Effective Strategies for Designing, Building, and Maintaining a USP / USP Compliant Sterile Compounding Facility 34th Annual CASHE Seminar

September 2016

Presented by

Leach Wallace Associates, Inc. &

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Why USP ? • Prevent harm to patients resulting from microbial bioburden, excessive bacterial endotoxins, content error, incorrect ingredients, or contamination of compounded sterile products • Protect operators and environment from Hazardous Drugs • Earlier efforts were disappointing since USP 1206 was voluntary and initial USP & versions were confusing and not comprehensive • Risk Management due to lack of QC/Quarantine • Roadmap for achieving documented a state of control over pharmacy

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New England Compounding Center (NECC) 2012 • Fungal meningitis outbreak from contaminated drugs, produced with expired ingredients under unsterile conditions • Tied to the deaths of 64 people and to illnesses in over 700 patients in 20 states. • NECC- shipped materials to 7 facilities in MD infecting 26 people and killing 3. • 14 people charged • Co-owner/head pharmacist, and its supervisory pharmacist, charged with 25 acts of second-degree murder in seven states, plus additional crimes

NECC FDA 483 Findings • Company shut off air conditioning at night • Bacteria and mold found in cleanrooms that exceed action limits • No identifications of bacteria/mold • No corrective actions or product impact investigations • Certain controlled areas were visibly soiled with damaged pass through gaskets

USP History Sterile Compounding Standards • 1992 First Standard proposed in PF18(2) April 1992 • 1996 Revised in USP23-NF18 5th supplement General Chapter • 2003 First Published in USP27-NF22 • 2004 1st version released • 2007 Revision Released • Official June 2008 • Next revision out for public comment September 2015 • Next steps include release of revised USP with substantial changes

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USP Major Changes • Removal of references to Hazardous Drugs • Defined Temperature & Relative Humidity Requirements – 20°C (68°F) or cooler – < 60% RH

• No in-room humidifiers or de-humidifiers • Defined interval for Environmental Monitoring- Monthly

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USP History General Chapter History• Part of USP 2004, 2008 • March 2014- 1st revision published for comment • October 2015- 2nd revision published for comment • February 1, 2016 Official- grace period current expected date for compliance- July 1, 2018 • Each State Board of Pharmacy will determine effective date-TBD

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Enforcement • Recognized as the national standard of practice • Enforceable by the FDA and 28 State Boards of Pharmacy and counting • Board undergoing training for inspectors • Inspectors will want to see how the “system” addresses excursions and adverse events-now in COMAR for MD • Virginia Board of Pharmacy Guidance Document: 110-36 • National Association of Boards of Pharmacy (NABP) taking active role in supporting guideline enforcement • JCAHO

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Overall Regulatory Trends • Expectation of Facility Improvements • Documented State of Control verified by data • Boards of Pharmacy want self reporting of adverse events • Regulators expecting compliance– Pharmacies tasked with creation/maintenance of Quality Program to maintain compliance (FDA like mentality). • USP chapters on compounding are federally recognized as the standard of practice in the U.S. - full stop 9

USP/ Compliance Model Procedures

Documentation

Facility Design

CONTROL

Personnel Practices

Environmental and Personnel Testing

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Facility Requirements-Design • • • • • • •

Temperature and humidity Positive pressure Negative pressure (Hazardous Drugs) Air changes Cleanable surfaces Sealed wall and ceiling junctures Appropriate equipment and essential activities only

Facility Requirements-Air • ISO Guidelines for clean areas must be met • ISO Class 5 Laminar Flow Hoods or BSCs • ISO Class 7 for Buffer Area/Cleanroom • ISO Class 8 for Anteroom (nonchemo) • Viable limits specified

Facility Requirements-Equipment • Hood and HEPA Filter Certification at 6 month interval • Calibration • SOPs • Documentation

Cleaning • Specifies procedures for routine cleaning, decontamination, deactivation and disinfection of the room(s) and Containment-Primary Engineering Controls (C-PEC)/Hoods. • Details location of dedicated cleaning equipment- no mop sinks! • Must be considered when selecting floor and millwork finishes

