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Clean Room_Presentation

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Clean Room_Presentation

  1. 1. Fundamentals of Clean RoomFundamentals of Clean Room inin Pharma IndustryPharma Industry Manoj Kumar VermaManoj Kumar Verma QA Deptt.QA Deptt.
  2. 2. IntroductionIntroduction What’s Clean room?What’s Clean room? An area/room which is designed, constructed, used and maintained in such a manner, soAn area/room which is designed, constructed, used and maintained in such a manner, so as to preclude or reduce the introduction, generation or retention of viable and non-viableas to preclude or reduce the introduction, generation or retention of viable and non-viable particulates.particulates. Clean room is also regulated and monitored for RH, Temp. and ∆P. So, in clean roomClean room is also regulated and monitored for RH, Temp. and ∆P. So, in clean room conditioned air is supplied.conditioned air is supplied. Quality, GMP and Cleanroom are relatedQuality, GMP and Cleanroom are related What’s Quality?What’s Quality? •Meeting the predetermined requirements of the user for a particular product or service.Meeting the predetermined requirements of the user for a particular product or service. •Totality of characteristics of an entity that bear on its ability to fulfill implied or statedTotality of characteristics of an entity that bear on its ability to fulfill implied or stated needs.needs. What’s GMP?What’s GMP? GMP is that part of QA, which ensures that the products are consistently produced andGMP is that part of QA, which ensures that the products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by thecontrolled to the quality standards appropriate to their intended use and as required by the marketing authorization.marketing authorization. A clean roomA clean room is a rigorously controlled environment that has a low level of environmentalis a rigorously controlled environment that has a low level of environmental pollutants such as dust, airborne microbes, aerosol particles and chemical vapors. Thepollutants such as dust, airborne microbes, aerosol particles and chemical vapors. The air entering a clean room is filtered and then continuously circulated through highair entering a clean room is filtered and then continuously circulated through high efficiency particulate air (HEPA) and/or ultra-low particulate air (ULPA) filters to removeefficiency particulate air (HEPA) and/or ultra-low particulate air (ULPA) filters to remove internally generated contaminants. Staff wearing protective clothing must enter and exitinternally generated contaminants. Staff wearing protective clothing must enter and exit through airlocks, while equipment and furniture inside the clean room is speciallythrough airlocks, while equipment and furniture inside the clean room is specially designed to produce minimal particles.designed to produce minimal particles.
  3. 3. Definition of CleanDefinition of Clean areaarea As per ISO 14644:As per ISO 14644: Room in which the concentration of airborne particle is controlled, and whichRoom in which the concentration of airborne particle is controlled, and which is constructed & used in a manner to minimize the introduction, generation,is constructed & used in a manner to minimize the introduction, generation, and retention of particles inside the room and in which other relevantand retention of particles inside the room and in which other relevant parameters (e.g., temperature, humidity, and Pressure) are controlled asparameters (e.g., temperature, humidity, and Pressure) are controlled as necessary.necessary. As per WHO-GMP:As per WHO-GMP: An area with defined environmental control of particulate and microbialAn area with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce thecontamination, constructed and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area.introduction, generation, and retention of contaminants within the area. As per USP Chapter 1116:As per USP Chapter 1116: A room in which the concentration of airborne particles is controlled to meetA room in which the concentration of airborne particles is controlled to meet a specified airborne particulate Cleanliness Class. In addition, thea specified airborne particulate Cleanliness Class. In addition, the concentration of microorganisms in the environment is monitored; eachconcentration of microorganisms in the environment is monitored; each Cleanliness Class defined is also assigned a microbial level for air, surface,Cleanliness Class defined is also assigned a microbial level for air, surface, and personnel gear.and personnel gear.
