makes clear that regulators are looking to better protect products, and one method is through rapid identification of viable contaminants.
In Chapter Ten “Quality Control”, Annex 1 further builds the case for rapid microbial methods, stating: “10.10 … For products with short shelf life, the environmental data for the time of manufacture may not be available... Manufacturers of these products should consider the use of rapid/alternative methods. 10.11 Where rapid and automated microbial methods are used for general manufacturing purposes, these methods should be validated for the product(s) or processes concerned.”
These statements would have been enough to drive a shift towards real-time viable particle detection, but there was one more new statement in Annex 1 that changed the very way that we look at contamination control… the contamination control strategy (CCS). The CCS is meant to be an evaluation of the potential sources of contamination, the means we use to control them and the tools we use to monitor the efficacy of our controls. It goes further exhorting us to “define all critical control points… and monitoring measures employed to manage risks”. This statement cements the need for rapid methods to provide meaningful and actionable control of viable contaminants.
It's this same CCS requirement that hints at other critical controls and monitoring, like automated inspection. Here, the timing between technology and regulatory intent is closer than ever with real-time viable counting. Automated visual inspection has been in use for over 20 years, but with the recent advent of AI applications, automated systems can easily surpass the reliability of manual inspections.
Annex 1 authors seem to recognize this as the two sentences about manual visual inspection in the 2008 version of Annex 1 giving way to a section three times that size in 2022, which outlines the many factors to be considered in manual inspection. Contrast this to the two sentences on automated visual inspection in the revised guide stating that the process should be validated and challenged at regular intervals, including during the batch.
The Role of Pharma 4.0™
The "Regulations and Pharma 4.0" track at the 2025 ISPE Aseptic Conference highlights the potential of digitalization and automation in aseptic manufacturing, showcasing real-world applications and innovative technologies that redefine inspection and quality control.
Deep Learning (DL) is emerging as a game-changer in Automatic Visual Inspection (AVI). Presenters Jorge Delgado and Jonathan Malave from Amgen will detail how DL-powered AVI addresses longstanding challenges like high false rejection rates in parenteral inspection, achieving superior detection accuracy (>99 percent) with a significantly reduced false eject rate (1 percent).
Max Scheible, PhD, from Vetter Pharma-Fertigung GmbH & Co KG will provide a practical roadmap for transitioning from manual to automated inspection processes. Attendees will gain insights into the principles of AVI, challenges in qualification, and statistical methodologies to bridge the gap between human and machine accuracy.
Jai Pathak from AstraZeneca will share hard-earned lessons from inspecting low-fill-volume parenterals. Through detailed case studies, he’ll discuss overcoming challenges like high false rejects and applying these insights to subsequent product designs. His talk will emphasize best practices for optimizing AVI performance, especially in complex cases like pre-filled syringes with low nominal fill volumes.
Each of these presentations connects directly to Annex 1’s emphasis on CCS and rapid, validated monitoring systems. The application of AVI, powered by technologies like DL, underscores the Pharma 4.0 vision of integrating data-driven systems with robust regulatory frameworks to improve quality, efficiency, and compliance.
Conclusion
The advent of new technologies does not often align with the development of new regulations. But in the advancing automation of sterile processes and the adoption of Annex 1, we see one of these rare synergies that will drive improvements in cost, reliability and safety. At the 2025 ISPE Aseptic Conference, the "Regulations and Pharma 4.0" track will explore these synergies, providing actionable insights into how the industry can embrace this transformative shift. Don’t miss the opportunity to learn how the latest advancements can improve cost, reliability, and safety in pharmaceutical operations.
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