The revision of EU GMP Annex 1, “Manufacture of Sterile Medicinal Products,” has significantly reshaped regulatory expectations for sterile pharmaceutical manufacturing.
The updated guidance, which came into effect in August 2023, introduces new requirements and reinforces established principles around contamination control, quality risk management (QRM), and the application of advanced aseptic processing technologies. For sterile fill-finish operations, Annex 1 represents a significant shift toward risk-based, lifecycle driven compliance with an emphasis on process robustness and contamination presentation.
Across global sterile manufacturing sites who supply commercial drug product to the European market, facilities are adapting to ensure Annex 1 compliance through integration of barrier technologies, robust contamination control strategies, enhanced environmental monitoring and employee training programmes.
At PCI, compliance is not simply a regulatory obligation it is a core pillar of our global sterile fill-finish (SFF) strategy and quality-driven culture. With a network of state-ofthe-art SFF facilities across North America and Europe, PCI has invested strategically to meet and exceed the enhanced expectations of Annex 1. Our approach integrates technological innovation, risk-based design, quality management systems, and workforce training to ensure both regulatory readiness and patient safety.
Understanding the revised annex 1
The revised Annex 1 brings a holistic and more stringent approach to the manufacturing of sterile medicinal products. Detailing a range of updated regulatory expectations, key areas of focus include:
- Establishment of a formal Contamination Control Strategy (CCS)
- Adoption of closed systems and barrier technologies (e.g., isolators and RABS)
- More stringent environmental monitoring and cleanroom classification protocols
- Clearer expectations for personnel qualification, gowning and behaviour
- Expanded guidance on media fill simulations and aseptic process validation
- Application of quality risk management (QRM) and data integrity principles throughout operations
These revisions reflect a broader regulatory shift from reactive compliance to proactive quality assurance.
The goal is to embed risk-based thinking and science-driven decision-making into the daily operations of sterile drug product manufacturing.
Contamination Control Strategy (CCS)
Annex 1 places a strong emphasis on the need for a formal, comprehensive Contamination Control Strategy (CCS) that spans the entire lifecycle of sterile manufacturing operations. The CCS must be rooted in quality risk management and incorporate all elements that may contribute to contamination risk, including facility design, equipment configuration, material and personnel flows, cleaning and disinfection, and environmental monitoring.
A robust CCS begins with clearly defined cleanroom zoning and the implementation of unidirectional flows for both personnel and materials. These controls help minimize cross-contamination between different processing areas. The use of physical and technological barriers to separate personnel from critical processing zones is also critical.
In addition, facilities must perform routine risk assessments such as Failure Mode and Effects Analysis (FMEA) to systematically identify and address contamination risks associated with equipment, procedures, and facility layout. Monitoring data, deviations, and CAPA outcomes should be regularly reviewed and fed back into the CCS for continual refinement.
Ultimately, the CCS is not a static document but a dynamic framework that must evolve alongside the manufacturing process. It should be updated in response to process changes, emerging risks, and performance trends to ensure it remains effective and aligned with regulatory expectations.
Barrier technologies and aseptic processing
The updated Annex emphasizes barrier technologies as a preferred approach to minimize contamination risks. Aseptic processing lines using isolators or RABS, automated systems, and closed transfers are increasingly the standard.
In aseptic fill-finish operations, implementation of isolator-based vial, PFS, and cartridge filling systems, combined with automated lyophilizer loading/unloading, significantly reduces human interaction with the sterile field.
One key technical expectation under Annex 1 is the routine use of Pre-Use Post-Sterilization Integrity Testing (PUPSIT) for sterilizing-grade filters. The requirement for PUPSIT aims to ensure filter integrity is maintained during sterilization and prior to use. While some debate continues around feasibility in certain closed systems, Annex 1 only allows for risk-based justification for not performing PUPSIT in specific, well-documented cases. Most manufacturers, therefore, are now implementing validated, automated systems to perform PUPSIT in alignment with regulatory expectations.