  4. 4. Clean room basic termsClean room basic terms Air Lock:Air Lock: An enclosed space with two or more interlocking doors. Its function is to act as a buffer zoneAn enclosed space with two or more interlocking doors. Its function is to act as a buffer zone between the clean room and the outside atmosphere. It helps keep the clean room pressurizedbetween the clean room and the outside atmosphere. It helps keep the clean room pressurized and free from infiltrating dirt. Two types of Air locks are Personnel Air Lock (PAL) and Material Airand free from infiltrating dirt. Two types of Air locks are Personnel Air Lock (PAL) and Material Air Lock (MAL)Lock (MAL) Air Shower:Air Shower: An enclosed chamber designed to clean personnel and their garments of contamination, prior toAn enclosed chamber designed to clean personnel and their garments of contamination, prior to entering the clean room, by means of high velocity of air jets.entering the clean room, by means of high velocity of air jets. Garments:Garments: These are lint-free garments made of synthetic fabrics such as Nylon, Dacron etc..These are lint-free garments made of synthetic fabrics such as Nylon, Dacron etc.. HEPA filter:HEPA filter: High Efficiency Particulate Air filter, capable of filtering out 0.3 micron particles or larger withHigh Efficiency Particulate Air filter, capable of filtering out 0.3 micron particles or larger with 99.97% efficiency99.97% efficiency Pass Box:Pass Box: A small enclosure that mounted through the clean room wall and allows product to be passedA small enclosure that mounted through the clean room wall and allows product to be passed through efficiently. Pass box cut down on personnel traffic, hence reducing contamination.through efficiently. Pass box cut down on personnel traffic, hence reducing contamination. Sticky Mat:Sticky Mat: Located at the clean room or air shower entrance, sticky mats are multiple layers of treated filmLocated at the clean room or air shower entrance, sticky mats are multiple layers of treated film with adhesive to clean shoe bottoms and sides before entering the room.with adhesive to clean shoe bottoms and sides before entering the room. ULPA filter:ULPA filter: Ultra Low Particulate Air filter, capable of filtering out 0.12 micron particles or larger. ULPA'sUltra Low Particulate Air filter, capable of filtering out 0.12 micron particles or larger. ULPA's operate with 99.9999% efficiency.operate with 99.9999% efficiency. HVAC:HVAC: The system consisted of AHU(s), ducts and Terminal HEPA filters to supply conditioned air.The system consisted of AHU(s), ducts and Terminal HEPA filters to supply conditioned air. HVAC helps to provide desired RH, Temp., Diff. Pressure in the controlled area.HVAC helps to provide desired RH, Temp., Diff. Pressure in the controlled area. AHU:AHU: Device used to condition and circulate air as part of a heating, ventilating, and air-conditioningDevice used to condition and circulate air as part of a heating, ventilating, and air-conditioning (HVAC) system. Usually, an air handler is a large metal box containing a blower, heating and/or(HVAC) system. Usually, an air handler is a large metal box containing a blower, heating and/or cooling elements, filter racks or chambers, sound attenuators, and dampers. AHUs usuallycooling elements, filter racks or chambers, sound attenuators, and dampers. AHUs usually connect to duct work that distributes the conditioned air through the building, and returns it to theconnect to duct work that distributes the conditioned air through the building, and returns it to the AHU.AHU.
