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USP 797 Compliance in the Laminar Flow WorkstationCabinet Design Attributes and Best PracticesChambre, Andre: CEO, Air Science LLCOctober 2016IntroductionRegulatory compliance procedures abound for the pharmaceutical industry, butperhaps one of the best-known in the compounding side of the industry is USP 797,Sterile Pharmaceutical Compounding Procedures. USP 797 compliance focuses onpractices that prevent harm or death to patients due to microbial contamination,excessive bacterial endotoxins, variability in the intended strength of correctingredients, unintended chemical and physical contaminants, or ingredientsof inappropriate quality.

Andre Chambre, CEO, Air Science, LLC.p:2October, 2016Sterile Pharmaceutical Compounding ProceduresDefinitions of TermsUSP 797 Sterile Pharmaceutical Compounding Procedures1essentially focus on maintaining air quality through the separation of contaminants from compounding materials. In relation toair quality, this typically involves maintaining a Class 5 or better(according to ISO air standards; see Table 1 below) environmentin all critical areas of compounding processes.In order to fully understand USP 797, some critical terms first needidentified and defined:Table 1. ISO Classification of Particulate Matter in Room Air(Limits are in particles of 0.5µm and larger per cubic meter[current ISO] and cubic feet [former Federal Standard No. 209E,FS 209E])*Class NameParticle CountISO ClassU.S. FS 209EISO, m3FS 209E, ft33Class 135.214Class 10352105Class 1003,5201006Class 1,00035,2001,0007Class 10,000352,00010,0008Class 100,0003,520,000100,000*Adapted from former Federal Standard No. 209E, General Services Administration, Washington, DC, 20407 (September 11, 1992) and ISO 14644-1 :1999, Cleanrooms and associated controlled environments—Part 1: Classification of air cleanliness. For example, 3,520 particles of 0.5 µm per m 3 orlarger (ISO Class 5) is equivalent to 100 particles per ft3 (Class 100)(1 m 3 35.2 ft3).Compounding personnel maintain Class 5 sanitation levelsthrough the use of primary engineering controls (PECs), whichinclude laminar flow cabinets (LFCs), biological safety cabinets(BSCs), compounding aseptic isolators (CAIs), and compounding aseptic containment isolators (CACIs). These PECs arecoupled with HEPA filtration to ensure a high level of purification.According to USP 797, one of the most important components ofany compounding sanitation system is the ability to provide “firstair”—the air exiting the HEPA filter in a unidirectional air streamthat is essentially particle-free.11.Compounded Sterile Preparations (CSPs): Anycompounded material containing sterile or nonsterileingredients or components that must be sterilized priorto administration to a patient.2. Critical Site: A location that includes any component orfluid pathway surfaces or openings exposed and at risk ofdirect contact with air, moisture, or touch contamination.3. Direct Compounding Area: A critical area within the ISOClass 5 (see Table 1) primary engineering control (PEC)where critical sites are exposed to unidirectional HEPAfiltered air, also known as first air.4. Primary Engineering Control: A device or room thatprovides an ISO Class 5 (see Table 1) environment for theexposure of critical sites when compounding CSPs. Suchdevices include, but may not be limited to, laminar airflowwork-benches (LAFWs), biological safety cabinets (BSCs),compounding aseptic isolators (CAIs), and compoundingaseptic containment isolators (CACIs).5. Unidirectional Flow: Airflow in a single direction, drawnacross filter media.6. First Air: Air exiting the filter media in a unidirectional flowthat is essentially particle-free.7.Turbulence: flow characterized by erratic or violentmovement.8. Stagnant Air: having no current or flow and containingparticulates as a consequence.“[797] Pharmaceutical Compounding—Sterile Preparations.”Revision Bulletin. The United States PharmacopeialConvention. 2008. Print.Air Science120 6th Street Fort Myers, FL 33907 T/239.489.0024 Toll Free/800.306.0656 F/800.306.0677 www.airscience.com

