Annex 1 for Small-Batch, High-Value Production

“First Air” refers to the clean, filtered airflow that must travel uninterrupted from the HEPA filter to exposed product and product-contact surfaces. Under the updated Annex 1, unidirectional airflow (UDAF) is mandatory in Grade A zones, with velocity specified at 0.45 m/s ±20% measured at the working position.

The challenge is keeping this airflow undisturbed, even around components like filling needles, which sit directly above open containers. To comply, equipment must be aerodynamically designed to minimise turbulence and capable of separate sterilisation and aseptic installation—ensuring critical airflow and sterility are not compromised.

Annex 1 places particular emphasis on minimising operator exposure and ensuring sterility when handling high-toxic products and radiopharmaceuticals. These products demand additional layers of protection beyond standard aseptic processing, both for patient safety and for the health of manufacturing staff.

For cytotoxic and radio-labelled IMPs, isolator systems are often the optimal solution. They provide a fully enclosed environment that separates operators from hazardous materials while maintaining controlled aseptic conditions. This is especially important for small-batch production, where frequent product changeovers and limited runs make efficiency and containment equally critical.

By combining risk-based contamination control strategies with modern isolator technology, manufacturers can achieve compliance with Annex 1 while also protecting personnel, reducing cross-contamination risks, and ensuring reliable supply of high-value, sensitive medicines.

At the heart of Annex 1 is a clear message: contamination control must be risk-based. A well-structured risk assessment provides the foundation for a robust Contamination Control Strategy (CCS), helping manufacturers identify vulnerabilities and implement proportionate controls. Rather than relying on one-size-fits-all solutions, a risk-based approach ensures measures are appropriate to the product, process, and facility, protecting both patient safety and production efficiency.

Effective CCS planning goes beyond documentation. The challenge lies in translating risk assessments into actionable steps, avoiding superficial or overly generic measures that fail to address real risks. This requires collaboration between quality, operations, engineering, and supply chain teams to ensure that mitigation strategies are both technically sound and operationally viable.

A critical element of Annex 1 implementation is finding the right balance between regulatory expectations and practical solutions. Over-engineering systems can introduce unnecessary complexity and cost, while underestimating risks can expose manufacturers to compliance failures. The most successful strategies are pragmatic and rigorous enough to satisfy regulators, yet achievable in day-to-day operations.

Risk-based thinking is equally vital when planning equipment upgrades, retrofits, or process changes. Whether deciding to invest in isolator technology, automate critical steps, or update environmental monitoring systems, decisions should be guided by structured risk assessments. This ensures capital investments directly mitigate the most significant risks while maintaining production continuity.

In short, adopting a genuine risk-based mindset transforms Annex 1 from a compliance hurdle into an opportunity, enabling smarter contamination control, stronger regulatory confidence, and more resilient operations.

For many drug manufacturers, legacy equipment is no longer compliant with the updated Annex 1 requirements. What once passed inspection may now fall short of the rigorous expectations around contamination control. Attempting to make older system comply brings its own set of issues: design changes, new components and requalification steps.

Another difficulty lies in the supply chain. Re-engaging original equipment suppliers for modifications can be time-consuming or even impossible, especially if models are discontinued or vendors no longer support older platforms. Even when retrofit pathways are viable, they introduce operational risks. Extended downtime during modification and recommissioning disrupts production schedules, which is particularly critical in small-batch, high-value manufacturing where every run matters.

Finally, the financial burden cannot be overlooked. High capital expenditure for new equipment or extensive retrofits puts pressure on budgets, forcing organisations to weigh compliance against investment priorities.

Risk assessments should be pragmatic and tailored to the process. While advanced solutions like gloveless isolators can reduce interventions, they come with significant cost and recovery risks. The key is to make engineering solutions appropriate and proportionate. With templates and examples widely available, the process is straightforward—but expert advice can help ensure assessments are practical and effective.

To establish and maintain sterility as required by Annex 1, pharmaceutical companies must conduct a contamination risk analysis and document it with measures in the form of a Contamination Control Strategy (CCS).

Annex 1 requires a holistic, site-wide CCS that demonstrates proactive contamination prevention. From cleanroom design to operator interventions, we guide you in building a CCS that stands up to regulatory scrutiny and supports long-term operational excellence.

Continuous, data-driven monitoring is central to Annex 1 compliance. Learn how to design programs that capture meaningful insights, integrate with digital quality systems, and provide actionable feedback for routine operations and investigations.