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Environmental Quality & Control • Air Quality – Viable – Non-viable • Differential Pressure • Surface Testing • Temperature and Humidity • Action and Alert limits

USP Challenges/Considerations • Square footage requirements and thorough analysis of personnel and material workflows critical in design/re-design process • Renovation vs. New Construction • Dedicated Exhaust and/or Air Handling • Back Up Power • Temp/RH • Detailed understanding/completion of SOPs prior to facility completion- cleaning, EM • Commissioning/As-Built verification • Facility Change Control

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USP Hazardous Drugs in Healthcare Settings • Comprehensive approach • Harmonization with 797 (sterile) and 795 (non-sterile) • To protect the patient, healthcare professional and environment

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USP Facility Design • • • • •

Restricted access Unpacking Storage Spills Non sterile and sterile compounding • No Positive Pressure Areas for Hazardous Drugs 18

USP Facility Requirements • Compounding areas away from breakrooms, refreshment areas, staff, patients, or visitors. • SEPARATE designated areas shall be available for: – – – –

Unpacking HDs* Non sterile HD Compounding Sterile HD Compounding Storing HDs (unless buffer area is used)

*Designated HD handling areas shall be segregated from non-HD areas. Unpacking HDs from external shipping containers shall NOT occur in an area used for sterile compounding. HDs shall not be stored, unpacked, compounded or otherwise manipulated in an area that is positive pressure relative to the surrounding areas. No LFH or CAIs can be used. 19

USP Storage • Storage (unpacking) room must be negative pressure, 12 ACH, and vented outside. • Cannot store on floors. • HDs stored in manner to prevent breakage or spillage • Substantial challenge for most pharmacy floor plans. • Specified PPE

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USP Facility Design Three options for sterile HD compounding 1.

2.

3.

Containment secondary engineering control (C-SEC): ISO Class 7 or better room that serves as a buffer/cleanroom, and ISO Class 7 Anteroom. Negative pressure required to provide containment. Anteroom is positive pressure to maintain cleanliness. All rooms minimum of 30 Air Changes Per Hour AND VENTED OUTSIDE. Containment segregated compounding area (C-SCA). Limited for use with a BSC (VENTED OUTSIDE) when preparing low or medium risk level CSPs with 12 hour or less BUDs. Negative pressure to provide containment. Minimum, 12 Air Changes Per Hour AND VENTED OUTSIDE. Containment segregated compounding area (C-SCA). When using validated CACI (VENTED OUTSIDE), BUD based on risk level. Negative pressure to provide containment. Minimum, 12 Air Changes Per Hour, AND VENTED OUTSIDE. 21

Hazard Communication Program • Required by OSHA • Employers required to establish policies and procedures to ensure worker safety in all aspects of distribution of drugs as part of OSHA Hazardous Communication Standard (HCS) • Specifies PPE for each activity associated with receiving, handling, stocking, compounding, administering, clean up, and spill remediation.

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Cleaning • Specifies procedures for routine cleaning, decontamination, deactivation and disinfection of the room(s) and Containment-Primary Engineering Controls (C-PEC). • References Cleaning Section of USP • Specifies PPE • Must be considered when selecting floor and millwork finishes

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USP Challenges/Considerations • Square footage requirements and thorough analysis of personnel and material workflows critical in design/re-design process • Renovation vs. new construction • Dedicated Exhaust and/or Air Handling • Temp/RH • Segregated Storage in its own room • External venting- hoods/rooms • Differential Pressure requirements • Detailed understanding/completion of SOPs prior to facility completioncleaning, EM • Commissioning/As-Built verification • Facility Change Control 24

CSP Considerations • Usually consist of an area within the pharmacy but separated by walls and hard ceilings with clean and dirty areas and a clean ante room • Direct Compounding Area (DCA) is the actual compounding work surface – Usually inside a hood in a clean air buffer area • Mixing of sterile products are prepared in an ISO Class 5 or better environment • Products have a shelf life of 30-48 hours

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General Pharmacy Design Criteria • • • • •

