Transcript
HVAC – GPG Practical Guidance for GMP Facilities By: Norman Goldschmidt VP Genesis Engineers
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Obj ti Objectives • P Provide id an overview i off th the new HVAC GPG • S Sett expectations t ti on what h t is i and d iisn’t ’t iin th the GPG
• Review some key concepts from the guide • Provide selected examples from the guide. • Discuss what’s in the 3 day HVAC class • Bust some Myths 2
Q Question ti #1 • Who are you? • Quality Control / Quality Assurance • Manufacturing Operations • Maintenance / Facilities /Utility Operations • Commissioning / Qualification/ Validation • Engineering • Project Management 3
Q Question ti #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 Question ti #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 5
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Overview O i off the th HVAC GPG What’s In and d What’s Out
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HVAC – Practical Guidance for GMP F iliti Facilities • What’s in the guide? • • • • • • • •
Table of Contents I t d ti and Introduction d Key K Concepts C t Design process for HVAC Design Considerations (w/ Airflow Diagrams) Design Review Equipment q p Spec, p , Install,, Qualify y and Operate p Documentation Requirements Appendices 7
Wh t’ in What’s i the th guide? id ? • Appendices A di • • • • • • •
Fundamentals of HVAC HVAC Applications pp and Equipment q p Psychometrics Science Based Risk Management Science and Risk Based Verification Economics and Sustainability Medical Devices • Misc.
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Wh t’ in What’s i the th guide? id ? • Th The guide id outlines tli structured, t t d rigorous i approach h to HVAC at all stages of it’s life • Key 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 process qualification, knowledge is paramount in cGMP. • Rules of thumb – are given for conceptual use • M May nott produce d an effective ff ti design. d i • Will not produce an efficient design • Are a way of going wrong with confidence 9
Wh t’ NOT in What’s i the th guide id • • • • • • •
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 guide S Summary off the new G GPG G •
Wh t it is: What i • 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
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Wh t it is What i not: t • A detailed reference on HVAC science • A cookbook
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What it intends to do: • The new GPG is intended to establish a common platform for pharmaceutical professionals of all disciplines to discuss HVAC 11
Key Concepts
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GMP IIs N Nott At The Th T Top Of A Hierarchy Hi h GMP
Not every decision is GMP driven
GEP
We don't engineer g for the sake of engineering!
GBP
We are in the pharmaceutical BUSINESS. We can't deliver products at a loss…. Well not for long. Well, long 13
GMP Interacts With Business And Engineering
GOOD BUSINESS PRACTICE Marketing Product Development Distribution R&D Community Relations Shareholders
GOOD ENGINEERING PRACTICE
GOOD MANUFACTURING PRACTICE
Product Patient (SISPQ)
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Facility Equipment Life Cycle Cost
Wh t Is What I A Classified Cl ifi d Space? S ? • • • • • •
T, RH, T RH airborne ib particles ti l controlled t ll d b below l specified ifi d lilimits it 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 • • • •
Syste s for Systems o classifying c ass y g ccleanrooms ea oo s FS209 ISO EU 15
ISPE S Bridge between Space S C Classifications f Air Classification
FDA CDER Asepetic Guideline 2004
EUROPEAN Annex 1
In Operation
Grade 5
Particle level per Action Level CFU/cu.m. cubic meter 0.5 g (plate)) (p micron and larger 3520 1 (ISO 5) (1)
In Operation
At Rest
A
3520 (ISO 5)
3520 (ISO 5)
B
352,000 (ISO 7)
3520 (ISO 5)
C
3,520,000 (ISO 8)
352,000 (ISO 7)
"D"
None
3,520,000 (ISO 8)
Description
CRITICAL AREA
Grade 6
35,200 (ISO 6)
7 (3)
Supporting clean
Grade 7
352,000 (ISO 7)
10 (5)
CONTROLLED AREA
Grade 8
3,520,000 (ISO 8)
100 (50)
CNC (with local monitoring) CNC Unclassified
NA
NA
NA
NA
Support
100 PCF =100 particles/cu.ft. = 3520 particles/cu.m. 16
CNC = Controlled, Not Classified Lifted from draft ISPE Sterile Baseline Guide
How Much Air Flow is Enough for a Cl Classified ifi d S Space? ? • Enough g to meet Regulation g • >20 air changes per hour (USA) • 15-20 minute recovery (Europe) • 10-20 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' an Air What's Ai Change? Ch ? • Air Ai change h = th the replacement l t off one room volume l • ACH (air changes per hour) = cubic feet supply air/hr (CFH or CuM/hr) divided by room volume (in cu.ft. or CuM) • Supply air CFH = CFM x 60 Question: • Do I subtract the volume of fixed items in the room?
