Annex 1 and First Air: Prioritizing Product Defense in Aseptic Manufacturing
The following article is part 1 of a blog series that has been adapted from AST’s VP of Sales and Marketing Josh Russell’s recent article in Cleanroom Technology.
One of the important points of emphasis in the revised Annex 1 is the regulatory codification of air handling guidelines and parameters, including the First Air principle. The stakeholders behind the Annex, last revised in 2008, took the opportunity to delve into greater specificity in prescription, application, scope, and language, in harmony with other prominent guidelines (“unidirectional” in place of “laminar” as an example1).
It’s clear that the regulation seeks to be cohesive, coherent, and exhaustive. While segmented, enumerated by section, the regulation is better viewed as a whole. And indeed, many of the new and augmented concepts within Annex 1, whether it’s the concept of a Contamination Control Strategy, the updates on environmental monitoring, air handling/airflow requirements, or the expanded focus on barrier technology, they all work together to address the central concern of the document: the safe manufacturing of sterile products. That’s where the collective efficacy of the concepts and parameters laid out in Annex 1 are evident.
Many are looking at these requirements through the lens of operational realities and day-to-day challenges. Taking the holistic perspective, a helpful guiding question is: What strategies must be implemented to harmonize the actions necessary for the integrity and protection of critical zones with the necessary operations and processes of sterile manufacturing? When critical zones are accounted for and prioritized in the design and execution of sterile production processes, then the safety and quality of the product is a repeatable, expected outcome.
This is where the quality of First Air becomes crucial. An indispensable aspect of proper aseptic technique, First Air, is defined generally as uninterrupted unidirectional filtered airflow, and specifically in Annex 1 as:
“… filtered air that has not been interrupted prior to contacting exposed product and product contact surfaces with the potential to add contamination to the air prior to reaching the critical zone.”
First Air as a concept is specified in name or function by multiple regulatory bodies and pharmaceutical organizations, including USP, PDA, ISO, and the FDA,2 amongst others, and its inclusion in the revised Annex 1 is evidence of the continuing global harmonization of standards across regulatory bodies. But how does unidirectional airflow interact with a critical zone from an operational point of view?
First Air speaks to the quality necessary to protect a product and maintain the integrity of a critical zone, and unidirectional airflow is the mechanism by which that happens. Annex 1 specifies that the airflow should be homogenous and sweep away from the product continuously at a specified and validated velocity. Originating as a principle of product protection during manual aseptic manipulations, First Air has long been considered necessary to maintain Grade A air over exposed and unsealed sterile products. With the advancements in technology, specifically isolator technology, First Air has been further strengthened by localized unidirectional airflow, an attribute Annex 1 highlights (4.4). The air handling attributes and low-risk environments offered by isolator technology have led to a marked change in the expectations around aseptic processing operations. This is reflected in Annex 1, which advocates explicitly for aseptic processing within an isolator or lesser barrier technology unless scientifically justified (4.3). Regulatory bodies like the FDA have also indicated that the justification should be strong, and such situations should be the exception.
And as those higher standards show, no one operational element or tool ever stands alone. The holistic approach outlined in Annex 1 invokes an important point: The entirety of the aseptic processing program should work towards the single goal of the safe, repeatable aseptic production of a product. The CCS, process design, and technology should all work to support the integrity of critical zones and the efficacy of First-Air defense.
In actual real-world settings, then, how can operators ensure First Air remains at its most effective and uninterrupted over critical zones? And what tools are available to industry professionals to design and evaluate aseptic processing solutions? Stay tuned for part two of our First Air series.
Reach out to one of our team members today for an in-depth walk-through of our aseptic manufacturing solutions.
1 This reflects common language used by other regulatory bodies including ISO, FDA, USP, and PIC/S.
2 USP 797 & 800, PDA TR 90, ISO 13408, ISO 14644, and FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing
