Compounding Pharmacy Cleanroom Design for USP FDA Compliance Chris

Compounding Pharmacy Cleanroom Design for USP/FDA Compliance Chris Munoz, Pharm. D

Why Are We Here Today? 1

New England Compounding Center 2

Our Goal: Demystify the Regulations 3

The Hard Facts About the DQSA 4

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2014 FDA/State Meeting 6

2014 FDA/State Meeting 7

Current Good Manufacturing Practice (c. GMP) 8

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c. GMP Guidance (Draft) 10

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c. GMP Guidance (Draft) 12

Today’s Regulatory Environment 13

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2015 FDA/State Meeting 15

2015 FDA/State Meeting 16

Section 503 A: Traditional Compounding Pharmacies 17

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ASHP Guidelines 19

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503 A Final Guidance 21

503 A Final Guidance 22

Quick Recap Before We Move On to USP 23

State Oversight: USP <797> (Under Revision) 24

USP <797> Draft 25

State Oversight: USP <800> (Draft) 26

USP <800> Draft 27

USP <800> Draft 28

USP <800> Draft 29

Compounding Cleanroom Design Mike Buckwalter Terra Universal, Inc.

Regulators: Who says what’s clean? Regulations & agencies that provide guidelines on cleanroom standards & practices: Regulation/Agency Industries Served Fed-Std-209 initially regulated Fed-Std-209 E/US General aerospace and semiconductor Service Administration industries, but assumed international scope All. Metric measurement adhere ISO 14644/International to international conventions. Standards Organization EU GMP* Classification British Standard (BS) 5295 Specified the familiar classifications: “Class 10, “ Class 100, ” etc. Each classification referred to the number of permissible particles per cu. ft. Officially canceled in 2001, but still widely used Superseded Fed-Std-209 E starting in 2001. Correlates roughly as follows: Fed-Std-209 E ISO 14644 Class 1 ISO 3 Class 10 ISO 4 ISO I, 2 and 9 Class 100 ISO 5 have no direct Class 1000 ISO 6 209 E equivalent Class 10, 000 ISO 7 Class 100, 000 ISO 8 Pharmaceutical Manufacturing in Uses the designations Class A, B, C and D. Classes both the European Union and US “A” and “B” correspond to ISO 5, but “A” specifies a stricter “in operation” air change rate. Great Britain Uses the designations Class 1, Class 2, Class 3, Class 4; superseded by ISO 14644 *European Union Good Manufacturing Practices 32 Background

Particles: ISO level limits Allowable airborne particulates, by cubic meter*: *For ISO 1 through 6, this list refers to quantities of 0. 3 micron-sized particles allowed in a controlled environment, and for ISO 7 through 9, it refers to 0. 5 micron-sized particles. Source: ISO 14644 -1 ISO Level Particle Count 1 2 103 4 1, 020 5 10, 200 6 102, 000 7 33 10 3 Particle Counter Less than 10 352, 000 8 3, 520, 000 9 35, 200, 000 FYI: A cubic meter of typical room air contains ± 52 million 0. 3 -0. 5 micron particles.

Laminar vs Turbulent Air Flow • Uni-directional air flow controls contaminants more effectively than uncontrolled, multi-directional air flow • Turbulence stirs-up particles • Fan/filter units force air through filters in a laminar fashion • FFUs also provide uniform air speed with proper control system • Presence of furnishings, equipment and personnel interrupts laminarity; air hits surfaces and bounces • Rapid movements create turbulence 34

Air Changes Per Hour (ACPH) Air movement promotes cleanliness. Filtered air sweeps particles toward the floor and exhaust vents. Air exchange rates shown here are IEST* recommendations but are occasionally revised downward: high ACR velocity can create unwanted turbulence. USP specifies 30 ACPH for ISO 7. Range dependent upon variables like room design and access frequency. FYI: Air change rates in an air-conditioned house average about one(1) per hour. ISO Level Recommended ACR Ceiling FFU Coverage 1 -2 360 – 600/hr 80 – 100% 3 360 – 540/hr 60 – 100% 4 300 – 640/hr 50 – 90% 5 ISO recommendations: 240 – 480/hr 35 – 70% 6 150 – 240/hr 25 – 40% 7 60 – 90/hr 15 – 20% 8 5 – 48/hr 5 – 15% 9 less than 5 – 48/hr Less than 5% *Institute of Environmental Sciences and Technology 35