  5. 5. HistoryHistory of Clean roomof Clean room • The principles of clean room design go back more than 150 yearsThe principles of clean room design go back more than 150 years, to the beginning of, to the beginning of bacterial control in hospitals. The clean room itself is a relatively modern development.bacterial control in hospitals. The clean room itself is a relatively modern development. • Development of the modern clean room began during the Second World War (1939 – 1945)Development of the modern clean room began during the Second World War (1939 – 1945) to improve the quality and reliability of instrumentation used in manufacturing guns, tanks andto improve the quality and reliability of instrumentation used in manufacturing guns, tanks and aircraft.aircraft. During this time, HEPA filters were also developed to contain the dangerousDuring this time, HEPA filters were also developed to contain the dangerous radioactive, microbial or chemical contaminants.radioactive, microbial or chemical contaminants. • Need for aNeed for a clean environment for industrial manufacturing during theclean environment for industrial manufacturing during the 1950s led to the1950s led to the modern clean room as we know itmodern clean room as we know it.. • The evolution of clean rooms gained momentum as a result of NASA’s space travelThe evolution of clean rooms gained momentum as a result of NASA’s space travel program in the 1950s and 1960sprogram in the 1950s and 1960s. It was during this time that. It was during this time that the concept of ‘laminar flow’the concept of ‘laminar flow’ was introducedwas introduced, which marked a turning point in clean room technology., which marked a turning point in clean room technology. • A document published by FDA in 1987 define two areas – A ‘Critical area’ where the sterilizedA document published by FDA in 1987 define two areas – A ‘Critical area’ where the sterilized dosage form, containers, and closures are exposed to the environment & a ‘Controlled area’dosage form, containers, and closures are exposed to the environment & a ‘Controlled area’ where unsterilized product, in-process materials, and container closures are prepared.where unsterilized product, in-process materials, and container closures are prepared. • Air in critical areas should be supplied at the point of use as HEPA filtered laminarAir in critical areas should be supplied at the point of use as HEPA filtered laminar flow air, having a velocity sufficient to sweep particulate matter away from theflow air, having a velocity sufficient to sweep particulate matter away from the filling/closing area. Normally, a velocity of 90 feet per minute, plus or minus 20%, isfilling/closing area. Normally, a velocity of 90 feet per minute, plus or minus 20%, is adequate.adequate. • In Controlled areas, it is important to achieve a sufficient air flow (20 to 60 ACPH) andIn Controlled areas, it is important to achieve a sufficient air flow (20 to 60 ACPH) and a positive pressure differential (10-15Pa) relative to adjacent uncontrolled areas.a positive pressure differential (10-15Pa) relative to adjacent uncontrolled areas. When doors are open, outward airflow should be sufficient to minimize ingress ofWhen doors are open, outward airflow should be sufficient to minimize ingress of contamination.contamination.
  6. 6. Clean room Standards andClean room Standards and ClassificationClassification •Most easily understood classification of Clean room used in earlier version (A to D) of FS 209 ofMost easily understood classification of Clean room used in earlier version (A to D) of FS 209 of US.US. •The first FS 209 was published in 1963 in the US and titled “Clean Room and Work StationThe first FS 209 was published in 1963 in the US and titled “Clean Room and Work Station Requirements, Controlled Environments.”Requirements, Controlled Environments.” •FS 209- US was revised in 1966 (209A), 1973 (209B), 1987 (209C), 1988 (209D) & 1992 (209E).FS 209- US was revised in 1966 (209A), 1973 (209B), 1987 (209C), 1988 (209D) & 1992 (209E). •FS 209 D was superseded by FS 209 E. The latter by the International Standard ISO 14644-1.FS 209 D was superseded by FS 209 E. The latter by the International Standard ISO 14644-1. •FS 209 E version accepted a metric unit i.e., per Cubic metre, but in 1999 ISO 14644-1 wasFS 209 E version accepted a metric unit i.e., per Cubic metre, but in 1999 ISO 14644-1 was published. The latter was adopted by all countries in the European Union and later by otherpublished. The latter was adopted by all countries in the European Union and later by other countries.countries. •FED-STD-209 E Titled “Airborne Particulate Cleanliness Classes in Cleanrooms and Cleanzones”FED-STD-209 E Titled “Airborne Particulate Cleanliness Classes in Cleanrooms and Cleanzones” was canceled on November 29, 2001 by the U.S. General Services Administration (GSA).was canceled on November 29, 2001 by the U.S. General Services Administration (GSA). •ISO Clean room classification that exists in Pharma are:ISO Clean room classification that exists in Pharma are: ISO 5 ; ISO 6 ; ISO 7 ; ISO 8 which are equivalent to Class A (100) ; Class B (1000) ; Class C (10,000)ISO 5 ; ISO 6 ; ISO 7 ; ISO 8 which are equivalent to Class A (100) ; Class B (1000) ; Class C (10,000) and Class D (100,000) respectively.and Class D (100,000) respectively.