p:3USP797 Compliance in the Laminar Flow Workstation: Cabinet Design Attributes and Best PracticesTesting ConditionsManufacturers and third-party testing facilities incorporate avariety of initial tests to ensure HEPA filtration in products designedfor pharmaceutical applications conform to industry standardsand certifications. These tests include aerosol challenge testing,particle count testing, airflow uniformity testing and airflowpattern visualization testing.Aerosol Challenge TestingAerosol challenge testing has been used since the mid-1950’sas a means to measure the effectiveness of HEPA filtration andappears in many different standards throughout the world.Individual test conditions can vary, but the general methodinvolves challenging a HEPA filter with a reference aerosol, testingfor initial leaks around the filter frame and gasket, and then measuring the filter media downstream of the filter by using an aerosolphotometer. Commonly referred to as DOP testing, the aerosolphotometry test method is good for measurements to 0.003% andmeets most requirements within the pharmaceutical industry, yetnew technology and instrumentation allows testing of 0.0003% tobe possible.The aerosol photometer uses a near forward scattered lightchamber and a photomultiplier tube as its detection method.The forward scattered light is directly proportional to the aerosolmass concentration, which makes the instrument a continuousreal-time detector and allows an alarm point to be set for easydetection of leaks.The standard requires that the challenge aerosol is used as the100% reference for the downstream measurement and must behomogeneously mixed resulting in an even challenge to the filter.The measurement downstream of the filter is measured as percentage penetration with maximum permissible leaks of 0.01%.Particle Count TestingParticle count testing is another method of aerosol challengetesting that involves a known recorded concentration of aerosol,an aerosol diluter and a discrete particle counter. This method isnewer than DOP testing and uses a discrete particle count (DPC)test method, which is good for measurements to 0.000005% andbetter. This exceeds the requirements for the pharmaceuticalindustry and is really good only for cleanrooms ISO Class 4 andlower because the particle counter is a batch measuring deviceand not designed to make continuous measurements.The particle counter uses a discrete detector measuring the peaklight scattered height of the individual particle passing throughthe detection chamber, and cannot count two particles in thechamber at a time (known as coincidence counting). A diluterhas to be used to measure the upstream aerosol challengebecause of the reliance of this method on a low challenge.Airflow UniformityThe objective of airflow uniformity testing is to meet the criteria setfor airflow velocity and uniformity set in the design specificationsof the unit, which should not be exceeded by more than 15% onaverage. Test methods are relatively straightforward, and involvedividing the environment into a grid, with velocities measured atthe center of each square in the grid by a thermal anemometer,vane-type anemometer, or equivalent. Measurement probesshould be located at a distance of 15 cm or six inches from thefilter face or before the air encounters an obstacle. Readingsat work height are taken for informational purposes only andturbulence induced by non-aerodynamically designed objectsupstream may impede the proper and accurate measurement.Airflow Pattern Visualization (Smoke Testing)Airflow pattern visualization studies (also known as smoke tests)are conducted to confirm unidirectional airflow exiting HEPA andULPA filters, providing visual evidence of airflow direction ratherthan quantitative results. Smoke tests are a useful demonstrationand diagnostic of unit performance. The basic requirements of asmoke test are:1.Airflow moves toward potential sources of contaminationand away from the product path2. Air is flowing in a single direction with no turbulenceor eddies3. Air should regain unidirectional flow quickly from movementwithin the air stream such as attendants manipulatingequipmentThere are minimal equipment and support requirements forperforming a smoke study, which include the fogger, a videocamera, and trained personnel to perform the testing. Adheringto good laboratory processes, personnel will set the fogger up torelease smoke or fog into the unit while the video camera recordsthe results. Various laboratory procedures will be performedwhile the unit is fogged to test the ability of airflow to recover fromdisturbance and the results documented both via video cameraand anecdotal note taking. By observing the patterns of the fogor smoke as it follows the airflow, inferences can be made aboutthe airflow patterns and unidirectional flow provided by the unitduring normal operating procedures.

USP797 Compliance in the Laminar Flow Workstation: Cabinet Design Attributes and Best Practicesp:4IEST TestingOverlap of Standards and TestingThe Institute of Environmental Sciences and Technology developsrecommended practices and testing procedures for the scientificand pharmaceutical communities to meet USP 797 standards2.First air quality standards are certified based on media-fill testingas outlined by USP 797:IEST recommendations directly overlap with USP 797 standardsand incorporate additional safeguards to ensure testing meetsall identified standards. One additional IEST requirement is thatwhen performing velocity testing, airflow velocity test points cannot be placed more than 12 inches apart in order to ensure thatsuch velocity tests take into account any dead spots or areas ofstagnant air. Smoke testing is a fast and effective technique thatcan help identify areas of stagnant or turbulent air in a unit priorto the actual velocity test, allowing personnel to visualize theairflow patterns within the unit and correct any issues caused byproducts or instruments.This test or an equivalent test is performed at least annuallyby each person authorized to compound in a low-risk levelenvironment under conditions that closely simulate themost challenging or stressful conditions encountered duringcompounding of low-risk level CSPs. Once begun, this test iscompleted without interruption.While the media-fill test is utilized to certify air cleanliness andthe capabilities of individual techniques to avoid contamination, this is not typically the main test used to certify PECs. Themedia-fill test is designed to represent the most challenging orstressful conditions encountered by personnel, and when thetest simulates high-risk level compounding, the test can verify thecapability of the compounding environment to produce a sterilepreparation.Typically, filter challenge testing using aerosol and particlecounts are the main tests to perform to certify PECs. The principle of this style of testing involves comparing the number ofparticles penetrating the filter as it is scanned or challenged tothe upstream particle count. The lower the level of downstreamparticles detected, the greater filter efficiency and increasedsafety.2IEST Standards and Recommended Practices: Complyingwith USP 797 Requirements for Cleanrooms and OtherControlled Environments. The Institute of EnvironmentalSciences and Technology (IEST), 2015.Typical Cabinet Design Features to meet USP 797and IEST standardsIn order to meet USP 797 and IEST standards, most cabinetdesigns involve unidirectional flow across HEPA filters. Any disruption in the flow pattern of the air through the cabinet can resultin stagnant or contaminated air being able to come in contactwith critical sites. While there may be a variety of methods toovercome these risks, Air Science laminar flow products incorporate sound design principles to effectively meet USP 797 and IESTtesting standards.