Compounding Pharmacy Cleanroom Design for USP/FDA

ComplianceChris Munoz, PharmD

Why Are We Here Today?

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New England Compounding Center

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Our Goal:Demystify the

Regulations

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The Hard Facts About the DQSA

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2014 FDA/State Meeting

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2014 FDA/State Meeting

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Current Good Manufacturing Practice

(cGMP)

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cGMP Guidance (Draft)

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cGMP Guidance (Draft)

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Today’s Regulatory Environment

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2015 FDA/State Meeting

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2015 FDA/State Meeting

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Section 503A: Traditional

Compounding Pharmacies

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ASHP Guidelines

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503A Final Guidance

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503A Final Guidance

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Quick RecapBefore We Move On to

USP

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State Oversight:USP <797>

(Under Revision)

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USP <797> Draft

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State Oversight:USP <800>

(Draft)

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USP <800> Draft

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USP <800> Draft

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USP <800> Draft

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Compounding Cleanroom Design

Mike Buckwalter Terra Universal, Inc.

Regulations & agencies that provide guidelines on cleanroom standards & practices:

Regulators: Who says what’s clean?

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Regulation/Agency Industries Served Background

Fed-Std-209E/US General Service Administration

Fed-Std-209 initially regulated aerospace and semiconductor industries, but assumed international scope

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

ISO 14644/International Standards Organization

All. Metric measurement adhere to international conventions.

Superseded Fed-Std-209E starting in 2001. Correlates roughly as follows:Fed-Std-209E ISO 14644Class 1 ISO 3Class 10 ISO 4Class 100 ISO 5Class 1000 ISO 6Class 10,000 ISO 7Class 100,000 ISO 8

EU GMP* ClassificationPharmaceutical Manufacturing in both the European Union and US

Uses the designations Class A, B, C and D. Classes “A” and “B” correspond to ISO 5, but “A” specifies a stricter “in operation” air change rate.

British Standard (BS) 5295

Great Britain Uses the designations Class 1, Class 2, Class 3, Class 4; superseded by ISO 14644

ISO I, 2 and 9 have no direct 209E equivalent

*European Union Good Manufacturing Practices

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

Particles: ISO level limits

ISO Level Particle Count

1 Less than 10

2 10

3 103

4 1,020

5 10,200

6 102,000

7 352,000

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.

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Particle Counter

• 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

Laminar vs Turbulent Air Flow

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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 ISO7.

Air Changes Per Hour (ACPH)

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%

5 240 – 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%

ISO recommendations:

Range dependent upon variables like room design and access frequency.

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FYI:Air change rates in an air-conditioned house average about one(1) per hour.

*Institute of Environmental Sciences and Technology

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’ 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.

Air Change Rate: FFU coverage

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• 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

Airflow Design Basics

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)

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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

Room Variables

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• 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

Pressure: Positive (USP-797)

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®Dwyer Instruments, Inc.

Pressure: Negative (USP-800)

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• 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 bio-hazards• Air enters through HEPA floor louvers or ceiling HEPA filters; recirculation generally not permitted• Requires appropriate ducting system tied to in-house exhaust system• 0.025” - 0.05” water column (WC) pressure difference between rooms of differing ISO ratings

Laminar-flow cleanroom

Sterile-to-Sterile HD Compounding

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Sterile-to-Sterile HD Compounding

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Non-Sterile-to-Sterile HD Compounding

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Non-Sterile-to-Sterile HD Compounding

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Temperature & Humidity

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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

Automated Control Systems

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Summary: Cost Considerations

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Modular Cleanrooms: Reduce cost and installation schedule compared to brick-and-mortar rooms – USP 797 designs begin around $15,000. FFUs can be added for nominal cost if requirements change.

Exhaust Air (503B 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 10-20% 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)

Pre-submitted Questions

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• 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)

Isolators (Glove Boxes)

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• 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

Laminar Flow Hoods

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*Electro-static discharge

Negative-pressure containment hoods; filtered exhaust removes pathogens (but not vapors). CDC/NSF classifications:Class I: partial containment protects personnel but not the productClass II: protects personnel and the product

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

Biological Safety Cabinets

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Class II Type Characteristics

A1 min. air velocity of 75 fpm; low to moderate risk; 30% exhausted air into lab

A2 min. air velocity of 100 fpm; low to moderate risk; exhaust into lab; some negative pressure

B1 min. air velocity of 100 fpm; hard-ducted, moderate risk with some volatile chemicals or radionuclides; 70% exhausted air out of lab

B2 min. air velocity of 100 fpm; low to moderate risk with some volatile chemicals or radionuclides; 100% exhausted air out of lab

Class II A2 BSC

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

Fume Hood

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• Interlocked doors prevent cross-contamination• 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

Transfer Options: Pass-Throughs

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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@TerraUniversal.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

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