How robotic isolator technology aligns to Annex 1 principles

The standards for pharmaceutical manufacturing are constantly rising. New and innovative drug products—like mRNA vaccines and cell and gene therapies—require extremely high precision and control in the manufacturing process. This is especially true of the crucial, final step of aseptic filling, where robotic gloveless isolator technology is playing an increasingly important role.

The European Union’s (EU) Annex 1 guidelines are part of the EU’s standards of Good Manufacturing Practices (GMP) (1, 2). Annex 1 sets a high bar for contamination control in pharmaceutical manufacturing. In the case of aseptic filling, robotic gloveless isolators offer an exceptionally high level of automation and eliminate human intervention to reduce contamination risk. Therefore, this technology offers a straightforward path to Annex 1 compliance.

Here are six ways robotic gloveless isolators align to the guidelines set forth in EU Annex 1.

Contamination control strategy (CCS)

Many considerations go into a CCS to minimize the risk of microbials, pyrogens, and nonviable particulates. Are operating conditions held constant?
Are robust in-process controls used? How do the methods and frequency of environmental monitoring align with Annex 1? Robotic gloveless isolators provide control over these factors, and substantially reduce variations in process, control, and operating parameters, maximizing run-to-run consistency and minimizing product exposure.

Process and monitoring systems

Annex 1 establishes detailed standards for grade A sterile environments, including air handling, material transfers, and continuous monitoring of viable and nonviable particles. Aseptic filling occurs in grade A zones with unidirectional airflow, aseptic connections, and a strict limit on particles larger than 0.5 µm. To achieve these standards, Annex 1 emphasizes the use of isolators and barrier systems.

Continuous improvement

Annex 1 calls for the continuous improvement of manufacturing and control methods (§ 2.3). Robotic gloveless isolators represent numerous advancements in robotics and automation, machine learning, and in some systems, complete environmental isolation. In these ways, robotic gloveless isolators bring continuous improvement to aseptic filling. The use of robotic gloveless isolators in combination with continuous real-time environmental monitoring of viable and nonviable particles offers additional opportunities for continuous improvement.

Quality risk management

Annex 1 requires thorough quality risk management (QRM) to prevent microbial, particulate, and pyrogen contamination. Robotic gloveless isolators support this with unidirectional and steady airflow in the filling chambers, consistent fill volumes, and repeatable process tolerances for every vial, cartridge, or syringe filled. Robotic gloveless isolators also remove manual interventions, the single largest source of variation and contamination, vastly reducing risk to support a robust QRM program.

Use of appropriate technologies

Annex 1 guidelines recommend, “The use of appropriate technologies (e.g. restricted access barriers systems (RABS), isolators, robotic systems, rapid microbial testing and monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of particulate and microbial contamination (§ 2.1.i).” Robotic gloveless isolators provide contaminant detection, bio-decontamination, unidirectional airflow, and other features appropriate to Annex 1’s requirements.

Automation

Annex 1 states that, “Robotics and automation of processes can also be considered to eliminate direct human critical interventions (§ 8.10),” and recommends automated control of the decontamination process. To this end, robotic gloveless isolators commonly employ vapor-phase hydrogen peroxide to maintain an aseptic environment. They can also optimize spatial configurations for drug filling to reduce cleanroom space, enhance filling speeds, and minimize product exposure.

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