Engineering Controls for Compliance with USP Chapters <797> and <800> FLORIDA SOCIETY OF HEALTH SYSTEM PHARMACISTS NOVEMBER 4, 2016 JAMES T WAGNER CONTROLLED ENVIRONMENT CONSULTING
Learning and Performance Objectives At the end of this session, you will be able to: Distinguish between primary and secondary engineering controls in the sterile compounding controlled environments. Utilize knowledge about the principles of airflow to compound with proper aseptic technique using first air regardless of the type of primary engineering control. Describe the function of HEPA filters in cleanroom environments and the application of airflow principles to create a sterile compounding environment Differentiate ISO Class 5, ISO Class 7 and ISO Class 8 work environments as related to cleanliness and particulate counts. Outline the different types of laminar airflow work centers (LAFWs) that may be utilized when preparing CSPs. Integrate an understanding of the term state of control into the certification report for primary and secondary engineering controls.
Engineering Controls Engineering controls eliminate or reduce the potential exposure of a product or personnel to contamination or a hazard through the use of engineered equipment or machinery Primary: Point of use Secondary: Facility design
Definitions Positive Pressure Net displacement of air out of the space Negative Pressure Net displacement of air into the space State of Control Points Engineering issues that affect room performance i.e. provide adequate HEPA filtered air to a cleanroom Desired Outcomes Objectives of state of control engineering criteria i.e. maintain an ISO class 7 buffer room
Primary Engineering Controls Laminar Air Flow Workbench Biological Safety Cabinet (BSC) Compounding Aseptic Isolator (CAI & CACI)
Engineering Controls Engineering controls employed in sterile compounding use Airflow through High Efficiency Particulate Air (HEPA) filters to create air of appropriate Cleanliness Classification Airflow Filtration Cleanliness Classification Maintain a State of Control to obtain and confirm the Desired Outcome (Objective)
Airflow Definitions Unidirectional flow Flow control to eliminate particles from critical work sites HEPA-filtered air should be supplied in critical areas at a velocity sufficient to sweep particles away from the compounding area and maintain unidirectional airflow during operations. Laminar vs. Unidirectional
Airflow Definitions (continued) Proper design and control prevents turbulence and stagnant air in the critical area In situ air-pattern analysis via smoke studies shall be conducted at the critical area to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic (working) conditions
Airflow Definitions (continued) Turbulent flow Dilution control to reduce particulate levels Adequate HEPA-filtered airflow supplied to the cleanroom and anteroom is required to maintain cleanliness classification during operational activity
HEPA Filter Specifications IEST-RP-CC001.5 Performance Levels: Type C Filter Tested for overall penetration and have been leak tested. Minimum filter efficiency is 99.99% on 0.3 µm particles Type K Filter Tested for overall penetration per IEST-RP-007 and has been leak tested. Minimum efficiency is 99.995% at either 0.1-0.2 µm or 0.2-0.3 µm particle size
Cleanliness Classification* Class Name Particle Count ISO Class FS 209E ISO m 3 FS 209E, ft 3 3 Class 1 35.2 1 4 Class 10 352 10 5 Class 100 3520 100 6 Class 1000 35,200 1000 7 Class 10,000 352,000 10,000 8 Class 100,000 3,520,000 100,000 *Classification of Particulate Matter in Room Air Limits are in particles 0.5 µm and larger per cubic meter (current ISO 14644-1) and cubic feet (former Federal Standard 209E) measured under dynamic operating conditions.
Cleanliness Classification (continued) <797> Environmental and Quality Control Ante Area ISO Class 7 or 8 Sterile preparations must be manipulated in an ISO Class 5 environment (Class 100) or better The ISO Class 5 environment is housed in an ISO Class 7 (Class 10,000) or better environment The ante areas are at least ISO class 8 (Class 100,000) Buffer Area ISO Class 7 PEC ISO Class 5 DCA Direct Compounding Area
Cleanliness Classification (continued) Particle Count Parameters ISO 14644-1 As-built, At-rest, Operational USP <797> counts to be taken during operations Particle size USP <797> 0.5µ and larger Locations ISO 14644-1 or Federal Std. 209E Based on room size for general room classification Not more than 1 foot away from the work site, within the airflow for critical site dynamic operating counts.
