Controlling Materials Migration using Flexible Containment

Flexible containment has played an important part in controlling fugitive releases and mitigating cross contamination. Most obvious, is wide usage at all stages of new drug development through to final processing. Less obvious benefits are practiced in the support areas of warehousing and dispensing, transportation, utility areas, and waste control.

While many development and production applications are discussed in other Technical Bulletins, and illustrated on our website, new applications continually develop. Unfortunately our commercial partners are reluctant for us to display images of their work areas, so we have to present them as verbal descriptions.

One of the greatest assets of using flexible isolators is just that – flexibility. Both new facilities and retrofits always have areas requiring containment, but with many constraints on space and headroom. Flexible isolators are custom designed to accommodate virtually any configuration, which are user friendly and economical cost.

In-process containment has become well practiced since we first partnered with a Containment Engineer/Occupational Health professional and the Technician during the design phase of a new Potent Compound Facility. They re-examined the evolution of the product to the development and scale-up process in their pilot plant. Several steps throughout the research and commercialization of drug materials required special conditions which were addressed and simplified using flexible isolators, from air and moisture sensitivity, to light sensitive molecules, simply by reducing the amount of space requiring enclosure and stmosphere conditioning. These ranged from sample splitting in the laboratory, in-process sample collection – both solid and liquid, to secure storage and transportation, at all scales conditions and size of storage for packaged goods in a warehouse, and even open material handling for integrity checks and packaging purposes. The net result was a significant cost savings, while proving able to address many otherwise untenable process situations.

More recent applications developed in the rapidly emerging Biotechnology area. Handling and incubation of specialized cell cultures is becoming an every day occurrence. Flexible isolators, both sterilized and non-sterilized are becoming commonly used enclosures in laboratory environments. The approach gives the ability to control the cell environment, e.g. air composition (CO2, O2, etc.), humidity and temperature control. Additional benefits come from ability to handle culture media during the incubation period without disturbing the growth environment which comprise, and eliminating cross contamination, since the volume within the flexible enclosure is totally isolated.

Less well known is the ability to further isolate a conditioned flexible enclosure within a second enclosure. This provides an additional barrier to minimize the effect of stray air currents such as hood and room ventilation, or door opening and people passage when stored on an open bench or cart.

The ability to safely remove a time dependent study from a hood, once prepared, is a bonus because it frees up workspace within a hood.

Using a mobile cart to store a study enables free movement within a facility, or even across a campus without fugitive release or contaminant pick-up.

Cleanup after completion of a study is a simple matter of recovering the product materials using a bag-out enclosure, which allows for safe transport and/or storage without contamination, while the enclosure itself is safely collapsed and confined to a collection point for subsequent disposal.

These benefits are expanded when the study enclosure is within a second, larger, enclosure for isolation during environmental conditioning. Enclosed bench or cart storage and shipment, without disturbing the culture environment extends study capabilities while minimizing time for intermediate transfers. This approach is also of benefit with materials having exceedingly high potency. A secondary enclosure also provides a supplementary level of containment well beyond the typical 1,000,000,000 fold containment factor experienced by practiced users.

Warehousing and dispensing benefit by creating the ability to handle highly potent compounds without costly retrofit of an existing facility other than modifying airflow patterns. Workers can use conventional protection during handling since the product is never exposed. Cleanup between lots or materials is greatly simplified since fugitive emissions are never allowed to happen; hence it is unnecessary to modify standing procedures.

Difficult handling procedures, such as open-top centrifuge unloading, have been contained by adding external connection points to the exterior of the centrifuge without affecting the validation status. Likewise, final formulation and packaging enclosures provide access for every step along the process line and are routinely practiced today.

Environmental controls, or lack thereof, can become a long term cost if measures are not taken to address them during drug development, from the bench through full-scale production, at every level of processing. Both the Seveso (Northern Italy), and later the Times Beach (Missouri), environmental disasters in the 1970’s claimed uncontrolled distribution of dioxin (2,3,7,8-tetrachlor-p-dibenxodioxin) found in soil samples. The source was traced to contamination residues produced during production of Phisohex active and herbicide manufacture. The levels of concern were at concentration of parts per billion (ppb) by weight, i.e. 1ppb =1nanogram per gram equivalent. The cleanup costs of both incidents became astronomical, exceeding the income for the product. One ppb of dioxin (molecular weight 322) equates to 3.1 X 10-9 of a gram mole per gram of soil, or ~2 X 10-14 molecules per gram of soil, water, or ~1 liter of air. This is a lot of molecules for detection as analytical procedures are enhanced. Both sites remain dormant even today. With todays knowledge the cost would be even higher because of the need to incinerate contaminated roadbeds and structures in specially constructed incinerators having a long residence time to ensure the fumes are completely destroyed. The same treatment is likely to be required for contamination by today’s small molecule products, which tend to be resistant to conventional degradation practices, to ensure their total destruction rather than degradation into other compounds of unknown toxicity.