Environmental monitoring and cleanroom controls
Environmental monitoring (EM) under the revised Annex 1 is expected to be continuous, risk-based, and capable of detecting deviations in real time. The requirement for continuous monitoring of both viable and non-viable particles in Grade A/B areas underscores the need for comprehensive, scientifically justified EM programs.
Viable particle monitoring should be conducted using active air sampling and settle plates during manufacturing operations. These techniques must be validated and strategically placed to ensure effective coverage of critical zones. Non-viable particle monitoring, typically performed using calibrated airborne particle counters, must operate continuously in Grade A areas to provide ongoing assurance of environmental control.
Alert and action limits should be established based on historical data, and any out-of-trend or out-of-specification results must trigger timely investigations. The revised Annex 1 encourages facilities to utilize real-time data acquisition systems that support advanced analytics and trend analysis, enabling early detection of anomalies and data-driven decision-making.
Periodic requalification of cleanrooms, including smoke studies and airflow visualization, remains a key part of EM programs. These activities validate that airflow patterns, pressure differentials, and other design features continue to meet their intended function over time.
Personnel training and qualification
Personnel remain one of the most significant contamination risks in sterile processing, and Annex 1 emphasizes the importance of minimizing human interaction with critical areas. The updated guidance reinforces that all operators working in aseptic areas must undergo comprehensive and ongoing training in aseptic technique, cleanroom behaviour, and gowning procedures.
Qualification is no longer a one-time event; operators must be requalified at defined intervals, with records maintained to demonstrate continued competence. This includes participation in media fills, as well as practical assessments of gowning and aseptic manipulations.
Behavioural observation is another requirement. Facilities must monitor operator behaviour within Grade A and B environments to ensure compliance with procedures and to identify patterns that may increase contamination risk. When deviations are observed, retraining or root cause analysis should be conducted to prevent recurrence.
Gowning practices must be validated for each cleanroom environment. This includes selection of materials, donning procedures, and environmental conditions under which gowning is performed. Effective training programs, paired with a culture of accountability and quality ownership, are essential for sustained compliance with Annex 1.
Process validation and media fills
Process validation through media fills, or aseptic process simulations, remains a cornerstone of sterility assurance under Annex 1. These exercises are intended to demonstrate that the aseptic manufacturing process can consistently maintain sterility under routine and stress conditions.
Annex 1 calls for media fills to reflect worst-case scenarios, such as extended batch durations, complex line setups, multiple operator shifts, and planned or unplanned interventions. The goal is to replicate real-world operational conditions and confirm that the process design and operator practices are capable of preventing contamination.
Media selection must be appropriate for the types of organisms expected in the manufacturing environment and must be incubated under validated conditions to ensure microbial recovery. The simulation must include full documentation of procedures, interventions, and environmental conditions.
Any contamination events must be thoroughly investigated, and results should be analyzed in the context of historical performance and environmental monitoring data. The frequency and design of media fills must be risk-based, tied to the complexity of the operation, recent process changes, or deviations identified in prior runs.
Quality risk management and digital integration
Annex 1 reinforces that Quality Risk Management (QRM) must be embedded throughout all stages of sterile drug product manufacturing, from facility design and equipment qualification to process validation and ongoing monitoring. The principle is to proactively identify, evaluate, and control risks that could compromise product quality or patient safety.
Facility layouts should be designed with airflow, pressure differentials, and segregation principles guided by QRM methodologies. Cleaning validation protocols should incorporate risk-based selection of disinfectants and rotation schemes to maintain microbial control. Critical utilities, such as water for injection (WFI) and compressed gases, must be assessed for risk to product sterility and controlled accordingly.
Filter qualification and sterilization cycles are other key areas where risk-based justification is essential. PUPSIT, for example, is now broadly expected unless scientifically justified otherwise. Digital systems can play a pivotal role in managing and documenting these risk-based activities.
