By: Mitch Valdmanis and Ron Rob
Part II: Air Cleanliness
In Part 1 of this series we discussed the importance of laminar airflow and the impacts it had on the design of RIVA’s air handling system. Laminar airflow is critical to preventing the spread of any contaminants in the airflow, but even better would be to prevent contaminants from entering the airflow in the first place. Once a clean airflow is established, it must also be maintained clean until it reaches the critical sites.
Clik here to view.
Each RIVA is outfitted with at least nine HEPA filters to ensure air cleanliness
USP<797> dictates that direct compounding areas (DCA) meet the ISO Class 5 specification, meaning that the airflow through the area must contain fewer than 3,520 particles of size 0.5μm or larger per cubic meter, equivalent to 100 particles per cubic foot. To put this in perspective, a typical urban environment is approximately ISO Class 9, or approximately 35 million particles per cubic meter. That means at least 99.99% of the particles must be filtered from the air between the outside and the compounding area. RIVA itself has been designed to be able to be placed in an ISO Class 8 environment – up to 3.5 million particles per cubic meter – of which at least 99.9% must be removed prior to the air entering RIVA.
There are two basic approaches to cleaning the air: isolation and filtration. First, the compounding area is isolated from the exterior by physical means. In RIVA’s case, the entire compounding chamber is designed to seal out the surroundings. The exterior components are tightly joined together and any seams that are not permanently sealed (by, for example, welding) are sealed with industrial grade silicone. All removable access panels and doors are equipped with gaskets to seal the openings when closed. Finally, the installation team meticulously tests each RIVA after assembly on site to ensure it is properly sealed.
Once the compounding area is properly sealed from the surroundings, clean air must be injected. This is where filtration comes in. High Efficiency Particulate Air (HEPA) filters are the workhorses of all cleanrooms. Each RIVA is outfitted with at least nine HEPA filters, most of which are rated to filter 99.99% of 0.3μm or larger particles from the airflow. Together they ensure that the RIVA compounding cell, inventory storage carousels, and inventory preparation vestibules are all provided with ISO Class 5 air or better.
Despite the effectiveness of isolating compounding cell and filtering the incoming air, it is not enough to ensure that the air present at the DCA during operation of the RIVA is sufficiently clean. Again, per USP<797>, DCAs must be exposed to “first air” – that is, air that has not been contaminated between the HEPA filter and the critical site. Herein lies the design challenge.
It was critical to layout the compounding cell such that no equipment is located between the filters and the DCAs. Equipment in this space would disturb the laminar flow and could liberate particulate or drug residue that could contaminate the critical sites. The upshot of this is that the different subsystems generally cannot be stacked vertically atop each other. During the initial design phase several concepts with stacked subsystems to allow a slightly smaller footprint for the machine were considered but ultimately rejected. With critical sites exposed downstream of the compounding activities in the cell, even perfect laminar air flow could not prevent the risk of contamination of those sites in the form of liberated particulate and cross contamination from drug residues. After review with the RIVA scientific advisory board and in light of the recommendations in USP<797> the risks to patients and staff of the stacking approach was deemed totally unacceptable.
Clik here to view.
It is critical that syringe caps be exposed to nothing but first air, lest any contaminants be caught in a cap and transferred to the fluid in the syringe. The RIVA syringe capping station is located high in the compounding cell, directly below the HEPA filters, and well away from all other activities.
Further, RIVA contains automation equipment that is potentially capable of generating particulate during operation. If not properly contained and controlled, such particulate would render the isolation and filtration of the exterior moot during operation of the RIVA. For this reason, all such equipment that may generate particulate is enveloped in covers. The space inside of the cover envelope is directly connected to the exhaust air ducts so as to be maintained at a lower pressure than the compounding area and always draw clean air into the covers. That way any particulate is contained in the exhaust air and cannot come in contact with DCAs.
One final consideration is any particulate that is generated during the compounding process itself, for example air that must be ejected from syringes that have had fluid in them. One instance of this is during the reconstitution of powder drug vials. Due to vial pressure management requirements, reconstitution diluent is generally added to vials over multiple injections, drawing syringe-fulls of air from the vial in between each injection. The air drawn into the syringe must be expunged to be able to draw the next bit of diluent. It was recognized in the design of RIVA that the air coming out would be at a high velocity and would be disruptive to the laminar airflow in the cell. It was also recognized that ejecting that air into the laminar flow environment would result in the risk of having the drug residue in it being deposited on other critical sites exposed to the airflow. A control for capturing that expelled air was deemed necessary to mitigate the risk, so RIVA was equipped with a “drip catcher” on the syringe manipulator that is used for vial reconstitution. The drip catcher is a funnel into which the tip of the needle is engaged into but does not touch, while expelling the air and fluid that may be contained in it. A discharge tube on the other end of the funnel is connected to the main exhaust air return and the suction on it prevents any air, vapor, or fluid from the syringe escaping back into the cell environment. The addition of a fluid separator in the drip catcher discharge hose provided the added benefit of having a safe and clean method of disposing of excess fluids from compounding processes such as in preparation of final volume IV bags without human intervention.
In summary, cleaning the airflow into RIVA, in particular ensuring that the airflow remains at ISO Class 5 levels with laminar flow until reaching any critical sites, posed a particular design challenge. The layout of the subsystems in the RIVA cell is a direct consequence of our unwillingness to compromise on patient and operator safety.
The final installment in this series will discuss inventory pass-through chambers and managing pressures and airflow rates in the cell. Watch this space.