HVAC – GPGPractical Guidance for GMP Facilities

By: Norman GoldschmidtVP Genesis Engineers

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Obj tiObjectives

P id i f th HVAC• Provide an overview of the new HVAC GPG

S t t ti h t i d i ’t i th• Set expectations on what is and isn’t in the GPG

• Review some key concepts from the guide• Review some key concepts from the guide

• Provide selected examples from the guide.

• Discuss what’s in the 3 day HVAC class

• Bust some Myths2

Bust some Myths

Q ti #1Question #1

• Who are you?• Quality Control / Quality Assurance• Manufacturing Operations• Maintenance / Facilities /Utility

Operations• Commissioning / Qualification/ Validation• Engineering• Project Management

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Q ti #2Question #2

• Why are you here?• Learn what’s unique to HVAC for GMP’s• Better understand what engineers are doing• Explore new resource for compliance• Looking for sustainability ideas• Boss ordered me to come

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Q ti #3Question #3

• What do you know about HVAC?• H, V… What?• A little exposure, but not much• Familiar, but not expert• Experienced in HVAC, but not for

pharma• My name is Willis Carrier, I invented

HVAC

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O i f th HVAC GPGOverview of the HVAC GPGWhat’s In

dand What’s Out

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HVAC – Practical Guidance for GMP F ilitiFacilities

• What’s in the guide?• Table of Contents

I t d ti d K C t• Introduction and Key Concepts • Design process for HVAC• Design Considerations (w/ Airflow Diagrams)• Design Considerations (w/ Airflow Diagrams)• Design Review• Equipment Spec, Install, Qualify and Operateq p p , , y p• Documentation Requirements• Appendices

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Wh t’ i th id ?

A di

What’s in the guide?

• Appendices• Fundamentals of HVAC• HVAC Applications and Equipmentpp q p• Psychometrics• Science Based Risk Management• Science and Risk Based Verification• Science and Risk Based Verification• Economics and Sustainability• Medical Devices

• Misc.

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Wh t’ i th id ?What’s in the guide?

Th id tli t t d i h• The guide outlines structured, rigorous approach to HVAC at all stages of it’s life

• Key to this approach is Understanding the ProductKey to this approach is Understanding the Product and Process• As is stressed in QBD, ICH Q9 and guides for

qualification the HVAC GPG highlights that processqualification, the HVAC GPG highlights that process knowledge is paramount in cGMP.

• Rules of thumb – are given for conceptual useM t d ff ti d i• May not produce an effective design.

• Will not produce an efficient design• Are a way of going wrong with confidence

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Wh t’ NOT i th idWhat’s NOT in the guide

• Equipment Sizing• Load Calculations• Recommended Manufacturers• Detailed Procedures and MOT• Environmental Monitoring• Offices and Vivariums• Your Product Considerations

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What’s in the guideS f G GSummary of the new GPG

Wh t it i• What it is:• A guide for pharmaceutical applications of HVAC technology• A quick reference for HVAC nomenclature• A guide for understanding HVAC in relation to Process

Development• A collection of practical tips on Pharma HVAC issues

Wh t it i t• What it is not:• A detailed reference on HVAC science• A cookbook

• What it intends to do:• The new GPG is intended to establish a common platform for

pharmaceutical professionals of all disciplines to discuss HVAC

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Key ConceptsKey Concepts

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GMP I N t At Th T Of A Hi hGMP Is Not At The Top Of A Hierarchy

Not every decision is GMP drivenGMP

We don't engineer for the GEP gsake of engineering!GEP

We are in the pharmaceutical BUSINESS.We can't deliver products at a loss….Well not for long

GBP

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Well, not for long.

GGMP Interacts With Business And Engineering

GOOD BUSINESSPRACTICE

MarketingProduct Development

DistributionR&D

GOOD ENGINEERINGPRACTICE

GOOD MANUFACTURING

PRACTICE

Community RelationsShareholders

FacilityEquipmentPRACTICE

Life Cycle Cost

Product Patient

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Patient(SISPQ)

Wh t I A Cl ifi d S ?What Is A Classified Space?