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Why Air Changes? Formula for Dilution of Contaminants
Where the ventilation rate has been adjusted by a mixing factor K.
C = concentration of a gas G = contaminant gas generation rate V = room volume Q = Ventilation rate into or out of the room Q' = adjusted ventilation rate of the volume 19
The Fallacy y of Air Changes g Contaminant Generation
Process Design
Process People Contaminant Ingress Pressurization
/ Direction of Airflow
Filtration
Risk Mitigation
Isolation
Contaminant Removal Containment Local
Exhaust Ventilation
Room
Performance
System
Performance
Ventilation Effectiveness 20
Ai Change Air Ch Rate R t Al Alone is i no Guarantee G t High airflow, localized entry and extract
Low Airflow well ll distributed di t ib t d
Brief residence time for room contaminant
D d spott Dead
• The ventilation rate ( airchange rate) does not guarantee a particular space classification classification. Performance depends on the effectiveness of air distribution in the space. 21
Eff ti Ventilation Effective V til ti Rate R t • 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 Ventilation Effective V til ti Rate R t • Tips to enhance ventilation effectiveness: • • • •
Capture contaminants at the source E h Exhaust t heat h t producing d i equipment i t Distribute supply and return evenly Design to sweep contaminants toward the return • Design distribution for displacement • Distribute air with uniform velocity across the space 23
Ai Change Air Ch R t Vs. Rates V Recovery R In Operation Recovery Period (15-20 (15 20 minutes)
At Rest R t 24
First Approximation – Contamination Control Equation • Cr = Cs + PGR/Q • Cr = average room count (C=particles/volume, (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 Historical t i ld data t for f similar i il equipment & gowning • PGR from powder operations could be high •
not part of "contamination PGR"
• PGR varies depending on number of people in the room, their g gowning g and activity y • People may be your most important source of contamination! t i ti ! 26
People eop e a are e Filthy t y
M Managing i Particle P ti l Generation G ti • D Design i equipment i t ffor llow contaminant contribution • Use barrier / isolation equipment • Provide cleanroom gowning appropriate 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 traditionally ll used. d 27
Q Question ti #4 • What typically generates most contamination in a cleanroom? 1. 2. 3. 4. 5.
Filling Equipment Conveyors Powder Charging / Discharging People Milling 28
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Examples from the guide
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Th HVAC Design The D i Process P • GMP = Understanding the Quality Risk: • Quality Risk Assessment • 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 dosage form, the more likely that tight control will be needed • The more sensitive the product or process process, the more likely that tight control will be needed • Often some parameters may have broad acceptance criteria while others will need tight control criteria, 30
Th HVAC Design The D i Process P • Quality Risk Assessment cont… • Parameters that typically may be controlled for GMP are: • Temp – control for comfort at a minimum, and for product • RH – control for comfort at a minimum, and for product p • Particulate – control to meet classification and to assure purity 31
The HVAC C Design Process
• Quality Risk Assessment cont… • Other Parameters that typically may be controlled for GMP are: • Pressurization or Airflow direction – associated with particulate • Bioburden – control to meet classification and to assure purity p y • Other Contaminants – Cross contamination must be controlled 32
Th HVAC Design The D i Process P • GEP = Other Risks: Business / Personnel & Environment • • • •
Operator Exposure Control Equipment Redundancy Filter Change frequency Non-Critical Environmental Parameter Selection • Control System Selection 33
Th HVAC Design The D i Process P (cont.) ( t) • Typical GEP / GMP Overlap Areas • Cross Contamination Control • Potent Compounds (both GEP&GMP) • Return filters (where used in recirc systems)
• • • •
Recirculation R i l ti vs. 100% OA Filter Selection U off Airlocks Use Ai l k Energy Recovery 34
S t System Components C t
One Large Air Handler – with everything on it… 35
THE BIG QUESTION
What makes it a PHARMA HVAC System?