First Air: Utilizing Unidirectional Airflow The advantages of unidirectional airflow should be exploited when considering placement of materials within the DCA. The use of unidirectional airflow can be used to prevent cross contamination within the DCA. First Air Zone Nothing to be placed between the HEPA filter and the critical compounding zone Zone of Confusion Turbulent area downstream of an obstruction possible source of cross contamination
First Air Improper hand placement disrupts first air
First Air (continued) Proper hand placement takes advantage of first air
Primary Engineering Controls (PECs) Laminar Air Flow Workbench (LAFW)
Placement of Primary Engineering Controls The primary engineering control should be placed within a buffer room in a manner to avoid conditions that could adversely affect its operation such as: Doors opening and closing Personnel traffic Cross drafts from HVAC Impact of other airflow devices
Primary Engineering Controls (continued) Compounding Aseptic Isolator Isolator specifically designed for compounding pharmaceutical preparations. Maintains an aseptic compounding environment inside the isolator throughout the compounding and material transfer processes. Air exchange from the surrounding environment should not occur unless the air has first passed through a microbial retentive filter (HEPA minimum). Compounding Aseptic Isolator (CAI)
Primary Engineering Controls Compounding Aseptic Containment Isolators (CACI) Designed to provide worker protection and to provide an aseptic environment. If volatile drugs are prepared, the exhaust air from the isolator should be appropriately removed by properly designed building ventilation.
Isolator Airflow Design The airflow in the PEC shall be unidirectional (laminar flow) This requirement applies to ALL PECS Turbulent Flow CAI Unidirectional Flow CAI Airflow Schematics Courtesy of Germfree Laboratories
Compounding Isolators Compounding Aseptic Isolators must be placed in an ISO Class 7 cleanroom unless they meet all of the following conditions: Must provide isolation from the room Must maintain ISO class 5 during dynamic operating conditions Transferring ingredients into and out of the isolator and during preparation of CSPs. Tests to prove above conditions are detailed in CETA CAG-002-2006
Positive Pressure CAI Most positive pressure isolators provide product protection only. HEPA filtered supply air provides at least ISO Class 5 conditions
Isolator Work-Practice Considerations Isolators may be located in either a classified or unclassified space Need to establish SOPs to reduce the chance of bringing contamination into the isolator by compromising the barrier Procedures will vary by isolator design (unidirectional vs. turbulent, pass-through) Ingress and egress of material Recovery (purge) time Cleaning and disinfection protocol
NIOSH Requirements For HD PEC Selection When asepsis is required or is the recommended work practice, the use of ventilated cabinets designed for both hazardous drug containment and asepsis is recommended The recommended ventilated cabinets include Class II Type B2, Class III BSC, and aseptic containment isolators Class II Type B2 BSC Class III BSC Negative Pressure CACI
NIOSH Requirements For HD PEC Selection Type A2 and B1 cabinets are allowed under certain conditions A ventilated cabinet with air recirculation, either within the cabinet or to the room environment, should only be used if the hazardous drugs in use will not volatize during process manipulations or after capture by the HEPA filter
Canopy Connection & Audible Alarm Requirement Enforced as of 4/15/2016 Class II, Type A BSC Direct-connection previous allowed was eliminated Requirement added for an audible alarm to canopy-connected Type A cabinets These requirements came out in 2011 but have not been enforced by field certifiers NSF encourages: Organizations using Class II cabinets to conduct internal risk assessment New cabinets manufactured must provide an alarm on these units Retrofit older cabinets in the field to conform with the audible alarm requirement NSF accredited field certifiers who certify a direct-connected Type A BSC or a nonalarmed canopy-connected Type A BSC will be considered in violation of code of conduct
Chapter <800> Requirements for HD PEC Selection All C-PECs used for manipulation of sterile HDs must be externally vented. Class II, Type A2, B1, B2, Class III BSC, and CACI are all acceptable. For most known HDs, Type A2 BSCs offer a simple and reliable integration with the ventilation and pressurization requirements of the C-SEC. A2 BSC less exhaust airflow than B2 B2 BSC adds complexity and do not integrate well in small rooms CACI risk contamination if leak in glove, sleeve or cabinet
Primary Engineering Control User Suggestions Primary engineering controls should not be turned off If turned off Requires recovery time Air-balance of room for externally vented devices Pre-filter change cycle Cleanliness of room Position of pre-filter on device Understand the monitoring gauges Magnehelic Gauge
Primary Engineering Control Applications
Primary Engineering Control Applications
Primary Engineering Control Applications
Summary Your choice of primary engineering control should be based on processes, with concessions given to protection of compounding personnel and environment. Engineering controls must be properly integrated into the facility and certified to be functioning correctly.