Air Change Rate: FFU coverage Calculate with this formula: No. of FFUs = (Air Changes per Hour ⁄ 60) × (Cubic feet in room ⁄ 650*) *Refers to the cubic feet/minute (CFM) of a typical 2′ x 4′ loaded FFU at medium speed. Example of a 10’ x 10’ ISO 7 room: 60 – 90 ACH is required, therefore, you need 2 -3 FFUs. Calculations: • (60/60) x (1000/650) = 1. 54 • (90/60) x (1000/650) = 2. 31 Discussion: An ISO 7 room is more forgiving than (for example) ISO 5, however the 10 -foot ceiling warrants a rounding up of the calculation fractions. 36

Airflow Design Basics • Moving (vs. stagnant) air = a cleaner environment • Too forceful = unnecessary turbulence • Consider room design: choose the higher end of the range to account for a higher ceiling (greater travel distance), for example ISO Level Air Speed* 1 -2 0. 305 – 0. 508 (60 – 100) 3 0. 305 – 0. 457 (60 – 90) 4 0. 254 – 0. 457 (50 – 90) 5 0. 203 – 0. 406 (40 – 80) 6 0. 127 – 0. 203 (25 – 40) 7 0. 051 – 0. 076 (10 – 15) 8 0. 005 – 0. 041 (1 – 8) 9 < 0. 005 – 0. 041 (1 – 8) *Expressed as meters/second (m/s). Within parentheses are feet/minute (f/m). (Source: IEST) 37

Room Variables Factors that can influence air speed (velocity), air changes rates, fan/filter coverage, turbulence and air balancing: • Personnel: quantity, speed and movement patterns • Equipment: quantity, energy consumption and exhaust • Vents and Plenums: location, quantity • Ceiling height • Entryways: types, quantity • Ducting: type, size, direction • Floor plan/number of rooms • Air handling systems/HVAC 38

Pressure: Positive (USP-797) • Forces air out of a room • Referred to as an “isolation” enclosure • Control systems and/or adjustable air vents control positive pressure • Protects samples, not external environment (leaks are relatively unimportant) • Softwall cleanrooms won’t maintain pressure • Air can be recirculated to extend filter life • Pressure requirement: typically 0. 025 - 0. 05” water column (WC) differential between rated and unrated space or between rooms of differing ISO ratings • Measure & log room pressure and differentials ®Dwyer Instruments, Inc. 39

Pressure: Negative (USP-800) • Exhaust system removes more air than enters room (min. 0. 01” WC negative pressure) • Referred to as a “containment” enclosure • Exhaust air fed to dedicated in-house removal system; may require “scrubbing” to remove biohazards • Leaks allow particle ingress; walls must be sealed • Protects people outside the room from biohazards • Air enters through HEPA floor louvers or ceiling HEPA filters; recirculation generally not permitted • Requires appropriate ducting system tied to inhouse exhaust system • 0. 025” - 0. 05” water column (WC) pressure difference between rooms of differing ISO ratings 40 Laminar-flow cleanroom

Sterile-to-Sterile HD Compounding 41

Sterile-to-Sterile HD Compounding 42

Non-Sterile-to-Sterile HD Compounding 43

Non-Sterile-to-Sterile HD Compounding 44

Temperature & Humidity Temperature: usually 5 - 10°F below ambient level to offset heat-generating equipment and provide comfort for garbed technicians Relative Humidity (RH): Usually 40 - 60%, but is dependent upon application/industry. Low RH invites static electricity (ESD); high RH provides environment for micro-organisms to flourish 45

