One year after the revised EU GMP Annex 1 came into effect, the 2024 PDA Survey reveals how the pharmaceutical industry is adapting to its stringent requirements.
The survey represented the global pharmaceutical industry with most of the responses concerning sites located in Europe (42%) and North America (27%) but includes responses from China/India (15%) and other regions.
While progress has been made, challenges remain, particularly in implementing Contamination Control Strategies (CCS), Barrier Technologies, and Environmental Monitoring.
In this post, we highlight 20 key findings from the survey, offering insights into compliance trends, regulatory expectations, and future innovations shaping the sterile manufacturing landscape.
Read to the end, there is a free gift for you...
Compliance and Challenges
The survey identified some interesting statistics on compliance levels and the cost and resource burden for Annex 1 implementation, including:
Overall Compliance – About 75% of survey participants declared at least 75% compliance with the new Annex 1 requirements as of July/August 2024.
Lagging Compliance Areas – The top two lagging areas were Contamination Control Strategy (CCS) and Barrier Technologies.
Time Extensions Required – 40% of participants reported needing a time extension for full compliance; 25% informed authorities proactively, 25% did so during an inspection, and 50% did not inform authorities.
Unexpected Resource Burden – Contrary to initial expectations, significant additional resources were required for Annex 1 implementation, with 40% of respondents reporting plant shutdowns exceeding routine maintenance durations.
Financial Investment Required – 50% of respondents reported needing investments over $100,000 for facility upgrades, while 30% reported costs exceeding $2 million.
Inspection and Regulatory Oversight
The survey gave very interesting insights on the action of regulators during inspections that we should be cognizant of, including:
Regulatory Scrutiny – Over 50% of respondents stated that regulatory inspectors evaluated Annex 1 compliance during inspections.
Top Inspection Focus Areas – The five most inspected areas were:
Contamination Control Strategy (CCS)
Aseptic Process Simulations
Premises/Facility Compliance
Environmental and Process Monitoring
Barrier Technologies.
Regulatory Interpretation Issues – Over 50% of respondents noted conflicting interpretations of Annex 1 requirements among different regulatory authorities, particularly regarding CCS, Barrier Technologies, and Aseptic Process Simulations.
Operational and Strategic Impact
The survey identified areas where a positive impact has been felt and some of the areas requiring further clarification, including:
Annex 1's Positive Impact – The top five areas where Annex 1 led to improvements were:
Contamination Control Strategy
Barrier Technologies
Aseptic Preparation and Processing
Aseptic Process Simulations
Pharmaceutical Quality Systems.
Areas in Need of Further Clarification – Topics where the industry seeks more clarity include:
PUPSIT (Pre-Use Post-Sterilization Integrity Testing)
Barrier Systems
Environmental Monitoring
Impact on Drug Substance/API Manufacturing
Implementation of Rapid Microbiological Methods (RMM) and AI in Pharma.
Non-Sterile Product Applications – Nearly 50% of respondents indicated that they apply certain Annex 1 principles to non-sterile products, mainly CCS, PQS, Water Systems, Cleanroom Qualification, and Environmental Monitoring.
Technical Implementation Challenges
The survey some of the technical challenges that manufacturing facilities faced when implementing Annex 1, including:
Barrier Technology Challenges – The implementation of Barrier Technologies (e.g., isolators, RABS) was one of the most difficult requirements due to its impact on facility design and operational workflows.
Pre-Use Post Sterilization Integrity Testing (PUPSIT) – About 40% of respondents stated that PUPSIT has not or will not be implemented for all processes, and about 35% stated that it has been implemented or will be implemented for all processes within the next 3 years. Interestingly, 74% of companies that will not implement PUPSIT, have not presented a risk assessment to their relevant Health Authority.
Environmental Monitoring (EM) Compliance – Companies reported challenges in meeting the new Annex 1 EM expectations, particularly for trend evaluation, alert/action levels, and continuous viable/non-viable monitoring.
Aseptic Process Simulation (APS) Struggles – Concerns were raised about APS execution and compliance, including:
Interpretation of APS media incubation timelines
Handling of interruptions during simulations
Validation strategies for isolator-based APS.
Cleanroom Classification & Qualification Issues – About 35% of companies struggled with meeting the stricter cleanroom classification and qualification standards, particularly related to airflow visualization and smoke studies.
Future Trends and Innovations
As pharmaceutical manufacturing evolves, AI, robotics and rapid microbial methods are expected to play an even greater role in contamination control. Some interesting trends highlighted include:
AI & Robotics in Compliance – Industry professionals expressed interest in leveraging AI and robotics for contamination control, real-time monitoring, and automation of aseptic operations.
Demand for Rapid Microbiological Methods (RMM) – There is growing demand for rapid/alternative microbiological methods, yet lack of regulatory harmonization slows adoption.
Increased Focus on Data-Driven Decision-Making – Companies are shifting towards advanced analytics for trend evaluation and risk-based decision-making in contamination control.
Digital Transformation & Annex 1 Compliance – Some companies are exploring digital twins, real-time monitoring, and cloud-based QMS solutions to facilitate Annex 1 compliance.
Next Steps for Annex 1 – Future updates may include more guidance on visual inspection, alternative sterilization methods (e.g., e-beam, UV), and enhanced clarity on ATMPs (Advanced Therapy Medicinal Products).
Key Takeaways
Some of the key takeaways from this important survey include:
Contamination Control Strategy (CCS) remains a significant challenge.
Barrier Technologies implementation is complex and costly.
Regulatory interpretations vary, creating compliance uncertainty.
Companies are leveraging digital solutions and AI for enhanced compliance.
The industry is calling for clearer regulatory guidance on emerging technologies.
Next Steps
The findings of the survey perfectly align with our core offering...
We assist companies to navigate the complexities of Annex 1 and Contamination Control through our CPD Certified Contamination Control Excellence Program.
To celebrate this important survey, we are making available 10 free access code to our Contamination Control Program: Fundamental.
Use Coupon Code at Checkout: Annex1Fundamental
More information and sign up to our Contamination Control Program: Fundamentals here: https://www.pharmalliance.ie/programs
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