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Typical Air Filters 85% High capacity Filter Roughing Filter Courtesy Joseph P Kennedy Co
High Capacity HEPA filter
Class 100 lay-in lay in ceiling Courtesy Camfil Farr
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Terminal HEPA
P i i l off Air Principles Ai Filtration Filt ti
HEPA filters have a minimum efficiency at a certain particle size which is dependent on velocity of the air through the media 38
HEPA Performance P f & Particle P ti l Size Si Example performance of a HEPA Filter
Viruses
Droplet Nuclei
100.000
Bacteria
Efficiency %
99.998
99.996
99.994
99.992
99.990
99 988 99.988 0.01
0.1
Particle Size (µm)
1
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Arrestance Versus Dust Spot Versus Penetration? Percent ARRESTANCE (mass) 50 60 70 80 90
98
99
Roughing Filters 20
50
High Efficiency
98
% Dust Spot Efficiency
% DOP Efficiency 10
Based on ASHRAE Systems and Equipment Handbook 2000
60
80 95+ HEPA
DP ~ Velocity squared (most filters) DP ~ Velocity (HEPA) 40
Filter Rating Systems Filter Comparisons - Pre-filters These comparisons of filter rating systems are only approximate as the test methods 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
G1
2
65-70%
<20%
EU 2
G2
3
70-75%
<20%
EU 2
G2
4
70-80%
<20%
EU 2
G2
5
80-85%
<20%
EU 3
G3
6
85-90%
<20%
EU 4
G4
7
>90%
25-30%
EU 4
G4
8
>90%
30-35%
EU 5
F5
9
>90%
40-45%
EU 5
F5
10
>95%
50-55%
EU 5
F5
11
>95%
60-65%
EU 6
F6
12
>95%
70-75%
EU 6
F6
13
>98%
80-90%
EU 7
F7
14
>98%
90-95%
EU 8
F8
15
<100%
95% >95%
EU 9
F9
16
<100%
>95%
EU 9
F9
16 * All EN 1822 tests at MPPS H = HEPA; U = ULPA
EU 10
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EN 1822 * H10
Typical Small S Molecule API Design Wet End
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B lk Bi Bulk Bio M Manufacture f t Closed p process usually y in "CNC" ("Unclassified Manufacturing”)
Minimum Requirements Almost “Mechanical”
Plus Discretionary Quality y Upgrades pg 43
Almost “Classifiedl”
T i lB Typical Bulk lk Bi Bio D Design i U Upstream t
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Typical yp Separation p of Compounds p Using g Multiple Airhandlers
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Typical Potent Aseptic Design for Potent P d Powders
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T Tunnel l Overpressure O Problems? P bl ?
Grade A in Grade B room DP = 30Pa Grade C room DP 15P DP=15Pa
Infeed I Internal l DP = 30P 30Pa 47 Courtesy Libra
Typical Pharmaceutical Integrated Line Aseptic Capping/Overseal Grade D or C N-UDF
Grade B Non-UDF Non UDF
CNC or Grade D Non-UDF
HEPA
Grade A
Depyrogenation Tunnel HEPA
Grade A Stoppers
Grade A
Caps
HEPA HEPA
Heat Zone
HEPA
Fill
Cooling Zone Accumulation
Grade A
Grade A
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Chapter 5 Slide 48
Typical Pharmaceutical Integrated Line Aseptic Capping/Overseal Grade D or C N-UDF
Grade B Non-UDF Non UDF
CNC or Grade D Non-UDF
HEPA
HEPA
Depyrogenation Tunnel HEPA
Grade A Stoppers
Grade A
Grade A Air Supply Caps
HEPA HEPA
Heat Zone
HEPA
Grade A
Fill
Cooling Zone Accumulation
Grade A
Grade A
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Chapter 5 Slide 49
T i l Barrier Typical B i Isolator I l t Design D i
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T diti Traditional l Medical M di l Device D i Cleanroom Cl
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T diti Traditional l Medical M di l Device D i Cleanroom Cl
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Q Question #5 # • Which of the following is a GMP concern? 1. Redundancy for Fans in a sterile area 2. Respirators for potent compound handling 3. Air flow in a classified space 4. Air change rate in an unclassified space 5. Temperature in the airlock
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Overview of the HVAC Class Wh t’ it allll About? What’s Ab t?
