Deciphering Pharmacy Codes <797> & <800> James T Wagner jimwagner@cenvironment.com

Learning and Performance Objectives At the end of this session, you will be able to: Breakdown the compounding facility requirement changes from current <797> to <800> and then to the <797> proposed changes Describe the types of compliant HD primary and secondary engineering controls for nonsterile and sterile HD compounding Discuss considerations relevant to the use of pass-through in HD applications Determine & Explain the tests required for certification of primary and secondary engineering controls

USP Chapters status USP <797> USP <800> Current Chapter Proposed changes USP <800> Effective date Possible changes? USP Chapters status

Engineering Controls for Containment: Definitions – USP <800> Ventilated device to minimize worker and environmental exposure For sterile compounding, the device provides product protection Containment Primary Engineering Control (C-PEC) The room in which the C-PEC is placed Containment Secondary Engineering Control (C-SEC) Adjunct controls to offer additional levels of protection Closed System Drug-Transfer Devices (CSTDs) Containment Supplemental Engineering Controls

C-PECs for Nonsterile HD Compounding Not required if only handling final dosage forms that do not produce particles, aerosols, or gases. Must provide personnel and environmental protection. Containment Ventilated Enclosure (CVE) Commonly called “powder hood” Consider ASHRAE 110 performance evaluation Class I Biological Safety Cabinet (BSC) Class II BSC or CACI also permitted Class II BSC or CACI (expensive, complicated installations, difficult to work in) C-PECs for Nonsterile HD Compounding

CVE for Nonsterile HD Compounding C-PEC not needed for nonsterile compounding if only handling final dosage forms (e.g. counting or repackaging of tablets and capsules) that do not produce particles, aerosols, or gasses. CVE for Nonsterile HD Compounding

C-SECs for Nonsterile HD Compounding Should be a different room from other preparation areas: Separate from non-HD preparation Separate from sterile preparation Occasional nonsterile use acceptable Must not occur while sterile compounding occurring C-PEC must be cleaned prior to resuming sterile compounding Must have an appropriate air exchange rate: Minimum 12 air changes per hour (ACPH) Must have an appropriate negative pressure: Negative 0.01” w.c. to 0.03” w.c. Cap of 0.03” relevance to nonsterile facilities

Engineering Controls for Sterile Compounding Primary and Secondary 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) This is the fundamental concept for establishing ISO classified spaces and for containment of airborne hazardous particulate contamination used throughout the sterile compounding and sterile manufacturing industries.

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 This is a definition from proposed changes to CETA and IEST documents. “Controlled airflow from the entrance plane of the work zone that makes a single pass along generally parallel streamlines to the exit plane of the work zone with minimal turbulence, without back-flow or re-entrainment and at a velocity sufficient to sweep particles away from critical areas.  Air is generally delivered to the work area through a HEPA or ULPA filter system or a diffuser that encompasses the entire entrance plane of the work zone.” Emphasis should be given to the entrance plane-to-return flow…and to the fact that the positioning of the returns in a vertical flow device is more important than the uniformity of the supply. Think of a string on a table; if you push if from the back, you cannot make it go where you want it to go to. If you pull if from the front you can pull it anywhere you like. We try not to use the term “laminar flow” anymore because you cannot create true laminar flow in a real life device. Even if you could, as soon as you reach into the device, you will no longer have laminar flow. True laminar flow would require the exact same velocity across the entire work area. It simply cannot be created.

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 (ACPH). Particulate contamination is reduced (not eliminated) in rooms by adding particulate free HEPA filtered airflow to the top of the room and pulling or pushing particulate contamination out to the returns and/or gaps at the bottom of the door. Ceiling mounted returns are still used (unfortunately) mostly in older installations. How can you effectively pull particulate contamination up to the ceiling. Ideally, returns are mounted low on the wall where the contamination is, near to the floor.

Facility Engineering Control Certification Certifier Qualification: NSF Accreditation CNBT Accreditation Certification reference material: Controlled Environment Testing Association (CETA) www.cetainternational.org There are currently two accreditation programs relevant to certifiers of sterile compounding facilities. A certification technician should be accredited by both. They are complimentary programs not competitive programs. The NSF program is for certification of Class II BSCs only The CNBT program is for certification of sterile compounding facilities excluding Class II BSCs CETA has many applications guides developed for the sterile compounding community relating to controlled environments. They are available for free through a qualified certifier.

