HVAC – GPG Practical Guidance for GMP Facilities

HVAC – GPG Practical Guidance for GMP FacilitiesBy: Norman Goldschmidt VP Genesis Engineers 1 Objectives Obj ti • P id an overview of th new HVAC Provide i f the GPG • S t expectations on what is and i ’t i th Set t ti h ti d isn’t in 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 Question #1 Q ti • Who are you? • Quality Control / Quality Assurance • Manufacturing Operations • Maintenance / Facilities /Utility Operations • Commissioning / Qualification/ Validation • Engineering • Project Management 3 Question #2 Q ti • 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 4 . Question #3 Q ti • What do you know about HVAC? • • • • H. but not expert Experienced in HVAC. V… What? A little exposure. but not for pharma • My name is Willis Carrier. but not much Familiar. I invented HVAC 5 5 . Overview of the HVAC GPG O i f th What’s In and d What’s Out 6 . Install. .HVAC – Practical Guidance for GMP Facilities F iliti • What’s in the guide? • • • • • • • • Table of Contents Introduction d Key Concepts I t d ti and K C t Design process for HVAC Design Considerations (w/ Airflow Diagrams) Design Review Equipment Spec. Qualify and Operate q p p . y p Documentation Requirements Appendices 7 . 8 .What’s i th Wh t’ in the guide? id ? • A Appendices di • • • • • • • Fundamentals of HVAC HVAC Applications and Equipment pp q p Psychometrics Science Based Risk Management Science and Risk Based Verification Economics and Sustainability Medical Devices • Misc. qualification the HVAC GPG highlights that process knowledge is paramount in cGMP.What’s i th Wh t’ in the guide? id ? • Th guide outlines structured. • Rules of thumb – are given for conceptual use • M not produce an effective design. ICH Q9 and guides for qualification. rigorous approach The id tli t t d i 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. May t d ff ti d i • Will not produce an efficient design • Are a way of going wrong with confidence 9 . What’s Wh t’ NOT in the guide i th id • • • • • • • Equipment Sizing Load Calculations Recommended Manufacturers Detailed Procedures and MOT Environmental Monitoring Offices and Vivariums Your Product Considerations 10 . What’s in the guide Summary of the new G G S f GPG • What i Wh t 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 • What i Wh t it is not: t • 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 11 . Key Concepts 12 . We can't deliver products at a loss…. Well not for long. long 13 . Well.GMP I N t At The T Of A Hierarchy Is Not Th Top Hi h GMP Not every decision is GMP driven GEP We don't engineer for the g sake of engineering! GBP We are in the pharmaceutical BUSINESS. GMP Interacts With Business And Engineering GOOD BUSINESS PRACTICE Marketing Product Development Distribution R&D Community Relations Shareholders GOOD MANUFACTURING PRACTICE GOOD ENGINEERING PRACTICE Facility Equipment Life Cycle Cost Product Patient (SISPQ) 14 . What I Wh t Is A Classified Space? Cl ifi d S ? • • • • • • T. and most exposed biopharm API REQUIRES PROCEDURES (people control) Regulatory Authorities define their own • • • • Syste s o c ass y g c ea oo s Systems for classifying cleanrooms FS209 ISO EU 15 . some inhaled products and ointments. RH i b T RH. airborne particles controlled b l ti l t ll d below specified li it ifi d limits Bioburden (surface and airborne) under control Particles and CFU as shown on Table 5-1 of ISPE Sterile Guide Applies to parenterals. Not Classified Lifted from draft ISPE Sterile Baseline Guide 16 .520.000 (ISO 7) 3.000 (ISO 7) 3.000 (ISO 7) 3.m.5 g (p (plate) ) micron and larger 3520 1 (ISO 5) (1) 35. = 3520 particles/cu.200 (ISO 6) 352.ISPE Bridge between Space C S S Classifications f Air Classification FDA CDER Asepetic Guideline 2004 In Operation Particle level per Action Level CFU/cu.520.m. cubic meter 0.000 (ISO 8) 100 PCF =100 particles/cu.ft.000 (ISO 8) NA NA 7 (3) 10 (5) 100 (50) NA NA Support Description EUROPEAN Annex 1 In Operation At Rest Grade 5 Grade 6 Grade 7 Grade 8 CNC (with local monitoring) CNC Unclassified CRITICAL AREA Supporting clean CONTROLLED AREA A 3520 (ISO 5) 3520 (ISO 5) B C "D" 352.000 (ISO 8) None 3520 (ISO 5) 352. CNC = Controlled.520. 