Automated Control Systems 46

Summary: Cost Considerations Modular Cleanrooms: Reduce cost and installation schedule compared to brick-andmortar rooms – USP 797 designs begin around $15, 000. FFUs can be added for nominal cost if requirements change. Exhaust Air (503 B and non-sterile-to-sterile compounding): Requires additional expense of air exhaust ducting and ceiling centrifugal exhaust fan, typically installed by a local contractor Air Conditioning: To keep control costs, use existing facility HVAC system. Supplemental A/C modules add cost and potentially fresh make-up air supply Certification: Automated control system adds up-front cost (but typically only 1020% of room cost) but simplifies and speeds up certification, saving in long-term expenses, as well as controlled operation expenses Energy: Upgrade to ECM fan/filter units to increase energy efficiency and comply with local energy requirements (e. g. , California’s Title 24) 47

Pre-submitted Questions 48

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Isolators (Glove Boxes) • Enclosed, controlled space; may serve as the ISO 5 primary engineering control (PEC) inside an ISO 7 secondary engineering control (SEC) cleanroom • Filtered, laminar airflow • Material compatibility • Controls: Particle filtration, pressure, sterilization, temperature, static neutralization • USP designs: - Compounding Aseptic Isolator (CAI): protects sample (no containment) - Compounding Aseptic Containment Isolator (CACI): protects sample and operator (for hazardous drug compounding) 51

Laminar Flow Hoods • AKA “clean bench” or “laminar-flow cabinet” • Horizontal or vertical laminar flow • Positive pressure • Compatible materials: - Acrylic: economical; damaged by IPA - Static-dissipative PVC eliminates ESD* - Polypropylene: resists damage from chemicals - Powder-coated steel: strong, damage-resistant - Stainless steel: strong, resists cleaner & solvent damage • Controls: ionizing bars (neutralizes static), UV sterilization (disinfects), differential pressure gauges, air-speed gauge • Specialty designs: PCR, IV rods, explosion-proof, perforated surfaces *Electro-static discharge 52

Biological Safety Cabinets Negative-pressure containment hoods; filtered exhaust removes pathogens (but not vapors). CDC/NSF classifications: Class I: partial containment protects personnel but not the product Class II: protects personnel and the product Class II Type Characteristics A 1 min. air velocity of 75 fpm; low to moderate risk; 30% exhausted air into lab A 2 min. air velocity of 100 fpm; low to moderate risk; exhaust into lab; some negative pressure B 1 min. air velocity of 100 fpm; hard-ducted, moderate risk with some volatile chemicals or radionuclides; 70% exhausted air out of lab B 2 min. air velocity of 100 fpm; low to moderate risk with some volatile chemicals or radionuclides; 100% exhausted air out of lab Class III: Maximum containment for highest-risk pathogens; small amounts of volatile toxic chemicals or radionuclides. Filtered exhaust and make-up air. This cabinet is a glovebox, not a hood 53 Class II A 2 BSC

Fume Hood • Purpose: exhausts fumes to ducting system • Negative pressure • Baffling system ensures no air escape (“secondpass air”) at the operator interface • Not ISO rated • Ductless designs incorporate carbon filters to allow in-door air release 54

Transfer Options: Pass-Throughs • Interlocked doors prevent crosscontamination • Smooth, chemical-resistant internal surfaces (electropolished SS) • Isolated electronic interlock • Optional Air Shower minimizes particle ingress • Security features include biometric readers, logged access, wireless remote access control 55

Open Q&A Session • During the webinar, please submit questions to us through the Q&A chat box within your interface • After the webinar has ended, please direct all questions to evan@Terra. Universal. com • Each participant will receive an email in the coming days containing a link to the video recording of this webinar and a PDF copy of Terra Universal’s white paper on the impact of shifting USP/FDA regulations on pharmacy cleanroom design • To contact Terra Universal directly, call 714 -578 -6000 56