Certification Current <797> Regulatory interpretations: “Certification procedures such as those outlined in …CAG-003…shall be performed by a qualified individual no less than every 6 month…” Regulatory interpretations: FDA 503A vs. 503B cGMPs BOPs USP Chapters CETA applications guides

Primary Engineering Control Certification CETA CAG-003-2006 BSC: NSF\ANSI std. 49 LAFW: ISO 14644-1 IEST RP CC 002 IEST RP CC 034 Compounding Aseptic Isolators (CAI) CETA CAG-002-006 ISO 14644-1 USP <797> states “certification procedures such as those outlined in CETA CAG-003 shall be performed by a qualified individual no less than every 6 months and whenever the device or room is relocated or altered or major service to the facility is performed. “ CAG-003 is a compilation of existing controlled environment standards. CETA references relevant sections of these standards as they relate to sterile compounding. International standards and the IEST recommended practices are general in nature. They do not give industry-specific requirements. That is provided by CAG-003. Primary Engineering Controls Specific requirements for isolator testing is found in CAG-002 (which is also referenced in USP<797>) Specific requirements for testing BSCs is found in NSF/ANSI 49 combined with ISO 14644-1(particle count procedures) Specific requirements for LAFWs are explained in CAG-003 and the specific test procedures referenced in IEST-RP CC002 &IEST-RP CC034 Airflow smoke pattern testing under dynamic operating conditions required by USP, FDA, and CETA

Secondary Engineering Certification CAG-003-2006: CETA Certification Guide for Sterile Compounding Facilities: Airflow testing: Room airflow Room segregation Airflow smoke pattern test HEPA Filter Installation Leak Test Particle Count Survey Optional tests: Light, sound, temperature, humidity “state of control points” Secondary Engineering Controls Ensuring Proper airflow volume to the cleanroom based on USP minimum acceptable values HEPA filters are leak free Room segregation (pressure or displacement airflow) “desired outcomes” Ensuring Particle count survey to ensure compliance with ISO Classification under dynamic operating conditions Smoke pattern test

Dynamic Tests Dynamic Tests (Room Objectives) require interaction between the certifier and the compounding staff Airflow smoke pattern test Particle Count Survey Dynamic smoke pattern testing and particle counting must be done with the actual compounding personnel performing simulations of the actual compounding processes Dynamic tests area required by USP Several FDA citations issued for not doing tests with actual compounding personnel under dynamic conditions Dynamic smoke tests are the best training tool possible for compounding personnel to understand how to properly set-up and use primary engineering controls

Secondary Engineering Controls Non-Viable Particle Counts Test Non Haz Buffer Anteroom C-SEC C-SCA Airflow ≥30 ACPH (at least 15 ACPH from outside the room) usually more ≥ 20 ACPH (from FDA guidance) but usually more is desirable ≥ 30 ACPH ≥ 12 ACPH for C-SCA or any area where HDs are stored Room Segregation Minimum differential pressure of 0.02” w.c. positive from buffer to anteroom and then again from anteroom to adjacent spaces Minimum differential pressure of negative 0.01 to 0.03” w.c. from C-SEC/C-SCA to adjacent space If displacement airflow (will no longer be acceptable when Proposed USP <797> becomes official), then velocity of 40 feet/minute from cleanroom to the anteroom across the entire opening Displacement airflow not allowed in HD compounding HEPA Filter Leak Test All HEPA filters in the secondary engineering controls are tested at each certification. Maximum allowable leakage is 0.01% of the upstream aerosol concentration. Smoke Pattern Testing Buffer rooms must be segregated from the ante-area and all other adjacent spaces. Use smoke around the opening of doors to ensure air is traveling in the correct direction. Non-Viable Particle Counts ISO Class 7 ISO Class 8 unless it serves HD buffer then ISO Class 7 ISO Class 7 in buffer room No ISO classification required in C-SCA Airborne particle counter used to sample particle levels in all ISO classified locations under dynamic operating conditions. Temperature Comfortable, typically a temperature of 64-66°F but Proposed USP <797> requires 20°C or cooler Humidity Not mandatory at this time but Proposed USP <797> requires relative humidity at or below 60% at all times Adapted from CETA Certification Matrix for Sterile Compounding Facilities CAG-003-2006-13, USP <797>, Proposed USP <797>, and USP <800> on 3/11/2016. Copyright © 2013-2016 CriticalPoint’s Sterile Compounding Boot Camp - All rights reserved

