UNC-Chapel Hill ENVR 754 - Method to Evaluate the Dustiness of Pharmaceutical Powders

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Ann. Occup. Hyg., Vol. 50, No. 5, pp. 453–458, 2006#The Author 2006. Published by Oxford University Presson behalf of the British Occupational Hygiene Societydoi:10.1093/annhyg/mel004Method to Evaluate the Dustiness ofPharmaceutical PowdersMARYANNE BOUNDY1*, DAVID LEITH and THOMAS POLTON21Department of Environmental Sciences and Engineering, University of North Carolina at ChapelHill, Chapel Hill, NC 27599, USA;2Pfizer Inc., 235 East 42nd Street, New York, NY 10017, USAReceived 13 October 2005; in final form 12 January 2006; published online 16 February 2006The trend among pharmaceutical companies to develop selective drugs of high potency haspushed the industry to consider the potential of each hazardous ingredient to become airborne.Dustiness issues are not unique to the pharmaceutical industry, but are relevant to any industrywhere powdered materials are mixed, transferred and handled. Interest in dustiness is alsodriven by concerns for worker health, the potential for plant explosions and the prevention ofproduct loss. Unlike other industries, the pharmaceutical industry is limited by the milligramquantity of powdered material available for testing during product development. These needshave led to the development of a bench-top dustiness tester that requires only 10 mg of powderand fully contains the generated aerosol. The powder is dispersed within a 5.7 liter glasschamber that contains a respirable mass sampler and a closed-face sampler to quantify therespirable and total dust that are generated with a given energy input. The tester distinguisheddifferences in dustiness levels of five different powders. Finer powders were dustier, and therespirable dust percentage was always less than that for total dust. Four testers have been builtand evaluated using pharmaceutical grade lactose. Dustiness measurements determined usingall four testers were comparable. The pharmaceutical industry uses surrogates such as lactoseto represent active compounds in tests that estimate the dust concentration likely to occur in anew manufacturing operation. Differences between the dustiness of the active compound and itssurrogate challenge the relevance of the surrogate tests to represent true exposures in theworkplace. The tester can determine the dustiness of both the active compound and its sur-rogate, and the resultant ratio can help to interpret dust concentrations from surrogate tests.Further, dustiness information may allow the pharmaceutical researcher to select powderformulations that present low airborne concentrations in the workplace.Keywords: dustiness measurement; pharmaceuticals; toxic powdersINTRODUCTIONPharmaceutical powders contain biologically activecomponents that are soluble in moist environmentsand are designed to produce biological effects at verylow dosages. These capabilities are beneficial to thepatient but can result in undesirable effects to theworker. Such health hazards have been recognizedsince at least the early eighteenth century whenRamazzini noted with irony that apothecary workersoften became seriously ill while ‘compoundingremedies that would restore others to health’(Ramazzini, 1713).Health risks to pharmaceutical workers are com-plicated by new drug formulations that target specificcells, interact at the gene level and express their bio-logical activity through altered protein synthesis(Binks, 2003). The enhanced specificity of these for-mulations increases their potency and emphasizes theneed to protect pharmaceutical workers. During theresearch stage of drug development, small teams ofscientists and workers involved in small batch pro-duction may be exposed to novel therapeutics (Heronand Pickering, 2003). Because these compounds areunique to one company, occupational exposure limits(OELs), threshold limit values (TLVs) and biologicalexposure indices (BEIs) are not available fromexternal authorities to guide the pharmaceuticalindustry in limiting occupational exposures.Historically, pharmaceutical industries havederived their own OELs for active ingredients by*Author to whom correspondence should be addressed.Tel: +1 919-966-7337; fax: +1 919-966-7911;E-mail: [email protected] exposure control limits (ECLs) based on ano-effect level for the most sensitive endpoint afterconsidering informations such as animal studies,bioavailability and pharmacokinetic data (McHattieet al., 1988; Sargent and Kirk, 1988; Agius, 1989).Difficulties in identifying an unambiguous no-effectlevel on which to base an ECL for these formulationshave led the industry to develop a performance-basedapproach and to set exposure limits based on engin-eering and containment principles referred to as ‘con-trol bands’ (Naumann et al., 1996; Heidel, 2001;Binks, 2003). Performance-based ECLs provide asystematic approach that involves assigning pharma-ceutical active ingredients to one of five control bandsbased on their potency, pharmacological and toxico-logical effects (Heidel, 2001). Each control band cor-responds to certain facility and process containmentstrategies that are known to provide exposure controlsufficient to protect the worker (Heidel, 2001). Inaddition to the exposure limits, highly sensitive ana-lytical methods are needed to measure workplaceconcentrations. Without this information, pharma-ceutical industries must rely upon surrogates or exist-ing monitoring data for other compounds to representworkplace exposures to new formulations.Although toxicological effects are important toconsider when establishing exposure controls, factorsassociated with the material may also affect exposureand should be considered. For example, physicalproperties will affect material dispersion. If the com-pound is a liquid and vapor inhalation is a concern,then volatility is important; volatility relates directlyto vapor pressure which can be predicted using well-established theory.If the compound is a powder and dust inhalation is aconcern, then dustiness is important. Dustiness can bedefined as the tendency of a powder to form an aero-sol after it receives a given energy input. Powderdustiness depends on many factors that affect inter-particle binding forces. These factors involve the sizeand shape of the powder particles, the powder mois-ture content and the powder surface chemistry. Evenrecent history is important as powders that have beencompressed can be more cohesive than uncompressedpowders, and powders that have been dried to reach acertain moisture content may be


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