Why You Suspect Fugitive Releases Yet Your Sampling Shows None

Working with API’s and intermediates having high potency, i.e. worker exposure guidelines of <μg/cu.m is not business as usual. Several factors come into play that would have negligible effect on particle concentrations in the mg/cu.m range as long as they are >0.2 μm diameter range, i.e. excluding nanoparticles at these concentrations. The smaller a particle size, the higher the surface area. API bulk and product finishing processes frequently involves particle size reduction to improve bioavailability. This leads to sub-micron particle formation. The consequences of non-quantitative sampling for sub-micron particles is a serious deficiency in the ability to anticipate where problems arise and their outcome.

The following observation are based on occurrences during investigation of incidents by a number of investigators:

1975 – Investigation of a lung disease caused by an Thermophilic Actinomycetes (later to become known as Legionnaires Disease after its occurrence in a hotel in Pennsylvania in 1976) led to a previously undisclosed fact. The sampling media traditionally used for sampling particulates, both solid and liquid, were found to be incapable of collecting the smaller particles (<0.2 μm diameter). The mixed cellulose ester filters perform the same as conventional High-Efficiency Particulate Air (HEPA) filters used for both ventilation and respirator use. When alternative methods were adopted to collect the sub-micron particles the resulting mass of airborne oil mist was >100 times higher than using conventional sampling methodology. When these same methods were used in other environments where particles were generated using high shear or condensation conditions, e.g. coal tar pitch volatiles, welding fumes, mining operations, the data was always at least 100-fold higher than conventional filter sampling data.

Filters are tested using a liquid aerosol of 0.35 μm diameter or larger (formerly dioctyl phthalate but recently replaced by Emerson 3000 or comparable material). This philosophy is the basis of ventilation and respirator filter testing, both for laboratory and documentation of performance. Filter manufacturers have been long aware that these filters have a breakthrough efficiency of >95% for particles of <0.2 μm diameter, which is why they are tested at 0.35 μm diameter efficacy. This has previously been of little concern since the HEPA filter challenges at major user sites (the food and oil industries) do not generate a large amount of sub-micron particulate, unlike current processes used in drug formulation, nanotechnology, and biotechnology.

The 0.8 and 0.45 μm mixed cellulose ester filters are typically used because of their low pressure drop demand. Microporous filters place a high pressure drop demand on battery operated pumps and are used for specific applications, e.g. sampling for crystalline silica where the filter has to be clarified during the analytical process.

Environmental research has focused heavily on this issue, and use of impaction methods to evaluate sub-micron components is common, but this is typically outside the realm of conventional Occupational Health practices. Environmental Protection Agency (EPA) has adopted standard methods for emissions measurement which the Occupational Health practitioners would be well advised to evaluate. Using impaction techniques to measure condensed liquids and solids becomes the method of choice to gain a fuller understanding of the work environment.

Late 1970’s – The National Institute of Safety and Health (NIOSH) began a campaign to establish guidelines regarding representative sampling. taking into account varying airflow rates encountered in the workplace. EPA sampling strategies require isokineticity (matched airflow rate) performance of 90% for industrial compliance and 95% for their research and development contractors. They have the advantage of industrial processes that tend to run on a continuous basis at relatively steady flow rates.

Add to this the fact that all sampling methods are inherently size selective based on the particle size cutoff as related to airflow entrance velocity and we are left with a dilemma. Practitioners often vary sampling airflow rates based on method sensitivity demands – more sample mass collected converts to enhanced method sensitivity, but at the cost of changing the method parameters. Some methodology, e.g. the original Standardized Measurement of Particulate Airborne Concentration (SMEPAC) and the updated version published by International Society for Pharmaceutical Engineering (ISPE) allow this variation unless using the Institute of Occupational Medicine (IOM) sampling device. The latter is optimized by having a total sample device opening of 9 mm at the specified sample rate (1.9 liters/min. ±10%)  to match the airflow rate approaching a worker entering a drift mine, i.e. a constant entrance velocity with no allowance for variable airflow rate. This is a preferred method since it allows for more reliable comparison between samples than when using optional sampling rates, but still not a true measure of the actual particulate mass.

