Spill Prevention: Engineering Decreased Risk of Uncontained Chemical Spills

Safe solvent management and storage are significant concerns in the pharmaceutical industry, particularly when purification systems are run unattended and are supplied by large volumes of organic solvent. By the nature of the design of such systems, there is the risk of continuously pumping solvent in excess of solvent waste container capacity due to unanticipated error states, which in turn results in overflow of solvent onto instrument/laboratory benches or onto the floor of the laboratory. To mitigate the risks of possible spills involving flammable or other hazardous liquids utilized by unattended automated analytical instruments, a Liquid Overflow Prevention System (L.O.P.S.) safety device was designed and deployed on several instruments at Lexicon Pharmaceuticals in Princeton, NJ.

Lexicon Pharmaceuticals, a biopharmaceutical company located in The Woodlands, TX, and Princeton, NJ, discovers and develops treatments for human disease using proprietary gene knockout technology. This technology has led to novel drug targets and turned into multiple drug candidates currently progressing through human clinical trials, including treatments for irritable bowel syndrome, carcinoid syndrome, rheumatoid arthritis, and diabetes.

At the Princeton site, medicinal and process chemistry groups work to discover and develop drug candidates targeted to unmet medical needs. Chemists utilize open-access analytical instrumentation to perform reaction monitoring as well as purification and characterization of their compounds. This environment allows chemists to perform “walk-up” experiments on analytical instruments employing HPLC, LC-MS, NMR (nuclear magnetic resonance), IR (infrared) spectroscopy, DSC (differential scanning calorimetry), TGA (thermogravimetric analysis), PXRD (powder X-ray diffraction), and automated flash chromatography techniques, rather than submitting samples to the analytical chemistry team. This policy allows experiments to be performed rapidly, and experimental results to become immediately available.

A significant part of the chemistry work flow includes flash chromatography for purification of final and intermediate compounds. Flash chromatography consists of solid stationary phase media (often silica) packed into a cylinder (column). Sample is loaded on top of the media, and mobile phase solvents (typically hexane, ethyl acetate, dichloromethane, and/or methanol) are then pumped onto and forced through the stationary phase, washing the sample along with it in order to obtain physical separation of the desired compounds from impurities and collect them as they elute from the column. Several  automated flash chromatography systems are commercially available. These automated systems allow chemists to mechanically pump solvent gradients over flash columns with minimal supervision.

The Princeton facility has four automated flash chromatography instruments set up in two workstations with two instruments per workstation. These instruments, which utilize positive displacement piston pumps, are capable of two separate binary solvent systems. In order to provide ample solvent efficiently to two systems per workstation, 56-L containers of each of the four solvents were selected, rather than using 4-L glass bottles, which would require frequent replenishment since the instruments can each consume up to 100 mL/min of a given solvent.

The 56-L Stainless Steel Pressure Dispense System (SSPDS) solvent containers currently used in the facility are provided by Honeywell Burdick & Jackson (Muskegon, MI) and deliver high-purity solvents in a safe, environmentally responsible, and convenient package that ensures product stability over time. These features are accomplished by utilizing inert materials of construction, safety devices meeting NFPA30 requirements, and inert gas pressurization to eliminate oxygen, which would degrade the solvents. Additionally, there are no packing materials associated with shipping these containers, helping to eliminate disposal costs.

Due to the quantity and hazardous nature of the solvents being used, safety precautions have been engineered into the physical configuration of these workstations; the instruments and all containers are electrically grounded to prevent sparking due to static buildup, and containers are kept in a separate, highly ventilated “solvent room.” The instrument waste containers are all ventilated and are themselves housed in secondary containment.

Figure 1 - SSPDS in an adjacent laboratory are plumbed through the wall (A), supplied with a constant nitrogen blanket (B), and have their solvent levels monitored remotely (C).

The SSPDS reservoirs are stored in rooms adjacent to the analytical laboratories where the automated flash instruments are located that meet Class I, Division II requirements, enabling storage of over 200 L of flammable solvent. Nitrogen is fed over the solvents within the SSPDS and out through a silicon oil bubbler. This configuration prevents the generation of either a vacuum or high pressure within the SSPDS, regardless of whether the instrument is withdrawing solvent or not. This constant nitrogen blanket also prevents the solvents from being exposed to atmosphere during use (Figure 1).

These solvents are pumped by each instrument through the walls of the storage room into the adjacent laboratories through stainless steel tubing to feed the two instruments stationed there. Downstream of the pumps, the solvents move through a disposable flash column, a detector, and into a Factory Mutual (FM)-approved safety waste container utilizing stainless steel quick-disconnects and laboratory system ventilation. On this system, if the waste container overfills, the resulting liquid waste overflow is channeled into the waste container’s secondary containment.

The application of four 56-L solvent reservoir containers connected to two instruments, with a 20-L waste container per instrument, allows for the possibility of overflow of both the waste container and its associated secondary containment. An overflow or waste container leak could create a hazardous environment that requires laboratory evacuation/isolation and emergency response. This risk can be reduced by using larger waste containers (and associated secondary containment) or smaller solvent reservoirs, or redesigning the system.

Decreasing the volume of solvent reservoirs would increase the frequency of instrument solvent replenishment. More frequent changing of solvent reservoirs would increase instrument down time (decreasing overall laboratory efficiency) and reserve container storage (removing space-saving and cost advantages provided by the SSPDS). Both points are considered suboptimal for the facility’s open-access environment. Increasing the volume of the waste containers would become problematic for waste management, effectively increasing satellite waste accumulation beyond the allowable limits set forth in 40 CFR 262.34(c). In addition, this solution increases the footprint required for the waste containers within the laboratory, congesting areas frequented by users of these instruments.