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The image itself is of a safety cabinet dedicated to the preparation of cytotoxics for individualised cancer infusions. In Germany, the requirements of safety cabinets and isolators used for such applications are defi ned in a relatively new version of a national standard called DIN 12980 established in 2017 [1].
Strict aseptic conditions according to GMP regulations [2] are required, as is the highest safety for the user because of cytotoxics’ CMR properties. Safety cabinets for cytotoxics, according to DIN 12980, act as a model for many other applications in pharmaceutical, biotechnological and other laboratory settings.
Air Guidance
As shown in Figure 1, the air path through the safety cabinet is driven by one or more energy-effi cient EC blowers typically located in the upper area which is called the plenum. Lab air is sucked in at the front opening. The medial air velocity must be ≥0.40 m/s according to DIN 12980. The airstream is guided under the worktop through the front grid to the fi rst and main H14-HEPA fi lter level and then through a double-walled backside up to the plenum. Here the total air volume is split into approximately 30% exhaust air and 70% recirculated air.
Exhaust air is directed to the outside through a second H14-HEPA fi lter to further protect the environment from potentially hazardous or infectious material. Through the largest and third H14-HEPA fi lter, which covers the
complete work space, clean recirculated air enters the work space as a uniform, downwards airfl ow, also called laminar airfl ow or downfl ow. The uniformity is important to prevent the spread of contaminants in a horizontal direction which can promote cross- contamination in the enclosure.
HEPA Filtration
High or ultra-effi cient particulate air fi lters (HEPA / ULPA) are basic elements of safety cabinets. Most are made from micro-glass fi bre material and can separate airborne particles like dust, aerosols, spores, bacteria and viruses effectively.
According to international standards these fi lters need to fulfi l defi ned requirements. In Europe, they must be at least class H14. That means they need to remove ≥99.995% of particles of the most penetrating particle size (MPPS) [3], typically in the range of 0.12 to 0.25 µm.
Safety cabinets for cytotoxics with three fi lter levels improve fi ltration signifi cantly because the air passing into the workspace to create the laminar airfl ow and the exhaust air is fi ltered twice.
Interaction of Downfl ow and Infl ow
The personnel and product protection function is intensively evaluated during type testing of safety cabinets with internationally harmonised and defi ned microbiological test procedures. For proof, bacillus subtilis spores are set free in different settings to document either product protection or personnel protection. In the European standard EN 12469 for microbiological safety cabinets [5] to date, only the standard settings for infl ow and downfl ow velocity given by the manufacturer are evaluated.
Other standards such as the US standard ANSI NSF49 [6] or the above mentioned new German standard DIN 12980 for safety cabinets for cytotoxics require more extensive evaluations. Figure 2 shows the scheme for varying infl ow and downfl ow according to DIN 12980:2017-05.
Airfl ow Velocity and Its Effect on Weighing
Balances in direct combination with a safety cabinet face conditions which usually reduce the overall performance of the weighing equipment, including vibrations and pressure fl uctuations caused by airfl ow. These are both typically in direct dependence to airfl ow velocity.
High-velocity airfl ow requires that the blower be run at high speed leading to a higher degree of vibration transmitted to the safety-cabinet housing and work surfaces. Therefore, all international standards during type-testing require measurement of work-surface vibrations expressed as the Root Mean Square Amplitude (RMS value) and must be ≤5 µm.
Increased downfl ow velocity is also accompanied by increased pressure fl uctuations, which add directly to vibration applied to the balance. Taken together, this is why a balance in a safety cabinet under GMP conditions for pharmaceutical applications with a required medial downfl ow velocity of 0.45 m/s ±20% always operates at suboptimal conditions.
In practice, this will be expressed in a higher minimum operating range for balances that are used in safety cabinets in comparison to the theoretical minimum weight under best conditions. It is also possible that, in the worst-case scenario, the calibration of a sensitive balance will fail completely, especially for analytical, micro and ultra-micro instruments. This makes choosing the right balance critical.
Achieving Accuracy and High Protection
Despite these diffi culties, there are several countermeasures you can adopt to adequately operate high performance balances in a safety cabinet without giving up either the highest personnel or product protection.
These include: • Use of a draft shield
• Solid worktops or enhanced integrated weighing segments. • Solid weighing stones or specialised metal plates.
Cable and Peripheral Options
Cables and connected peripherals such as power supplies or control boxes can also interfere with weighing performance. Connections between balance, peripheral devices and data- management interfaces should be kept as short as possible because space is limited inside a safety cabinet and because they increase spill risk. Connecting cables may also transfer vibrations, so any contact between cable wrappings and the balance must be avoided.
Peripheral devices can be positioned on the outside of the cabinet for reduced interference and good accessibility. They can also be integrated below the worktop or behind the back wall. Safety-cabinet manufacturers should be able to offer options that achieve short cable lengths along with integrated interfaces and connections.
Fully Integrated Balances
The most challenging solution to vibrational interference is the full integration of a balance into a special worktop. This highly specialised solution - while currently only a vision for the future - could potentially provide a signifi cant range of benefi ts including:
• Enhanced ergonomics to promote safe handling of potentially hazardous substances.
• Elimination of cables or peripheral devices, helping to provide a best-case scenario for cleaning and the avoidance of cross-contamination.
• Minimised interference with safety-cabinet airfl ow due to inherent design and elimination of cables and peripherals.
• Improved personnel and product protection through all of the above. External Infl uences
Finally, external factors can also have a strong infl uence on weighing performance, especially when using sensitive micro and ultra-micro balances. As noted above, these external factors can be caused by the cleanroom environment or the HVAC system and include temperature and pressure variations.
Figure 2. Performance testing for safety cabinets for cytotoxics according to DIN 12980:2017-05. © Berner International GmbH
These infl uences can be limited through the application of weighing best practices, including appropriate placement of the safety cabinet and observing practices that limit drafts and changes in temperature and humidity.
Addressing Challenges in the Weighing Process
The functional principle of a safety cabinet with the interaction of infl ow and downfl ow is of high importance for understanding the challenges in weighing sensitive and hazardous materials.
The primary challenge is obtaining required accuracy in an environment where airfl ow is a constant presence to ensure safety. Airfl ow requirements coupled with balance technology that addresses the need for accuracy follow.
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