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Why a Course on Pharma HVAC? Many citations regarding HVAC: • • • • •
Record keeping Maintenance a test procedures not followed Alarm responses Performance issues Lesser observations
HVAC engineer i often ft gets t th the bl blame "Many Many people like to display knowledge without understanding understanding" - R. R Farnsworth 55
Traditional Reward for the HVAC Engineer
56 © Columbia pictures
The Most Painful HVAC Observation? It appears that the owner has no idea how the HVAC works to protect the product or if it does. • Highlights from a warning letter 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 findings • HEPA Filter Reliability Maintenance Engineer... did not know the air handling system specification for air flow 57
Add d Benefits? Added B fit ? • HVAC consumes a significant % of the energy in pharmaceutical facilities: • 100% ffresh h air i = $4 $4-8/yr 8/ per ft3/min / i • 60 AC/hr Recirculation = $1-3/yr per ft3/min
• Eliminating HVAC waste improves sustainability • Decrease in natural resource consumption • Reduction of greenhouse 58
S Scope off Th The Class Cl • HVAC for: • • • • • • • •
Bulk Pharmaceutical Chemicals (BPC – API) Oral Solid Dosage Oi t Ointments t and d Creams C Sterile pharmaceutical products Bulk Biopharmaceuticals Warehousing Medical Devices Labs – Quality Labs
• NOT covered: • Vivariums • Offices Offi • Central Utilities
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S Scope off Th The Class Cl • HVAC: • • • •
Design (and a touch of basics) Regulation g Verification, commissioning, qualification Documentation
• NOT covered: • HVAC load calculations • Equipment sizing and selection
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HVAC Cl Class A Agenda d Dayy One • • • •
Introductions = Why are we here? Who are you? HVAC Fundamentals (or nap time) HVAC Equipment "Cleanroom" HVAC Basics
Day Two • • •
HVAC Regulation g Design Process and Considerations Typical Designs by Product Type
Day Three • • • •
Verification, commissioning and qualification Documentation Maintenance and inspections p Final exam 61
Myth Busting Summary
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T i l HVAC Design Typical D i F Fallacies: ll i • 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 p very y small p particles • Humidity in pharma mfg. needs tight control • Temperature in pharma mfg. needs tight control 63
Q Question ti #6 • How many people have heard these principles before? 1. 2. 3. 4. 5.
One of them Two of them Three of them All of them None of them 64
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A Answers tto HVAC F Fallacies ll i • R Regulations l ti iimply l air i change h rates t ffor St Sterile il product processing only: • US 20 Air Changes g – FDA Sterile Guide • 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)
•
Air change rate relates to recovery time, not classification.
• HEPA filters stop nearly 100% of very fine particles particles. • Humidity and Temperature standards for most Pharma Manufacturing are product or process specific. Broad ranges are often ft possible. ibl 65
So, What parameters do I design to?
Typical Parameters – for conceptual design use • Bulk B lk intermediates i t di t - Human H C Comfort f t C Conditions diti • 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 • <77F <80%RH 67
Q Question #7 #
• Room particle count is controlled by which factors? 1. 2. 3. 4. 5.
Air flow Air change rate Room Size Particle Generation Rate Room Ventilation Effectiveness
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Summary • Provide an overview of the new HVAC GPG • Set e expectations pectations on what hat is and isn’t in the GPG
• • • •
Review some key concepts from the guide Provide selected examples from the guide. Discuss what’s what s in the HVAC Class Bust some Myths 69
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Q Question ti and d Answer A Session S i
Q&A 70
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Thank you! Norman Goldschmidt Principal, VP Engineering Genesis Engineers Inc.
[email protected]