085 x Q in cfm x ∆T in °F • Enough to offset exhaust + exfiltration • Enough clean air to offset particle generation • Dilution • Displacement 17 .How Much Air Flow is Enough for a Classified S Cl ifi d Space? ? • Enough to meet Regulation g g • >20 air changes per hour (USA) • 15-20 minute recovery (Europe) • 10 20 cfm fresh air/ person (usually no issue) 10-20 • Enough to meet cooling load • Sensible btu = 1. or CuM) • Supply air CFH = CFM x 60 Question: • Do I subtract the volume of fixed items in the room? 18 .What's Wh t' an Air Change? Ai Ch ? • Ai change = th replacement of one room volume Air h the l t f l • ACH (air changes per hour) = cubic feet supply air/hr (CFH or CuM/hr) divided by room volume (in cu.ft. 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 of Air Changes y g  Contaminant Generation  Process  People  Contaminant Ingress  Pressurization  Filtration  Process Design / Direction of Airflow Risk Mitigation Isolation  Contaminant Removal  Containment  Local  Room Exhaust Ventilation Performance Performance 20 Ventilation Effectiveness  System . Air Ch Ai Change Rate Al R t Alone is no Guarantee i G t High airflow. localized entry and extract Low Airflow well distributed ll di t ib t d Dead D d spot t 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 classification. distribution in the space. 21 . ) 22 .0 being the theoretical performance of dilution.Effective V til ti R t Eff ti Ventilation Rate • The efficiency of the room distribution design at removing contaminants is described by the “Effective ventilation rate” (with 1. Effective V til ti R t Eff ti Ventilation Rate • Tips to enhance ventilation effectiveness: • • • • Capture contaminants at the source Exhaust h t producing equipment E h t heat d i 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 . Recovery In Operation Recovery Period (15 20 (15-20 minutes) At Rest R t 24 .Air Change R t V R Ai Ch Rates Vs. First Approximation – Contamination Control Equation • Cr = Cs + PGR/Q • Cr = average room count (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) 25 . (C=particles/volume. Particle Generation Rate Is Tough to Establish • Hi t i l d t for similar Historical data f 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 gowning and activity g g y • People may be your most important source of contamination! t i ti ! 26 People a e Filthy eop e are t y . Managing Particle Generation M i P ti l G ti • D i equipment f l Design i t for low 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 traditionally used. t diti ll d 27 . 4.Question #4 Q ti • What typically generates most contamination in a cleanroom? 1. 3. 5. 2. Filling Equipment Conveyors Powder Charging / Discharging People Milling 28 28 . Examples from the guide 29 . likely that tight control will be needed • Often some parameters may have broad acceptance criteria.The Th HVAC Design Process D i 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. criteria while others will need tight control 30 . the more likely that tight control will be needed • The more sensitive the product or process the more process. The Th HVAC Design Process D i 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 Design Process C • 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 . The Th HVAC Design Process D i P • GEP = Other Risks: Business / Personnel & Environment Operator Exposure Control Equipment Redundancy Filter Change frequency Non-Critical Environmental Parameter Selection • Control System Selection 33 • • • • . The Th HVAC Design Process (cont. 100% OA Filter Selection Use f Ai l k U of Airlocks Energy Recovery 34 .) D i P ( 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. System Components S t C t One Large Air Handler – with everything on it… 35 . THE BIG QUESTION What makes it a PHARMA HVAC System? 