T RH i b ti l t ll d b l ifi d li it• T, RH, airborne particles controlled below specified limits• Bioburden (surface and airborne) under control• Particles and CFU as shown on Table 5-1 of ISPE Sterile

Guide• Applies to parenterals, some inhaled products and

ointments, and most exposed biopharm API• REQUIRES PROCEDURES (people control)• Regulatory Authorities define their own

• Systems for classifying cleanroomsSyste s o c ass y g c ea oo s• FS209 • ISO• EU

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EU

S S C fAir

ClassificationFDA CDER Asepetic Guideline 2004 EUROPEAN Annex 1

ISPE Bridge between Space Classifications

In Operation At Rest

Particle level per cubic meter 0.5

micron and larger

Action Level CFU/cu.m.

(plate)

Description

In Operation

g (p )Grade 5 3520

(ISO 5)1

(1)CRITICAL AREA A 3520

(ISO 5)3520

(ISO 5)

Grade 6 35,200 (ISO 6)

7 (3)

Supporting clean

Grade 7 352,000 (ISO 7)

10 (5)

CONTROLLED AREA

B 352,000 (ISO 7)

3520 (ISO 5)

Grade 8 3,520,000 (ISO 8)

100 (50)

C 3,520,000 (ISO 8)

352,000 (ISO 7)

CNC (with local monitoring)

NA NA Support "D" None 3,520,000 (ISO 8)

CNC NA NA Unclassified

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Lifted from draft ISPE Sterile Baseline Guide

100 PCF =100 particles/cu.ft. = 3520 particles/cu.m.CNC = Controlled, Not Classified

How Much Air Flow is Enough for a Cl ifi d S ?Classified Space?

• Enough to meet Regulationg g• >20 air changes per hour (USA)• 15-20 minute recovery (Europe)• 10 20 cfm fresh air/ person (usually no issue)• 10-20 cfm fresh air/ person (usually no issue)

• Enough to meet cooling load• Sensible btu = 1.085 x Q in cfm x ∆T in °F

• Enough to offset exhaust + exfiltration• Enough clean air to offset particle generation

• Dilution • Displacement

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Wh t' Ai Ch ?What's an Air Change?

Ai h th l t f l• Air change = the replacement of one room volume

• ACH (air changes per hour) = cubic feet supply air/hr (CFH or CuM/hr) divided by room volume (inair/hr (CFH or CuM/hr) divided by room volume (in cu.ft. or CuM)

• Supply air CFH = CFM x 60Supply air CFH CFM x 60

Question:

• Do I subtract the volume of fixed items in the• Do I subtract the volume of fixed items in the room?

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Why Air Changes?Why Air Changes?

Formula for Dilution of ContaminantsFormula for Dilution of Contaminants

Where the ventilation rate has been adjusted by a mixing factor K.

C = concentration of a gasG = contaminant gas generation rateV = room volumeQ = Ventilation rate into or out of the room

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Q = Ventilation rate into or out of the roomQ' = adjusted ventilation rate of the volume

The Fallacy of Air ChangesThe Fallacy of Air Changesy gy g

Contaminant GenerationContaminant Generation

Process People

Process Design

Contaminant Ingress

Pressurization / Direction of Airflow Filtration

RiskMitigation Filtration

Isolation

Contaminant Removal

Mitigation

Containment Local Exhaust VentilationRoom Performance

VentilationEffectiveness

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Room Performance System Performance

Ai Ch R t Al i G tHigh airflow, localized

entry and extractLow Airflowll di t ib t d

Air Change Rate Alone is no Guarantee

entry and extract well distributed

D d t Brief residence timeDead spot Brief residence time for room contaminant

• The ventilation rate ( airchange rate) does not guarantee a particular space classification Performance depends on the effectiveness of air

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space classification. Performance depends on the effectiveness of air distribution in the space.

Eff ti V til ti R tEffective Ventilation Rate

• The efficiency of the room distribution design at removing contaminants is described by the “Effective ventilation rate” (with 1.0 being the theoretical performance of dilution.)

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Eff ti V til ti R tEffective Ventilation Rate

• Tips to enhance ventilation effectiveness:• Capture contaminants at the source

E h t h t d i i t• Exhaust heat producing equipment • Distribute supply and return evenly• Design to sweep contaminants toward the• Design to sweep contaminants toward the

return• Design distribution for displacement • Distribute air with uniform velocity across the

space

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Ai Ch R t V RAir Change Rates Vs. Recovery

In Operation

Recovery Period(15-20 minutes)(15 20 minutes)

At R t24

At Rest

First Approximation –Contamination Control Equation

Cr Cs + PGR/Q• Cr = Cs + PGR/Q• Cr = average room count

(C=particles/volume, PCF or PCM)(C particles/volume, PCF or PCM)• Cs = C in supply air• PGR = particle generation rate per minute• Q = supply air volume/minute (CFM or

M3/minute)

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Particle Generation Rate Is Tough to Establish

Hi t i l d t f i il• Historical data for similar equipment & gowning

• PGR from powder operationsPGR from powder operations could be high• not part of "contamination PGR"

• PGR varies depending on number of people in the room, their gowning and activity

People are Filthy

g g y• People may be your most

important source of t i ti !