Secondary Engineering Controls Sterile Compounding Boot Camp
Learning and Performance Objectives At the end of this session, you will be able to: Explain the facility and environmental requirements for compounding sterile preparations for each of the three risk levels outlined in USP <797>. Differentiate the engineering controls used in the preparation of nonhazardous versus hazardous compounded sterile preparations. Summarize how the primary and secondary engineering controls work together to contribute to the overall sterile compounding facility state of control.
Secondary Engineering Controls Traditional ISO class 7 Buffer room with (Laminar Airflow Work hood) LAFW ISO class 7 Buffer room with Integral ISO class 5 Vertical Laminar Flow (VLF)
Facility Requirements The facility design must ensure: the ability to get components into the primary engineering control without introduction of contamination into the Direct Compounding Area (DCA) the ability to provide a safe working environment to the compounding staff and to protect the environment from products produced
Direct Compounding Area (DCA) No brown corrugated cardboard in controlled areas. White, plastic-coasted boxes limited to the ante-room and the hazardous drug buffer room. When unpacked from any shipping containers, components wiped down with an appropriate disinfectant (preferably a sporicidal) in general prep area or on dirty side of anteroom before moving across line of demarcation into the buffer room. Components are wiped again with sterile IPA just prior to being placed inside the ISO class 5 device. Nothing but sterile components and disinfected materials are moved into the DCA within the ISO class 5 device.
Activity of unwrapping to left or right of DCA Ante room Typically ISO 7 or 8 Buffer room Typically ISO 7 General Prep Area Non classed Wipe surfaces with sipa just prior to placing in PEC D C A ISO Class 5 PEC Wipe surfaces with agent that can disinfect (preferably with activity against mold spores)
Airflow Definitions Turbulent flow Dilution control to reduce particulate levels Adequate HEPA filtered airflow supplied to the cleanroom and anteroom is required to maintain cleanliness classification during operational activity
Secondary Engineering Controls The buffer area (a.k.a., cleanroom) must maintain at least ISO class 7 conditions for 0.5µm and larger particles under dynamic operating conditions Non-hazardous applications The ante room must meet at least ISO class 8 Hazardous applications The ante room must meet at least ISO class 7
Ante-Area Non-hazardous applications: Anteroom must achieve at least ISO class 8 conditions & be positive pressure to uncontrolled spaces Negative to compounding room
Ante-Area Hazardous applications: Anteroom must achieve at least ISO class 7 & be positive to uncontrolled spaces Positive to the HD compounding room
Secondary Engineering Controls Segregation The room must be segregated from surrounding, unclassified spaces to reduce the risk of contaminants being blown, dragged, or otherwise introduced into the filtered unidirectional airflow environment, and this segregation shall be continuously monitored. Physical separation 0.02 to 0.05 inches water column (w.c.) positive pressure Open concept (Displacement airflow) 40 feet per minute (fpm) across the line of demarcation May not be applied in high risk level compounding applications
Secondary Engineering Controls High Risk application Differential pressure controlled Low Risk application Displacement flow controlled
Secondary Engineering Controls Adequate HEPA filtered airflow supplied to the cleanroom and anteroom is required to maintain cleanliness classification during operational activity through the number of air changes per hour. Minimum of 30 HEPA filtered Air Changes Per Hour (ACPH) in Buffer Area No less than 15 ACPH must be provided as fresh HEPA air supplied through the room s HVAC system This assumes additional HEPA filtered air is provided to the room through the primary engineering control. Supply airflow typically not continuously monitored Room pressure monitored