  7. 7. The benchmark international clean roomThe benchmark international clean room standardsstandards • US Federal Std 209E 1992US Federal Std 209E 1992 • EEC cGMP 1989EEC cGMP 1989 • France AFNOR (France AFNOR (Association Française de Normalisation)Association Française de Normalisation)19891989 • German VDI 2083 1990German VDI 2083 1990 • British BS 5295 1989British BS 5295 1989 • Japan JIS B 9920 1989Japan JIS B 9920 1989 • ISO EN 14611-1 1999ISO EN 14611-1 1999
  8. 8. Cleanroom Certification and ValidationCleanroom Certification and Validation Guidelines and RegulationsGuidelines and Regulations GuidelinesGuidelines • 􀂄􀂄 Indian FDA GMP GuidelinesIndian FDA GMP Guidelines IndiaIndia • 􀂄􀂄 WHO GMP GuidelinesWHO GMP Guidelines InternationalInternational • 􀂄􀂄 EEC GMP Guidelines EUEEC GMP Guidelines EU InternationalInternational • 􀂄􀂄 U.S. FDA GMP Guidelines USAU.S. FDA GMP Guidelines USA InternationalInternational • 􀂄􀂄 ISPE GuidelinesISPE Guidelines InternationalInternational RegulationsRegulations • 􀂄􀂄 DIN EN ISO 14644, part 1 (2000)DIN EN ISO 14644, part 1 (2000) InternationalInternational • 􀂄􀂄 ISO-DIS 14644, part 3 (2000)ISO-DIS 14644, part 3 (2000) InternationalInternational • 􀂄􀂄 DIN EN 12599 (2000) EUDIN EN 12599 (2000) EU InternationalInternational • 􀂄􀂄 NEBB (1996) USANEBB (1996) USA InternationalInternational DIN Stands forDIN Stands for Deutsches Institut fur NormungDeutsches Institut fur Normung (German Institute for Standardization)(German Institute for Standardization) NEBB stands for National Environmental Balancing BureauNEBB stands for National Environmental Balancing Bureau
  9. 9. Why clean rooms?Why clean rooms? • Clean, safe and contaminant-free environment is imperative forClean, safe and contaminant-free environment is imperative for manufacturing efficacious, safe and good quality drug products.manufacturing efficacious, safe and good quality drug products. • Also critical to protect employees from contact with hazardous materials orAlso critical to protect employees from contact with hazardous materials or pathogens and prevent health problems from prolonged exposure topathogens and prevent health problems from prolonged exposure to chemicals or allergenschemicals or allergens • Clean rooms are part of GMP requirement and GMP is statutory inClean rooms are part of GMP requirement and GMP is statutory in nature.nature.
  10. 10. FilterSilencer Terminal filter Weather louvre Control damper FanFlow rate controller Humidifier Heating coil Cooling coil with droplet separator Production Room Overview components + Prefilter Exhaust Air Grille Heater Secondary Filter Recirculated air HVAC System (1)
  11. 11. • Weather louvreWeather louvre • SilencerSilencer • Flow rateFlow rate controllercontroller • Control damperControl damper • To prevent insects, leaves, dirtTo prevent insects, leaves, dirt and rain water from enteringand rain water from entering • To reduce noise caused by airTo reduce noise caused by air circulationcirculation • Automated adjustment of volumeAutomated adjustment of volume of airof air • Fixed adjustment of volume of airFixed adjustment of volume of air Components: HVAC System (2)
  12. 12. •Heating unitHeating unit •CoolingCooling unitunit// dehumidifierdehumidifier •HumidifierHumidifier •FiltersFilters •DuctsDucts • To heat the air to the properTo heat the air to the proper temperaturetemperature • To cool the air to the requiredTo cool the air to the required temperature or to remove moisturetemperature or to remove moisture from the airfrom the air • To bring the air to the proper humidity,To bring the air to the proper humidity, if too lowif too low • To eliminate particles of predeterminedTo eliminate particles of predetermined dimensions and/or microorganismsdimensions and/or microorganisms • To transport the airTo transport the air Components: HVAC System (3)