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eop e a e t ycontamination!

M i P ti l G tiManaging Particle Generation

D i i t f l• Design equipment for low contaminant contribution

• Use barrier / isolation equipment• Use barrier / isolation equipment

• Provide cleanroom gowning appropriate to the classificationappropriate to the classification

• Practices that limit the number of operator interventions limit risk

• Airflows for cleanrooms with these practices can be much lower than t diti ll d

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traditionally used.

Q ti #4Question #4

• What typically generates most contamination in a cleanroom?1. Filling Equipment2. Conveyors3. Powder Charging / Discharging4. People5. Milling

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Examples from the guideExamples from the guide

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Th HVAC D i PThe HVAC Design Process

• GMP = Understanding the Quality Risk: • Quality Risk Assessment

• Environments that touch API (which is not further• Environments that touch API (which is not further purified) drug product and product contact parts require control

• The greater the risk to the patient inherent in a• The greater the risk to the patient inherent in a dosage form, the more likely that tight control will be needed

• The more sensitive the product or process the more• The more sensitive the product or process, the more likely that tight control will be needed

• Often some parameters may have broad acceptance criteria while others will need tight control

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criteria, while others will need tight control

Th HVAC D i PThe HVAC Design Process

• Quality Risk Assessment cont…• Parameters that typically may be

controlled for GMP are:• Temp – control for comfort at a minimum,

and for productand for product• RH – control for comfort at a minimum, and

for productp• Particulate – control to meet classification

and to assure purity

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CThe HVAC Design Process

• Quality Risk Assessment cont…• Other Parameters that typically may be

controlled for GMP are:• Pressurization or Airflow direction –

associated with particulateassociated with particulate• Bioburden – control to meet classification

and to assure purity p y• Other Contaminants – Cross contamination

must be controlled

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Th HVAC D i PThe HVAC Design Process

• GEP = Other Risks: Business / Personnel & Environment• Operator Exposure Control • Equipment Redundancy• Filter Change frequency• Non-Critical Environmental Parameter

Selection• Control System Selection

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Th HVAC D i P ( t )The HVAC Design Process (cont.)

• Typical GEP / GMP Overlap Areas• Cross Contamination Control

• Potent Compounds (both GEP&GMP)• Return filters (where used in recirc systems)

R i l ti 100% OA• Recirculation vs. 100% OA• Filter Selection

U f Ai l k• Use of Airlocks• Energy Recovery

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S t C tSystem Components

35One Large Air Handler – with everything on it…

THE BIG QUESTIONTHE BIG QUESTION

What makes itWhat makes ita PHARMA a PHARMA

HVAC System?HVAC System?HVAC System?HVAC System?

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Typical Air Filters85% High capacity

Filter

Courtesy Joseph P Kennedy Co

Roughing Filter

High Capacity HEPA filter

Class 100 lay-in ceiling

37Courtesy Camfil Farr

Class 100 lay in ceilingTerminal HEPA

P i i l f Ai Filt tiPrinciples of Air Filtration

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HEPA filters have a minimum efficiency at a certain particle size which is dependent on velocity of the air through the media

HEPA P f & P ti l SiExample performance of a HEPA Filter

HEPA Performance & Particle Size

100.000

Viruses BacteriaDroplet Nuclei

99.996

99.998

%

99.992

99.994

Effic

ienc

y %

99 988

99.990

99.992

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99.9880.01 0.1 1

Particle Size (µm)

Arrestance VersusDust Spot Versus Penetration?Dust Spot Versus Penetration?

Percent ARRESTANCE (mass)50 60 70 80 90 98 99

Roughing Filters

% Dust Spot Efficiency20 9850 High Efficiency

% DOP Efficiency10 80 95+6010 80 95+60

Based on ASHRAE Systems and Equipment Handbook 2000DP ~ Velocity squared (most filters)

HEPA

40DP ~ Velocity (HEPA)

Filter Rating SystemsFilter Comparisons - Pre-filters

These comparisons of filter rating systems are only approximate as the test methods

Filter Rating Systems

are different.