By convention, particulate sampling using light scattering is used for qualifying clean rooms. Even this methodology is subject to low results since particles smaller than the wavelength of light are not measured. The method has the advantage of sampling at a constant rate almost matching the 95 linear ft/min entrance velocity of IOM sampling.

ca.1983 – Swedish researchers presented a paper at the American Industrial Hygiene Conference revealing the effects of the thermal convection gradient surrounding body parts, with emphasis on the hand, arm, and sleeve. Their video clearly showed condensed (fog) particles ascending up the sleeve of the worker ending in the vicinity of the workers breathing zone. Particles captured in this flow path remained there regardless of a high rate of air exchange access the work zone.

1995 – A matrix sampling study revealed that a researcher working with a potent compound in a performance tested laboratory hood left a trail of contamination between his hood and the shared balance room. The concentrations were highest at the hood opening and the balance area. The researcher followed written procedures for protective clothing use at each location. Contamination was identified on his laboratory coat from just below, to just above, the top of the hood opening. A subsequent study was conducted while tracking the researcher to observe work practices. A similar contamination profile was detected, yet the operator appeared to follow procedure. The conclusion was that over-sleeves and apron are a necessity for work performed in a standard bench hood. In addition, protective garb and gloves need encapsulation before removal and disposal inside the hood

1997 – Studies to measure the efficacy of ventilated enclosures were conducted using a dust effusor to introduce milled desiccated lactose of ≤3 μm diameter in the same configuration as the gas infuser used in standardized ASHRAE testing. The enclosures were in conformance with airflow operating requirements, as tested by an independent agency. Air clearly entered, and exited, the enclosure at recommended flow rates. The lactose feed rate was 4 mg/ cu.m throughout the duration of the 30 minute test cycle. Samples taken in the breathing zone of the static mannequin showed less than detectable concentration of lactose (<0.4 μg/cu.m) for all enclosures.

After 3 test cycles of the enclosures, both balance enclosures and Biological Safety Cabinets (BSC), a clear pattern of material deposition was revealed on the inside of the enclosures in front of the mannequin. The particulate flow crossed the path normally occupied by the hands and sleeves during routine manipulations. Addition of air vanes to the front edges of the balance enclosure served to disperse the pattern, but not eliminate it. In the streamlined airflow BSC enclosure, the emissions from the effusor were efficiently collected and drawn to the exhaust slots in front of the mannequin. The pattern again revealed that the workers hands and sleeves would be in the path of the full flow of contaminant, while the midriff is subject to particle bounce effects. In all cases the midriff was prone to contamination due to the focusing effect displayed by airflow disturbance.

Summary

Conventional sampling does not represent the airborne load of <0.2 μm diameter particles. Data for <0.2 μm diameter particle airborne concentrations is scarce.

Collectively these observations lead one to the conclusion that particles in the <0.2 μm diameter range exhibit anomalous behavior attributable to colloidal suspension patterns. The surface charge (zeta potential) inherent in the formation of these particles has major impact on their behavior. All containment systems having physical openings are subject to one or more of the failure modes described below:

  1. regardless of open front enclosure performance criteria, activities outside the enclosure will have a profound impact on containment results
  2. <0.2 μm diameter particles do not agglomerate
  3. <0.2 μm diameter particles repel each other
  4. <0.2 μm diameter particles are repelled from like surfaces, e.g. already plated with identical particles
  5. <0.2 μm diameter particles will bounce when they contact a surface
  6. t<0.2 μm diameter particle are not collected on conventional filters
  7. <0.2 μm diameter particles are not detectable using light scattering
  8. <0.2 μm diameter particles have high potential bioavailability relative to their mass
  9. <0.2 μm diameter particles are immeasurable by conventional means since they have characteristics that lead to passing through the smallest mechanical opening without hindrance
  10. once an escape pathway is created they have propensity to continue to progressively build up deposition on external surfaces, and to contaminate ventilation systems

For more information on sampling for <0.2 μm diameter particles, contact FabOhio, Inc.

A paper on the topic "The Nano-particle Conundrum" was presented at the 2nd NANO CONTAINMENT SUMMIT HELD ON October 27, 2015.

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