Common Airflow Distribution Options Low wall mounted returns are somewhat more difficult to install but are a great deal more efficient in removal of airborne particulate contamination. Low wall returns should be well distributed throughout the room and ideally have adjustable louvers or dampers. Turbulent Flow Low Wall Return Supply Supply Turbulent Flow - Ceiling Return Supply Return Supply Hepa Filter Hepa Filter Hepa Filter Hepa Filter Return Return
Ceiling mounted HEPA filters Low-wall mounted returns
Common Airflow Distribution Options A mixed flow cleanroom combines the ISO class 5 unidirectional primary engineering control space directly into the ISO class 7 turbulent flow room. The ISO class 5 area should be separated from the ISO class 7 space with a physical barrier such as a plastic or Plexiglas curtain. This design option is usually more flexible for positioning larger equipment. Mixed Flow Supply Supply Supply Hepa Filters Hepa Filter Return
Ventilation Efficiency Mixed Flow Room ISO class 7 space Turbulent flow ISO class 5 space Unidirectional airflow Relief gap to low wall returns
Cleanroom Design Elements HVAC system Most existing HVAC systems do not have the capacity to handle the additional demands of a cleanroom. An experienced HVAC engineer will need: Existing HVAC drawings and specs How many people will be working in room Process equipment BTU load Airflow requirements (required ACPH for each room) Filter requirements and specs Amount of air exhausted by engineering controls
Secondary Engineering Controls All HEPA filters should be efficiency tested at the most penetrating particle size leak tested at the factory and leak tested again in situ after installation. IEST type C or K HEPA filter CETA guide CAG-003-2006 for field certification Filter leak tested and repaired
Hazardous Drug (HD) Applications Hazardous drugs shall be stored separately from other inventory in a manner to prevent contamination and personnel exposure. Minimum of 12 ACPH Negative pressure The ISO class 5 BSC or CACI shall be placed in an ISO class 7 room that is physically separated, e.g., a different room from other preparation areas, and optimally has no less than 0.01 inches water column (w.c.) negative pressure to adjacent rooms. HD Buffer rooms housing CACIs must meet the minimum 0.01 w.c. negative pressure and 12 ACPH requirements.
HD Applications (continued) The BSC and CACI should be 100% vented outside of the facility See the Ventilated cabinet section in the NIOSH Alert & <800> NIOSH Alert also on thumb drive Accommodation for facilities that prepare a very low volume of HDs (e.g.,< 5 preparations/week) and use 2 tiers of containment (e.g., CSTD within a BSC or CAI) Separate negative pressure room not needed Note that the low-volume exemption is not recognized in <800> and the exemption goes away so consider other long term solutions
USP <800> Intent to Revise USP Expert Committee already approved this change: Removes requirement that the C-SEC be externally vented through highefficiency particulate air (HEPA) filtration Section 5.3 FACILITIES AND ENGINEERING CONTROLS, Compounding will be revised to indicate that the C-SEC used for sterile and nonsterile compounding must be externally vented but the C-SEC does not need to be vented through HEPA filtration
ISO Class 5 Sources, Buffer Areas, and Ante Areas Segregated Compounding Area Low risk level CSPs 12 hour BUD Low, Medium, or High Risk Level Compounding Facility <797> limits to non-hazardous applications, <800> adds HD SCA
Low Risk with 12 Hour or Less BUD Rooms Appropriate for non-hazardous low risk compounding only Area does not need to meet environmental conditions of a cleanroom Area must have: Sink for hand washing Sink can not be located adjacent to the ISO class 5 PEC Recent study findings demonstrate sink should be more than 3 feet away from any PEC* *Hota S, Hirji Z, Stockton K, Lemieux C, Dedier H, Wolfaardt G, Gardam MA. Outbreak of Multidrug Resistant Pseudomonas aeruginosa Colonization and Infection Secondary to Imperfect Intensive Care Unit Room Design. Infect Control Hosp Epidemiol 2009; 30:25 33.