Modern manufacturers are increasingly turning to digital platforms to enhance compliance and data integrity. Electronic batch records (EBRs), deviation tracking systems, and integrated analytics tools allow for real-time oversight, simplified audit readiness, and proactive quality management. These systems also ensure traceability and help reduce human error, thereby supporting a more robust approach to Annex 1 compliance.
PCI Pharma Services’ strategy for annex 1 compliance across global sterile manufacturing operations
At PCI Pharma Services, Quality Assurance leads the strategic implementation of Annex 1 compliance across all sterile manufacturing operations. This approach is consistently applied to new facility builds, filling line installations, upgrades of existing assets, and during the integration of acquired sites, such as Ajinomoto Althea in San Diego. Central to our contamination control strategy is the adoption of isolator-based aseptic filling systems, designed to minimize human intervention and environmental exposure. At our North American sites in Bedford, NH and San Diego, CA, as well as our European facility in León, Spain, we have a number of vial, prefilled syringe, and cartridge filling lines within isolator technology, equipped with automated decontamination cycles and integrated environmental monitoring systems. Additionally, automated lyophilizer loading and unloading systems have been implemented at our latest facility build at 7 Commerce Drive to eliminate manual handling risks during critical process steps, aligning with Annex 1’s heightened focus on contamination risk reduction.
Filter integrity testing is a critical control point, and PCI has fully embedded Pre-Use/Post-Sterilization Integrity Testing (PUPSIT) into our operations to ensure compliance with Annex 1 mandates. This process verifies sterilizing-grade filter performance under actual process conditions, thereby safeguarding against potential microbial ingress.
Our aseptic process simulation (media fill) program has been redefined to adopt a risk-based frequency and design, ensuring full alignment with Annex 1 requirements. These simulations rigorously challenge processes through the inclusion of worst-case scenarios, simulation of routine and non-routine interventions, and validation of maximum batch sizes and run durations. Qualified growth media and controlled incubation conditions are utilized, with comprehensive reviews of contamination events and trend data conducted by cross-functional teams comprising QA, Production, and Microbiology. Media fills are treated as critical validation activities, forming a key element of our ongoing contamination control verification.
Our commitment to Quality Risk Management (QRM) is embedded across all aspects of equipment and process lifecycle management. This includes applying QRM principles to equipment and process design through design qualification and risk-based User Requirement Specifications (URS), developing environmental monitoring and cleaning validation strategies based on facility-specific risk assessments, and ensuring robust filter integrity and sterilization validation protocols.
To further enhance compliance and control, PCI leverages digital systems that reinforce data integrity and provide real-time process oversight. Our electronic batch records (EBRs) streamline process traceability, while automated deviation workflows, real-time process analytics, and fully integrated change control and CAPA systems ensure a proactive approach to quality management.
Through this comprehensive QA-led strategy, PCI ensures that all facilities whether newly built, retrofitted, or acquired consistently meet or even exceed global regulatory requirements including the expectations of Annex 1, safeguarding both product sterility and patient safety.
Conclusion: A proactive, global approach to compliance
The 2023 revision of Annex 1 has set a new benchmark for sterile pharmaceutical manufacturing. It challenges manufacturers to rethink their approach to contamination control, validation, and process oversight not as reactive tasks, but as proactive, integrated elements of a quality-focused operation.
At PCI Pharma Services, we view Annex 1 not as a checklist, but as a framework to strengthen the consistency, sterility assurance, and overall robustness of our fill-finish operations.
By combining state-of-the-art barrier technologies, rigorous training, advanced EM systems, and integrated quality oversight, we are proud to deliver sterile manufacturing solutions that meet the highest global standards. With fully Annex 1-compliant sites across the U.S. and Europe, PCI is ready to support our partners in developing and supplying the next generation of sterile, patient-centric therapies – safely, reliably, and at scale.
We are committed to supporting clients at every stage of the manufacturing cycle, delivering best-in-class services efficiently and effectively.
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