  13. 13. Types of clean rooms (as per Supplied air flow pattern):Types of clean rooms (as per Supplied air flow pattern): 1.1. Conventional:Conventional: • Air Flow Pattern: Turbulent;Air Flow Pattern: Turbulent; • Air circulated at optimum rate in room;Air circulated at optimum rate in room; • Room environment cleansed by Dilution Principle;Room environment cleansed by Dilution Principle; • Clean rooms having cleanliness Class ISO 6 and beyond falls under this category.Clean rooms having cleanliness Class ISO 6 and beyond falls under this category. 2.2. Unidirectional Flow (Laminar Air Flow):Unidirectional Flow (Laminar Air Flow): • Air Flow Pattern: Unidirectional;Air Flow Pattern: Unidirectional; • Air circulated at high velocity in room;Air circulated at high velocity in room; • Room environment cleansed by displacement Principle;Room environment cleansed by displacement Principle; • LAF Cabinets having Cleanliness Class ISO 5 falls under this category.LAF Cabinets having Cleanliness Class ISO 5 falls under this category. 3.3. Mixed flowMixed flow 4.4. Isolator or mini environmentIsolator or mini environment • Do not principally depend on airflow for isolation but uses walls of SS and Fibre-glass.Do not principally depend on airflow for isolation but uses walls of SS and Fibre-glass. • In the pharmaceutical manufacturing area, this technology is generally known asIn the pharmaceutical manufacturing area, this technology is generally known as isolator or barrier technology, whereas in the semiconductor industry it is generallyisolator or barrier technology, whereas in the semiconductor industry it is generally known as mini environments.known as mini environments. • SS Laminar Flow Glovebox /Isolator (LFGI) falls under this category.SS Laminar Flow Glovebox /Isolator (LFGI) falls under this category. • LFGI provides a contained environment that allows for greater protection for bothLFGI provides a contained environment that allows for greater protection for both personnel and product than traditional open front laminar flow equipment thus arepersonnel and product than traditional open front laminar flow equipment thus are used for Hazardous work with toxic chemicals or dangerous bacteriaused for Hazardous work with toxic chemicals or dangerous bacteria
  14. 14. Uni-directional / laminarUni-directional / laminar displacement of dirty airdisplacement of dirty air TurbulentTurbulent dilution of dirty airdilution of dirty air 0,45 m/s ± 20% Air flow patterns in Clean roomAir flow patterns in Clean room
  15. 15. PrefilterAir flow patterns AHU Main filter Uni-directional TurbulentTurbulent 1 2 3 AIR SUPPLY IN CLEAN ROOM BY HVAC SYSTEMAIR SUPPLY IN CLEAN ROOM BY HVAC SYSTEM
  16. 16. Sterile Suite Pressure CascadeSterile Suite Pressure Cascade = Room Pressure = ISO Cleanroom Class T = Turbulent U = Uni-directional 8 FILLING MACHINE 15Pa AUTO- CLAVES AUTO- CLAVES STERILE FILLING RM FINISHED PRODUCT STAGING MAT. A/L MAT. A/L A/L FORMULATION ROOM PERSONEL A/L CHANGE A/L STERILE CHANGE STERILE STAGING COMPONENT PREP 5 T 6 0 P a 5 T5 0 P a 4 0 P a 4 0 P a 4 0 P a 4 0 P a 2 5 P a 4 0 P a 63 0 P a 2 0 P a 2 0 P a 2 0 P a 2 0 P a 1 5 P a 2 0 P a 1 5 P a 2 0 P a 1 5 P a 2 0 P a 81 0 P a 7 5T 6 7 5T 5T 6 6 7 8 8 9 5U 6/7
  17. 17. Sterile suite withSterile suite with ––ve Pressure areasve Pressure areas PRODUCTION PASSAGE -25Pa -15Pa ROOM PRESSURE RELATIVE TO AMBIENT AIR LEAKAGE DIRECTION LEGEND WEIGH ROOM -40Pa FINISHED GOODS AIR LOCK MALE ABLUTIONS GRANULATING SYRUPS FILLING SUPER- VISOR FEMALE CHANGE MALE CHANGE FEMALE ABLUTIONS PACKING PRODUCT STOREA/L MAT A/L PACKING GOODS DRY POWDER FILLING TABLET COMPRES- SION SYRUPS PREPARATION WASH UP MIXING CAPSULE FILLING STAGING -40Pa -35Pa -30Pa -30Pa -35Pa -25Pa -15Pa -30Pa -20Pa -30Pa -10Pa -35Pa -25Pa -45Pa -35Pa -35Pa -35Pa -35Pa -35Pa -15Pa -25Pa -25Pa -45Pa -25Pa
  18. 18. PositioningPositioning of HEPA filtersof HEPA filters Filter in terminal positionAHU mounted final filter Production Room + Production Room HEPA Filter HEPA Filter