ASHRAE 52.2 ASHRAE 52.1 EU type EN 779

MERV Designation

Arrestance (Gravimetric Efficiency)

Dust Spot (Colorimetric

Efficiency) Designation Designation

1 <65% <20% EU 1 G 1

2 65-70% <20% EU 2 G 2

3 70-75% <20% EU 2 G 2

4 70-80% <20% EU 2 G 2

5 80-85% <20% EU 3 G 3

6 85-90% <20% EU 4 G 4

7 >90% 25-30% EU 4 G 4

8 >90% 30-35% EU 5 F 5

9 >90% 40-45% EU 5 F 5

10 >95% 50-55% EU 5 F 5

11 >95% 60-65% EU 6 F 6

12 >95% 70-75% EU 6 F 6

13 >98% 80-90% EU 7 F 7

14 >98% 90-95% EU 8 F 8

15 <100% >95% EU 9 F 9

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15 95% EU 9 F 9

16 <100% >95% EU 9 F 9

EN 1822 *

16 EU 10 H10 * All EN 1822 tests at MPPS H = HEPA; U = ULPA

STypical Small Molecule API Design Wet End

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B lk Bi M f tClosed process usually in

Bulk Bio Manufacturep y

"CNC" ("Unclassified Manufacturing”)

Minimum Requirements

Plus Discretionary

Quality UpgradesAlmost

“Mechanical”Almost

“Classifiedl”

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y pg

T i l B lk Bi D i U tTypical Bulk Bio Design Upstream

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Typical Separation of Compounds Using yp p p gMultiple Airhandlers

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Typical Potent Aseptic Design for Potent P dPowders

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T l O P bl ?Tunnel Overpressure Problems?

Grade A inGrade B roomGrade B room

DP = 30PaGrade C

roomDP 15PDP=15Pa

Infeed

I l DP 30P47

Internal DP = 30Pa

Courtesy Libra

Typical Pharmaceutical Integrated Line Aseptic Capping/OversealAseptic Capping/Overseal

Grade D or C Grade B Non UDF CNC or Grade D

HEPA

Grade D or CN-UDF

Grade B Non-UDF CNC or Grade DNon-UDF

HEPA

HEPA

HEPAHEPA

Fill

StoppersGrade AGrade A

Caps

Depyrogenation Tunnel

HEPA

Heat Zone Cooling Zone

Fill

AccumulationGrade A Grade A Grade A

48Chapter 5

Slide 48

Typical Pharmaceutical Integrated Line Aseptic Capping/Overseal

Grade D or C Grade B Non UDF CNC or Grade D

Aseptic Capping/Overseal

HEPA HEPA

Grade D or CN-UDF

Grade B Non-UDF CNC or Grade DNon-UDF

HEPA

HEPAHEPA

Fill

Stoppers

HEPAGrade A

Grade A

Grade A Air Supply

Caps

Depyrogenation Tunnel

HEPA

Heat Zone Cooling Zone

Fill

AccumulationGrade A Grade A Grade A

Grade A

49Chapter 5

Slide 49

T i l B i I l t D iTypical Barrier Isolator Design

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T diti l M di l D i ClTraditional Medical Device Cleanroom

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T diti l M di l D i ClTraditional Medical Device Cleanroom

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Q #Question #5

• Which of the following is a GMP concern?1. Redundancy for Fans in a sterile area2. Respirators for potent compound

handling3. Air flow in a classified space4. Air change rate in an unclassified space5. Temperature in the airlock

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Overview of the HVAC ClassWh t’ it ll Ab t?What’s it all About?

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Why a Course on Pharma HVAC?

Many citations regarding HVAC:

Why a Course on Pharma HVAC?

Many citations regarding HVAC:• Record keeping • Maintenance a test procedures not followed• Maintenance a test procedures not followed• Alarm responses• Performance issues• Performance issues• Lesser observations

HVAC i ft t th blHVAC engineer often gets the blame

"Many people like to display knowledge without understanding" - R Farnsworth

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Many people like to display knowledge without understanding R. Farnsworth

Traditional Reward for the HVAC Engineer

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© Columbia pictures

The Most Painful HVAC Observation?

It appears that the owner has no idea how the

The Most Painful HVAC Observation?

It appears that the owner has no idea how theHVAC works to protect the product or if it does.

• Highlights from a warning letter• Highlights from a warning letter…• Quality control unit did not assure adequate validation

of the HVAC system • Did not assure that adequate systems and controls

were in place to monitor… HVAC• Did not review HEPA bank test report findingsDid not review HEPA bank test report findings

• HEPA Filter Reliability Maintenance Engineer... did not know the air handling system specification for air flow

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Add d B fit ?