4 ACH 2 OA Positive pressurization Temperature 70°-75°F RH < 60%

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Architectural Considerations • Seamless Flooring • Drywall Ceilings – Eliminate or minimize access panels – Place dampers, junction boxes out of room – Provide remote HEPA module fan speed switches below ceiling • Door Sweeps/Seals • Pass-Throughs (Sealed) • Sink Locations • Eyewash Locations • Powered Door Operators

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Example Pharmacy

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Environmental Design Requirements • Sterile Compounding Rooms – Temperature: 68°F • Continuous Visual Monitoring/ Trending Required – Humidity: Maximum 60% • No minimum humidity level indicated Room

Pressure Relationship

Additional Requirements

Chemo Clean Room

Negative (-0.02” W.G.) to Ante Room

ISO 7 Ante Room

Admixture Room

Positive (+0.02” W.G.) to Ante Room

ISO 8 Ante Room unless shared with Chemo Clean Room

Ante Room

Positive (+0.02” W.G.) to Adjacent Corridor/ Space. Negative to Clean Rooms.

Unpacking / Storage

Negative (-0.02” W.G.) to Corridor/ Adjacent Space.

USP

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Room Air Change Rates and Filtration Requirements VELOCITY & AIR CHANGE RATES FOR SELECTED CLEAN SPACE CLASSES Space Classification ISO

Federal Standard 209E

Average Room Velocity (fpm)

Air Changes per Hour

Filtered Ceiling Coverage

5

100

40-80

240-480

100%

7

10,000

10-15

30-60

5-40%

8

100,000

1-8

5-30

--

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Cooling Loads • Cooling Load Calculations – Room Envelope • Walls • Roof Load – Internal Loads • People • Lighting Equipment • Hood(s) – Heat Gain from Fan-Powered HEPA Module Fans – Consider Source • System 24/7/365 • Typical Outpatient Facility HVAC systems operate on occupied/unoccupied modes 31

HVAC Systems: Air Handling Systems • Typical In-Hospital Systems – Operate 24/7/365 – Higher Percentages of Outdoor Air • To accommodate Chemo Hood and Unpacking Room makeup air requirements

– Reheat Systems • 60% Maximum humidity threshold ok with 68°F Room Temperature

• Typical Outpatient Systems – DX (Direct Expansion) – Designed for minimum outdoor air – Additional features/controls are needed to maintain maximum 60% space humidity due to increased outdoor air • Digital scroll compressor(s) for capacity control • Hot gas reheat/ dehumidification controls

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HVAC Design Options • ISO 7 Clean Room – Compounding within an ISO 5/ Class 100 Clean Room • Room Air Change Requirements – 30 to 60 Air Changes Per Hour • Provide “House” airflow for cooling loads and pressurization requirements • Air Change Requirements provided by ceiling-mounted fanpowered HEPA modules

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Airflow Summary

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Airflow Schematic

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AIRVELOPE Model 39

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Compounding Airflow

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Electrical Design Requirements • Emergency Power – – – – – –

HEPA Fan-Powered Filter Modules Chemo Hood Chemo Hood Exhaust Fan USP Room Exhaust Fan Room Pressure Monitors Sealed Lighting Fixtures

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Key Questions for Pharmacy Management • Does our facility meet requirements? • Do our personnel and material workflows work with or against our specific facility and engineering controls? • Do we have a documented state of control? • Do we identify, investigate, correct and document adverse environmental events? • Does the C-Suite understand the risk associated with non-compliance? • What is our compliance budget/resources?

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Resource Impacts on Pharmacies • Investment in facilities to meet regs. • Investment to ensure as-built conditions • Investment in establishing robust Quality System/Program based on regs., then id resources to execute and maintain • Investment of resources/infrastructure to respond to adverse events and regain state of control • Staff buy-in to create/maintain a culture of compliance • Can small satellite/oncology practices afford compliance?

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Questions • Jeff Lange, Quality Solutions, LLC, [email protected], 410-852-5267

• Bob Leach, Leach Wallace Associates, Inc., [email protected], 410-579-8100 • Chris McCarthy, Leach Wallace Associates, Inc., [email protected], 410-579-8100

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