  19. 19. Air Supplied in Clean room by HVACAir Supplied in Clean room by HVAC The filtered air entering a production room can be: 100% exhausted or 100% fresh air Normally where toxic products are processed, and recirculation not recommended a proportion re-circulated There should be no risk of contamination and cross- contamination when air is recirculated
  20. 20. Ventilation with 100% fresh air (no air re-circulation)Ventilation with 100% fresh air (no air re-circulation) W Washer (optional) Central Air Handling Unit Production Rooms Exhaust Unit
  21. 21. Ventilation with re-circulated air + make-up airVentilation with re-circulated air + make-up air Central Air Handling Unit Return air Exhaust Unit
  22. 22. What is contamination?What is contamination? • Addition of foreign substance and altering of product qualityAddition of foreign substance and altering of product quality.. Contaminants are particulate, liquid, gaseous, film or biological inContaminants are particulate, liquid, gaseous, film or biological in nature. Some authorities also include radiation and electromagneticnature. Some authorities also include radiation and electromagnetic interference (EMI) as contaminants.interference (EMI) as contaminants. What is difference b/w contamination & Cross-contamination?What is difference b/w contamination & Cross-contamination? ContaminationContamination: Mixing of foreign substance which may alter the: Mixing of foreign substance which may alter the product quality.product quality. Cross-contaminationCross-contamination: Mixing of a RM, intermediate or finished: Mixing of a RM, intermediate or finished product into another RM, Intermediate or finished product whichproduct into another RM, Intermediate or finished product which may alter the product quality.may alter the product quality. Sources of particulate matter (contaminant):Sources of particulate matter (contaminant): • The supply air, i.e., externally sourcedThe supply air, i.e., externally sourced • The Internal particle generationThe Internal particle generation • The infiltration from adjacent spacesThe infiltration from adjacent spaces
  23. 23. Rationale for Monitoring Non-viable particles (1)Rationale for Monitoring Non-viable particles (1) • Though viable microbes cause the greatest concern in Pharmaceutial cleanThough viable microbes cause the greatest concern in Pharmaceutial clean room, control over non-viable particle contaminants is required for followingroom, control over non-viable particle contaminants is required for following reasons.reasons. i.i. Proof of control over particulate contaminantsProof of control over particulate contaminants The U.S. EPA has classified particles into following four size categories:The U.S. EPA has classified particles into following four size categories: a.a. UltrafineUltrafine : ≤ 0.1: ≤ 0.1μμmm b.b. FineFine : >0.1: >0.1 μμm to 2.5m to 2.5 μμmm c.c. CoarseCoarse : > 2.5 to 10: > 2.5 to 10 μμmm d.d. SupercoarseSupercoarse : > 10: > 10 μμmm  If these particulate matter makes its way into IV solutions orIf these particulate matter makes its way into IV solutions or injectibles/parenterals, they present a challenge to the patients organs andinjectibles/parenterals, they present a challenge to the patients organs and vascular system. If conc. is high and human body’s defense system is unable tovascular system. If conc. is high and human body’s defense system is unable to combat then it may lead to shock. Sufficiently sized particle may effect bloodcombat then it may lead to shock. Sufficiently sized particle may effect blood flow.flow.  The air borne particulate contaminants are stopped or reduced by installation ofThe air borne particulate contaminants are stopped or reduced by installation of HEPA Filters. The MPPS of HEPA filter is 0.3HEPA Filters. The MPPS of HEPA filter is 0.3μμm with increasing efficiency ofm with increasing efficiency of capture for smaller and larger particles.capture for smaller and larger particles.