36 . Typical Air Filters 85% High capacity Filter Roughing Filter Courtesy Joseph P Kennedy Co High Capacity HEPA filter Class 100 lay-in ceiling lay in Courtesy Camfil Farr 37 Terminal HEPA . Principles f Ai Filt ti P i i l of Air Filtration HEPA filters have a minimum efficiency at a certain particle size which is dependent on velocity of the air through the media 38 . 000 Droplet Nuclei Bacteria 99.994 99.996 99.01 0.992 99.1 1 Particle Size (µm) 39 .988 99 988 0.990 99.998 Efficiency % 99.HEPA Performance & Particle Size P f P ti l Si Example performance of a HEPA Filter Viruses 100. Arrestance Versus Dust Spot Versus Penetration? Percent ARRESTANCE (mass) 50 60 70 80 90 Roughing Filters 20 % Dust Spot Efficiency 50 High Efficiency 98 98 99 % DOP Efficiency 10 60 80 95+ HEPA Based on ASHRAE Systems and Equipment Handbook 2000 DP ~ Velocity squared (most filters) DP ~ Velocity (HEPA) 40 . 2 MERV Designation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 ASHRAE 52.Filter Rating Systems Filter Comparisons .Pre-filters These comparisons of filter rating systems are only approximate as the test methods are different.1 Arrestance (Gravimetric Efficiency) <65% 65-70% 70-75% 70-80% 80-85% 85-90% >90% >90% >90% >95% >95% >95% >98% >98% <100% <100% Dust Spot (Colorimetric Efficiency) <20% <20% <20% <20% <20% <20% 25-30% 30-35% 40-45% 50-55% 60-65% 70-75% 80-90% 90-95% 95% >95% >95% EU type EN 779 Designation EU 1 EU 2 EU 2 EU 2 EU 3 EU 4 EU 4 EU 5 EU 5 EU 5 EU 6 EU 6 EU 7 EU 8 EU 9 EU 9 Designation G1 G2 G2 G2 G3 G4 G4 F5 F5 F5 F6 F6 F7 F8 F9 F9 16 * All EN 1822 tests at MPPS H = HEPA. U = ULPA EU 10 41 EN 1822 * H10 . ASHRAE 52. Typical S Small Molecule API Design Wet End 42 . Bulk Bio Manufacture B lk Bi M f t Closed process usually in p y "CNC" ("Unclassified Manufacturing”) Minimum Requirements Almost “Mechanical” Plus Discretionary Quality Upgrades y pg 43 Almost “Classifiedl” . Typical Bulk Bio Design Upstream T i l B lk Bi D i U t 44 . Typical Separation of Compounds Using yp p p g Multiple Airhandlers 45 . Typical Potent Aseptic Design for Potent Powders P d 46 . Tunnel Overpressure Problems? T lO P bl ? Grade A in Grade B room DP = 30Pa Grade C room DP=15Pa DP 15P Infeed Internal DP = 30P I l 30Pa 47 Courtesy Libra . Typical Pharmaceutical Integrated Line Aseptic Capping/Overseal Grade D or C N-UDF Grade B Non-UDF Non UDF HEPA CNC or Grade D Non-UDF HEPA Depyrogenation Tunnel HEPA Heat Zone HEPA HEPA Cooling Zone Accumulation Grade A Grade A Stoppers Fill Caps Grade A Grade A Grade A 48 Chapter 5 Slide 48 . Typical Pharmaceutical Integrated Line Aseptic Capping/Overseal Grade D or C N-UDF Grade B Non-UDF Non UDF HEPA CNC or Grade D Non-UDF HEPA HEPA Depyrogenation Tunnel HEPA Heat Zone HEPA HEPA Cooling Zone Accumulation Grade A Stoppers Fill Grade A Air Supply Caps Grade A Grade A Grade A Grade A 49 Chapter 5 Slide 49 Typical B i I l t D i T i l Barrier Isolator Design 50 Traditional Medical Device Cleanroom T diti l M di l D i Cl 51 Traditional Medical Device Cleanroom T diti l M di l D i Cl 52 . Air change rate in an unclassified space 5. Air flow in a classified space 4. Temperature in the airlock 53 53 .Question #5 Q # • Which of the following is a GMP concern? 