In the 1990’s, Rudy Buser and Chris Rappe identified and reported measurable levels (ppb) of Pharmaceuticals in river waters throughout Europe. The techniques they used in the 1970’s to quantify dioxin and related contaminants at these levels were again used for these studies. Both researchers have proven to be meticulous in their studies and have set the precedent for validation of all responsible environmental reporting. The EU is still in the throes of deciding what to do about this, while local bodies are attempting to control processing and handling emissions during site licensing oversight. One can only imagine the burden of decontaminating waterways and preventing further deterioration, especially when so many of the industries products are excreted by patients. Were the same criteria established for sewage wastes that have been adopted for dioxin, the manufacturing costs could stifle the Pharmaceutical Industry. Even today, many European sites are required to collect and incinerate all liquid wastes such as those generated during manufacture of endocrine disruptors.

Failure to address such concerns can lead to long, drawn out, expensive, law suites which are difficult to defend when the primary driver is an emoyional issue. The absence of data from the manufacturer makes defence exceedingly difficult to pursue.

The old maxim of “the solution to pollution is dilution” has no validity in the world of potent, sensitizers, and biologically active compounds – dioxon being one of them because of its effect on T-cell stimulation. The lowest destruction costs are achieved when solid waste is collected and handled at its highest concentration, or further processed until the volume or mass of waste is at a minimum. This minimizes:

Volumes of materials for transportation
Special handling at the processing incineration sites
Paperwork burden
Waste manifest control
Discrete surveillance to ensure the waste contractor handles your wastes responsibly.

Simple bag-in and bag-out procedures used for spill containment are cost effective and require little operator effort compared with cleanup because of minimized distribution across uncontained, and non-cleanable room surfaces.

Liquid handling enclosures have been adopted for many utilities areas, most commonly sample loops, and process filter and piping change-out during and between operations. Since many utilities areas are out of sight, a process leak can go undetected long enough to create a major spill cleanup in an area where cleaning was never a design criterion. Strategically placed simple and low costs flexible isolators will minimize or eliminate lost worker time and volumes of cleanup waste. More extensive use of flexible enclosures contain potential leak points, e.g. valve, valve stems and actuators, flanges, sample taps, gage connections, in fact anywhere a thread or compression point is in contact with process fluids in both processing and utility areas.

Visible liquid leaks are often preceded by invisible micro-aerosol releases which are readily distributed through airborne suspension, creating widespread contamination within a utilities suite, and even further if the ventilation is provided through a common system. Adopting flexible enclosures as described above can be further enhanced using absorbent mats inside the enclosure, which will reveal build up of solids after evaporation of any solvent. In all cases, vent filters are used to allow the enclosure to breath and also collect liquid aerosol releases of >0.2 micrometer diameter through impaction and smaller droplets through diffusional collection. FabOhio Inc. pioneered in aerosol containment through their fundamental knowledge of the behavior of liquid aerosols garnered from industrial emissions control technologies.

Experience over the last 17 years with outdoor polyurethane enclosures has proven their durability in relatively hostile environments. They have been used to enclose dedicated piping, tanks, waste processing equipment (mills, pressure gauges, flanges, valves, etc.) sampling taps, and for cleaning screen used for removing suspended solids. Waste liquid filled sample bottles are delivered to laboratories for analysis protected within a polyurethane sleeve to prevent spills on roadways.

We have the experience (over 170 years of accumulated professional know-how) and knowledge garnered providing containment solutions to the Nuclear Industry anddeveloping containment solutions for the Pharmaceutical Industry since 1993. Our database of tried, tested, and proven solutions is the starting point when addressing client issues, thereby saving much conceptual time and development costs.

If you have a difficult process to contain, it is well worth your time to discuss it with a professional who has a vast experience in laboratory, pilot plant, full-scale bulk, finishing, product packaging, transportation, and environmental waste containment practices. It simply costs too much in original design, prototype development, and application when similar work may have already been done. If not with us, at all costs select a consultant with an extensive range of hands-on experience. At a minimum, repeat visits to our website usually provides food for thought.

We would be pleased to discuss your needs.

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