The revision of EU GMP Annex 1 has redefined expectations for sterile manufacturing across the life sciences sector and nowhere is this felt more acutely than in the cell and gene therapy (CGT) space. With high-value, sensitive products and complex fill-finish requirements, CGT manufacturers must now rethink how they approach aseptic processes to remain compliant and competitive.
One of the most obvious areas of weakness when it comes to Annex 1 compliance is the filling of cryovials, either for reference samples or master cell banks. This activity is still routinely carried out manually by an operator in an open BSC. There are very few process checks to ensure the quality and sterility of each vial filled. Any lapses in quality or sterility may only be found several months later, once the vial has been thawed for further processing. The implication is both a time and money loss for the company. At 3P innovation, we’ve engineered our cryovial filling platform to address the most critical challenges identified in Annex 1. In particular, three key principles stand out:
Clean ‘first-air’ protection to open vials.
Minimising operator interaction through automated vial handling.
Minimising open vial exposure time.
These aren’t just regulatory checkboxes; they’re essential to ensure patient safety and product integrity.
Annex 1 emphasises that product exposure must occur in environments where air cleanliness is consistently maintained at Grade A. More importantly, “first-air” (the direct, clean airflow from a HEPA filter) must not be disrupted as it passes over critical process areas.
cryoFIL® has been designed with first-air principles in mind. Our systems ensure that the open vial is continually exposed to unidirectional, laminar airflow, with all process elements arranged to avoid obstruction. Robotic movements, nozzles, and grippers are positioned to maintain airflow integrity, even during dynamic operations. The CFD study below shows the unidirectional airflow over the open container, where minimal processing hardware is located above the open vial.
This reduces the risk of contamination at the precise moment when product sterility is most vulnerable, during open-vial exposure.
CFD image of cryoFIL®
Manual handling is one of the greatest risks of contamination, so the removal of operators from the production processes is of critical value. Our advanced automation platform significantly reduces the need for manual interactions by automating the vial handling process. This not only enhances process consistency and repeatability but also mitigates the risk of human error and ensures compliance with aseptic best practices.
The shorter a vial is open and exposed to the automation environment, the lesser the risk of contamination. Annex 1 is clear: manufacturers must minimise exposure time wherever possible and justify their approach through risk assessment.
In response to this, we've optimised our fill-finish process to enable a precisely choreographed sequence of vial uncapping, filling and recapping, ensuring consistent, fast cycle times per vial along with parallel processing of multiple vials to improve throughput. This not only supports Annex 1 compliance, it also provides operators with traceable data that can stand up to regulatory inspection.
4.100% IPC dose weight check.
The system houses an high precision weigh cell that works together with an integrated peristaltic pump, enabling accurate, closed-loop filling control. This ensures tighter fill tolerances and eliminates product loss during priming at start-up. In addition, the system can weigh every individual vial, providing a 100% dose weight check to confirm that each vial is within specification. All data is securely captured and stored in a 21 CFR Part 11, compliant batch report, marking a significant step forward in aligning cell therapy manufacturing with established biotech and pharmaceutical standards.