• HVAC consumes a significant % of the

Added Benefits?

• HVAC consumes a significant % of the energy in pharmaceutical facilities:

100% f h i $4 8/ ft3/ i• 100% fresh air = $4-8/yr per ft3/min• 60 AC/hr Recirculation = $1-3/yr per ft3/min

• Eliminating HVAC waste improves sustainability• Decrease in natural resource consumption• Reduction of greenhouse

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S f Th ClScope of The Class • HVAC for:HVAC for:

• Bulk Pharmaceutical Chemicals (BPC – API)• Oral Solid Dosage

Oi t t d C• Ointments and Creams• Sterile pharmaceutical products• Bulk Biopharmaceuticals• Warehousing• Medical Devices • Labs – Quality LabsLabs Quality Labs

• NOT covered:• Vivariums

Offi59

• Offices • Central Utilities

S f Th ClScope of The Class • HVAC:HVAC:

• Design (and a touch of basics)• Regulationg• Verification, commissioning, qualification• Documentation

• NOT covered:• HVAC load calculations • Equipment sizing and selection

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HVAC Cl A dHVAC Class AgendaDay One y

• Introductions = Why are we here? Who are you? • HVAC Fundamentals (or nap time)• HVAC Equipment• "Cleanroom" HVAC Basics

Day Two• HVAC Regulationg• Design Process and Considerations • Typical Designs by Product Type

Day ThreeDay Three• Verification, commissioning and qualification• Documentation• Maintenance and inspections

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p• Final exam

Myth BustingSummary

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T i l HVAC D i F ll iTypical HVAC Design Fallacies:• Regulations require air change rates that are proportional

to area classification

• 20 Air Changes = Class 100,000

• 40 Air Changes = Class 10,000

• 60 Air Changes = Class 100

• Design principles require air change rates that are proportional to area classification

• HEPA filters don’t stop very small particlesp y p

• Humidity in pharma mfg. needs tight control

• Temperature in pharma mfg. needs tight control

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Temperature in pharma mfg. needs tight control

Q ti #6Question #6

• How many people have heard these principles before?1. One of them2. Two of them3. Three of them4. All of them5. None of them

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A t HVAC F ll iAnswers to HVAC Fallacies

R l ti i l i h t f St il• Regulations imply air change rates for Sterile product processing only:

• US 20 Air Changes – FDA Sterile Guideg• EU 15-20 minute recovery (~20 AC/hr) - EU Annex 1

• Design principles require that air flow be proportional to area classification ( and particle generation rate)classification ( and particle generation rate)

• Air change rate relates to recovery time, not classification.

• HEPA filters stop nearly 100% of very fine particles• HEPA filters stop nearly 100% of very fine particles.

• Humidity and Temperature standards for most Pharma Manufacturing are product or process specific. Broad ranges

ft ibl65

are often possible.

So, What parameters do I design to?

Typical Parameters – for conceptual design use

B lk i t di t H C f t C diti• Bulk intermediates - Human Comfort Conditions

• Final API (exposed)• CNC with local monitoring, 66-74F, 30-60% RH

• Oral or Topical Products• CNC with local monitoring, 66-74F, 30-60% RH (may be lower)

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Typical Parameters – for conceptual design use

• Typical Parameters – for conceptual design use• Terminally Sterilized

• Grade 8, 66-74F, 30-60% RH

• Aseptic Processing

• Grade 5 (supporting spaces are lower) in Grade 7 Background

• 64-68F, 40-60% RH

• Warehouse / Transit

67• <77F <80%RH

Q #Question #7

• Room particle count is controlled by which factors?

1. Air flow2. Air change rate3. Room Size4. Particle Generation Rate5. Room Ventilation Effectiveness

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SSummary

• Provide an overview of the new HVAC GPG

Set e pectations on hat is and isn’t in the• Set expectations on what is and isn’t in the GPG

• Review some key concepts from the guideReview some key concepts from the guide• Provide selected examples from the guide.• Discuss what’s in the HVAC Class• Discuss what s in the HVAC Class• Bust some Myths

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Q ti d A S iQuestion and Answer Session

Q & A70

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Q & A

Thank you!Thank you!

Norman GoldschmidtPrincipal, VP EngineeringGenesis Engineers Inc.

ngoldschmidt@geieng.com