1. Respirators for potent compound handling 3. Redundancy for Fans in a sterile area 2. Overview of the HVAC Class What’s Wh t’ it all About? ll Ab t? 54 . R Farnsworth Many understanding" R. 55 .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 often gets th bl i ft t the blame "Many people like to display knowledge without understanding . Traditional Reward for the HVAC Engineer 56 © Columbia pictures . did not know the air handling system specification for air flow 57 ..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.. Added B Add d Benefits? fit ? • HVAC consumes a significant % of the energy in pharmaceutical facilities: • 100% f h air = $4 8/ per ft3/ i fresh i $4-8/yr /min • 60 AC/hr Recirculation = $1-3/yr per ft3/min • Eliminating HVAC waste improves sustainability • Decrease in natural resource consumption • Reduction of greenhouse 58 . Scope of Th Class S f The Cl • HVAC for: • • • • • • • • Bulk Pharmaceutical Chemicals (BPC – API) Oral Solid Dosage Ointments and Creams Oi t t dC Sterile pharmaceutical products Bulk Biopharmaceuticals Warehousing Medical Devices Labs – Quality Labs • NOT covered: • Vivariums • Offi Offices • Central Utilities 59 . Scope of Th Class S f The Cl • HVAC: • • • • Design (and a touch of basics) Regulation g Verification. commissioning. qualification Documentation • NOT covered: • HVAC load calculations • Equipment sizing and selection 60 . commissioning and qualification Documentation Maintenance and inspections p Final exam 61 Day Two • • • Day Three • • • • .HVAC Cl Class A Agenda d Day One y • • • • Introductions = Why are we here? Who are you? HVAC Fundamentals (or nap time) HVAC Equipment "Cleanroom" HVAC Basics HVAC Regulation g Design Process and Considerations Typical Designs by Product Type Verification. Myth Busting Summary 62 . 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 particles p y p • Humidity in pharma mfg.000 • 40 Air Changes = Class 10.Typical T i l HVAC Design F ll i D i Fallacies: • Regulations require air change rates that are proportional to area classification • 20 Air Changes = Class 100. needs tight control • Temperature in pharma mfg. needs tight control 63 . Question #6 Q ti • 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 64 . not classification. • HEPA filters stop nearly 100% of very fine particles particles. Broad ranges are often possible. What parameters do I design to? . • Humidity and Temperature standards for most Pharma Manufacturing are product or process specific.Answers t HVAC F ll i A to Fallacies • R Regulations i l air change rates f St il l ti imply i h t for Sterile product processing only: • US 20 Air Changes – FDA Sterile Guide g • EU 15-20 minute recovery (~20 AC/hr) . ft ibl 65 So.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. 30-60% RH • Oral or Topical Products • CNC with local monitoring.Typical Parameters – for conceptual design use • B lk i t Bulk intermediates . 30-60% RH (may be lower) 66 . 66-74F. 66-74F.H di t Human C f t C diti Comfort Conditions • Final API (exposed) • CNC with local monitoring. 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 . 4. 5.Question #7 Q # • Room particle count is controlled by which factors? 1. 2. Air flow Air change rate Room Size Particle Generation Rate Room Ventilation Effectiveness 68 68 . 3. Discuss what’s in the HVAC Class what s Bust some Myths 69 69 .Summary • Provide an overview of the new HVAC GPG • Set e pectations on what is and isn’t in the expectations hat GPG • • • • Review some key concepts from the guide Provide selected examples from the guide. Question and Answer Session Q ti dA S i Q&A 70 70 . Thank you! Norman Goldschmidt Principal.com . ngoldschmidt@geieng. VP Engineering Genesis Engineers Inc.