Traditional Primary Engineering Controls TEST LAFW BSC (NSF International Criteria) Placement of Primary Engineering Control Placed in ISO Class 7 cleanroom; 0.02” w.c. positive or SCA Placed in ISO Class 7 Cleanroom, 0.01 to 0.03”w.c. negative to anteroom (if placed in a C-SEC) or negative to the adjacent space (if placed in a C-SCA) Airflow Velocity Velocity 80 to 100 feet/minute 6-12” from the filter Downflow Velocity Profile and Face Velocity Tests HEPA Filter Leak Test HEPA filters must be certified to be free from leaks > 0.01% of upstream aerosol concentration HEPA filters must be certified to be free from leaks > 0.01% of upstream aerosol concentration or aerosol penetration not > 0.005% of upstream concentration for filters that cannot be scanned Airflow patterns smoke test An observation using smoke to visualize airflow under “dynamic operating” conditions (with pharmacy staff performing surrogate compounding) conducted to confirm that laminarity of the air is undisturbed by compounding processes. Specific smoke pattern tests to ensure the device is functioning properly is also performed under “at rest” conditions. Site Installation Assessment Tests N/A Verifies that the BSC is properly integrated into the facility by testing airflow and sash alarms; interlocks and exhaust system performance Non-Viable Particle Counts Particle counters capable of detecting 0.5 μm size particles are used to verify ISO Class 5 air conditions under dynamic operating conditions Copyright © 2013-2016 CriticalPoint’s Sterile Compounding Boot Camp - All rights reserved

Compounding Isolator Type Engineering Controls Test CAI CACI Placement of PEC Preferably room or area devoted to compounding but Proposed USP <797> requires placement in an ISO 7 area for full beyond-use dating Placed in ISO Class 7 C- SEC that is 0.01 to 0.03”w.c. negative to anteroom In C-SCA with at least 12 ACPH and 0.01 to 0.03” w.c. negative to adjacent space Airflow Velocity Measurement of actual airflow to manufacturer’s design intent. The main chamber is expressed as a range of feet/min with a designated % uniformity. Chamber Pressure Test Determines that ante-chamber and main chamber pressures adequate to provide isolator separation between main chamber and ambient spaces. Pressure range determined by manufacturer. Site Installation Assessment Tests Tests to verify proper alarm function; pass-through door interlock function; and proper canopy or exhaust connection performance. HEPA Filter Integrity Leak Test All HEPA filters in the secondary engineering controls are tested at each certification. Maximum allowable leakage is 0.01% of the upstream aerosol concentration. Airflow Smoke Pattern An observation using smoke to visualize airflow under dynamic operating conditions (with pharmacy staff performing surrogate compounding) to confirm laminarity of the air is undisturbed Preparation Ingress and Egress Test Determine if the pass-through system is capable of supporting material transfer while maintaining ISO Class 5 conditions during the transfer. Non-Viable Particle Counts Particle counters capable of detecting 0.5 μm size particles are used to verify ISO Class 5 air conditions both at rest and during dynamic operating conditions. Adapted from CETA Compounding Isolator Testing Guide. CAG-002-2006, USP <797>, Proposed USP <797>, USP <800> on 3/11/2016. Copyright © 2013-2016 CriticalPoint’s Sterile Compounding Boot Camp - All rights reserved

Primary Engineering Controls for Sterile Compounding Laminar Air Flow Systems (LAFS): 01 Restricted Access Barrier System(RABS): 02 Isolators: 03 Primary Engineering Controls for Sterile Compounding

01 Laminar Air Flow System (LAFS) LAFW: Diffuser screens Cleaning Blower placement

01-LAFS BSCs: A2 vs. B2 Canopy connections Exhaust alarms Only source of exhaust

C-PECs for Sterile HD Compounding: Class II, A2 Class II Type A2 BSC

Canopy Connection & Audible Alarm Requirement Enforced as of 4/15/2016 Class II, Type A BSC Direct-connection previously allowed now eliminated Requirement added for an audible/visual 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 exhaust alarm requirement NSF accredited field certifiers who certify a direct-connected Type A BSC or a non-alarmed canopy-connected Type A BSC will be considered in violation of the NSF code of ethics Canopy Connection & Audible Alarm Requirement Enforced as of 4/15/2016

C-PECs for Sterile HD Compounding: Class II, B1 Class II Type B1 BSC

C-PECs for Sterile HD Compounding: Class II, B2 Class II Type B2 BSC

C-PECs for Sterile HD Compounding: Class III Class III BSC

C-PECs for Sterile HD Compounding: CACI Negative Pressure CACI

01-LAFS Built-In VLF: Typically very problematic Immediate source of FDA/ BOP scrutiny What’s wrong with this picture

02-RABS CAI/CACI: Must be placed in ISO Class 7 for Category 2 (full dating) If in unclassified area, restricted to 12 hour BUD per <800> Separate rooms required!