Low Risk 12H BUD Rooms (continued) Area may not: Have unsealed windows or doors that connect to high traffic or outside space Be adjacent to construction sites Be adjacent to warehouses Be adjacent to food preparation
Ceilings Epoxy-coated gypsum board (sheet rock) Anodized aluminum T grid with cleanroom ceiling tiles Tiles must be caulked in place to ensure seal Caulking of individual ceiling tiles allows caulking to be removed so servicing can occur then re-caulked Smooth, non-porous tiles that stand up to disinfectants Wall junctions coved or caulked
Copyright 2013-2017 CriticalPoint s Sterile Compounding Boot Camp - All rights reserved Use of this educational material by a 3rd party does not constitute endorsement by CriticalPoint or ClinicalIQ Lighting Cleanroom lighting Sealed Especially for negative pressure rooms Flush Mounted Easily cleaned
How will you get components in? How will you get finished CSPs out? Staff need to understand use Wall-mounted Cart pass-through
Pass Throughs Used to transfer materials from one room to another with limited particle transfer Materials of construction Interlocks Never allow both doors to open at same time
Pass-Through Usage/Location Pass-Through Position Classified to Classified Classified to Unclassified FDA Position BOP Positions
Pass-Throughs Possible solution Classified to Unclassified HFM @ unclassified area directly over outer P/T door
Walls and General Considerations Epoxy-coated gypsum board Interlocking panels made of cleanroom-compatible materials Junction with floor to be coved and sealed. No ledges, gaps or right angles that make cleaning difficult Coving and wall joint should be flush Avoid flat horizontal surfaces that can collect dust Sills Horizontal exposed piping or conduit Large door jams and window frames Cabinets; use carts restocked 1-2 times daily with essential supplies only
Floors Wide-sheet vinyl flooring with heat-welded seams and coving to side walls Must withstand continuous cleaning with disinfectant agents No gaps or crevices for microorganisms to accumulate and grow No floor drains
LOD Applications Donning Doffing HD considerations
Floors (continued) Ideally coving and/or caulking at the base of all permanently mounted fixtures to facilitate cleaning If building from scratch, suggest line/s of demarcation built into floor with different color vinyl Coving Drywall 5/8 ½
Monitoring Differential Pressure Gauges Pressure differential from ISO Class 7 to non classed area must be a cascading pressure gradient 0.02 cleanroom to gowning (anteroom) 0.02 ante to prep area
Temperature Considerations Conditions that need to be taken into consideration when considering optimum temperature Operator comfort wearing appropriate garb Product considerations Typical cleanroom temperature range: 66º F to 72º F Range recommended for compounding pharmacies based on garbing required 64º F to 68º F
Humidity Considerations The amount of moisture in the air is critical. The factors to consider are: Microbial growth Effects on product and process Worker comfort Static electricity Typical values of cleanroom humidity range from 30% RH to 60% RH
Other Considerations Careful consideration should be given to placement of particle generators such as computers, printers and refrigerators. Material storage and prep Hand hygiene Gowning Line of demarcation
Facility Engineering Control Certification Certifier Qualification NSF Accreditation CNBT Accreditation Certification reference material Controlled Environment Testing Association (CETA) www.cetainternational.org Do not allow certification personnel into your controlled environments without completing hand hygiene and garbing!
Summary Consider all of the primary engineering control options before designing the facility Design the facility to positively interact with your chosen primary engineering control