03-Isolator (cGMP specs) Must be placed in ISO Class 8 for Category 2 (full dating) High-Integrity transfer ports Sporicidal decontamination process Min. 0.05” w.c. positive Continuously maintain ISO Class 5 (including material transfer)

HD Receiving/Storage HDs should be shipped from the distributor in zip-lock bags in totes (separate from non HD) Receiving: Must be unpacked in an area that is neutral/normal or negative pressure relative to surrounding areas Storage: Must be stored separate from non-HDs in an appropriate negative pressure environment Non-Antineoplastic, reproductive risk only, and final dosage forms of antineoplastic HDs may be stored with other inventory

Minimum Requirements for HD Storage Separate room with fixed walls Negative pressure between 0.01” and 0.03” water column (w.c.) Differs from current USP <797> which says at least 0.01” w.c. Vented to the outside At least 12 air changes per hour (ACPH) Reason for range of negative pressure WSSHE Northwest Networking Conference October 2017

Facility Design Requirements The room temperature must be maintained at 20° or cooler and a humidity below 60% at all times Temperature and humidity must be controlled through an efficient heating, ventilation, and air conditioning (HVAC) system rather than through use of humidifiers and dehumidifiers, which can contain standing water that can contribute to microbial contamination

Facility Design Requirements HEPA Filtered Air Supply “Air must be introduced through HEPA filters located at the ceiling of the buffer area containing the PEC, and returns should be mounted low on the wall, creating a general top-down dilution of area air through HEPA filtered air.” Remote HEPA banks no longer recognized as acceptable Low wall returns recommended Accommodations for leak testing

Facility Design Requirements HEPA Filtered Air Supply A minimum of 30 HEPA filtered supply ACPH for all ISO Class 7 areas negative pressure rooms Points of contamination Ante Room Negative pressure rooms ACPH augmentation from PEC Facility Design Requirements

Sterile and Nonsterile Compounding The C-SEC used for sterile and non-sterile compounding must: Be externally vented through high- efficiency particulate air (HEPA) filtration Be physically separated Have an appropriate air exchange Have a negative pressure between 0.01 and 0.03” w.c. relative to all adjacent areas

USP <800> Errata USP Expert Committee approved this change: Removes requirement that the C-SEC be externally vented through high-efficiency 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

External Venting/ Negative pressure

Facility Design Requirements Room Pressure Requirements: Proposed <797> “A minimum differential positive pressure of 0.02” w.c. is required to separate each ISO Classified area” Previous “minimum of pressure of between 0.02” and 0.05” w.c.” USP <800> “has a negative pressure between 0.01 and 0.03” w.c. relative to all adjacent spaces” Recommendation (based on FDA citations) Digital pressure monitor with audible and visual alarm at each room Calibration vs. Field Verification

Pass-Through for HD Areas Transporting materials into and out of the HD buffer room Interlocks Verify that particles do not compromise the air quality in the buffer room during material transfer FDA vs. BOP positions Pass-through refrigerators must not be used to a negative pressure buffer room C-PEC not needed for nonsterile compounding if only handling final dosage forms (e.g. counting or repackaging of tablets and capsules) that do not produce particles, aerosols, or gasses.

Containment Segregated Compounding Area (C-SCA) A type of Secondary Engineering Control: Unclassified room with fixed walls dedicated to preparation of low to medium risk level HD CSPs Defined perimeter to separate functions Limited to 12 hour BUD (proposed 797 is 12 hour room/24 hour refrigerated) PEC must be externally vented Minimum 12 ACPH (probably have to request from certifier) 0.01” w.c. to 0.03” w.c. negative pressure (request from certifier) Hand washing sink at least 1 meter from C-PEC Can be either inside or directly outside the C-SCA Note that proposed <797> eliminate low, medium, high risk level terms Note that proposed <797> allows 12 hour room temp BUD or 24 hour refrigerated BUD

Placement of CACIs All C-PECs used for HD compounding must be placed in an ISO Class 7 buffer room to qualify for full beyond-use date (BUD) allowed in <797> When a CACI is placed in an unclassified C-SCA, preparations are limited to 12 hour BUD Proposed <797> allows 12 hour room temp or 24 hour refrigerated BUD

C-PECs for Sterile HD Compounding Must be dedicated to sterile hazardous compounding … … unless the non-HD preparation is placed into a protective outer wrapper after it is decontaminated inside the C- PEC and is labeled to require PPE handling precautions C-PEC not needed for nonsterile compounding if only handling final dosage forms (e.g. counting or repackaging of tablets and capsuls) that do not produce particles, aerosols, or gasses.

Ante Room Considerations Sink Placement Size Hands-free operation LOD Gowning process Hand drying ISO Classification Appropriate activities Ideally for gowning only

Cleanable Surfaces Millwork Walls Floors Ceilings Laminate Cleaning nooks, crannies, corners, drawers Adjustable shelves Stainless steel tables shelves Walls Paint Epoxy Covered No pebbling Molding Windows Flush No openings, ledges Floors Sheet vinyl Seems welded and sealed Poured epoxy, other Smooth vs. slip resistant Coving to the wall (preferably not over the wall) Corners coved, sealed Ceilings Gyp Access panels Tiled Smooth, impervious tiles Caulked to grid Grid caulked to walls Sprinkler heads Ceiling Height BSCs HEPA change @ EdgeGard LAFWs Cleanable Surfaces