  24. 24. Rationale for Monitoring Non-viable particles (2)Rationale for Monitoring Non-viable particles (2) ii.ii. Proof of control over viable particulate contaminants:Proof of control over viable particulate contaminants:  GMP accepts roughly proportional relationship b/w viable and Non-viable i.e.,GMP accepts roughly proportional relationship b/w viable and Non-viable i.e., control over non-viable shall also bring control over viable.control over non-viable shall also bring control over viable.  Total particulate conc. measurement does not give quantitative information onTotal particulate conc. measurement does not give quantitative information on the bioburden of the environment.the bioburden of the environment.  William whyte, during his studies, found that a viable contaminant existed b/wWilliam whyte, during his studies, found that a viable contaminant existed b/w 10 and 1510 and 15 μμm and no smaller, due to dessicating nature of the dry clean roomm and no smaller, due to dessicating nature of the dry clean room environment.environment.  The USP chapter <1116>, Microbial Evaluation of Clean Rooms states thatThe USP chapter <1116>, Microbial Evaluation of Clean Rooms states that “while airborne microbes are not free floating or single cells, they frequently“while airborne microbes are not free floating or single cells, they frequently associate with particles of 10 – 20associate with particles of 10 – 20 μμm.m.  So by controlling the large particles (>5So by controlling the large particles (>5 μμm), clean room sterility or risk of losingm), clean room sterility or risk of losing sterility, can be monitored.sterility, can be monitored.  Controlling the general particulate burden offers control over the viableControlling the general particulate burden offers control over the viable contamination risk, it does not alleviate the requirement for monitoring for thecontamination risk, it does not alleviate the requirement for monitoring for the viable fraction using other technologies (Dynamic air sampler, Settle plates,viable fraction using other technologies (Dynamic air sampler, Settle plates, Contact plates etc.)Contact plates etc.)
  25. 25. Rationale for Monitoring Non-viable particles (3)Rationale for Monitoring Non-viable particles (3) iii.iii. Proof of control over clean room activities both Personnel andProof of control over clean room activities both Personnel and Process oriented:Process oriented:  On performing particle monitoring we will always remain better informed. TheOn performing particle monitoring we will always remain better informed. The better informed we are, the better we can control particulate contamination.better informed we are, the better we can control particulate contamination. For e.g.,For e.g., a.a. Poorly gowned operator sheds more particles than properly gowned one.Poorly gowned operator sheds more particles than properly gowned one. b.b. New clean room gowns shed fewer particles than those laundered multipleNew clean room gowns shed fewer particles than those laundered multiple times.times.
  26. 26. Why All the Concern About Dust?Why All the Concern About Dust? Typical size relationship between dust, bacteria and viruses Virus (0,006µm to 0,03µm) Dust Particle (0,5µm to 500µm) Bacteria (0,2µm to 2µm) Dust Is a Bacteria Carrier
  27. 27. Eliminating sub-micron airborne contaminants are challengingEliminating sub-micron airborne contaminants are challenging Minuscule particles cannot be handled by regular cleaning toolsMinuscule particles cannot be handled by regular cleaning tools (Mops, Vacuum cleaners etc.)(Mops, Vacuum cleaners etc.) • ASHRAEASHRAE 66 defines particles smaller thandefines particles smaller than 2.52.5 μm in diameter as fine mode and thoseμm in diameter as fine mode and those larger thanlarger than 2.52.5 μmμm as coarse mode. Fine mode particles generally are less likely to setas coarse mode. Fine mode particles generally are less likely to set tle in ambient conditions and aretle in ambient conditions and are just as likely to deposit on vertical surfaces as on horijust as likely to deposit on vertical surfaces as on hori zontal surfaces. Coarse mode particles willzontal surfaces. Coarse mode particles will generally settle, and thus have a shorter lifgenerally settle, and thus have a shorter lif etime in the airborne state.etime in the airborne state. For exampleFor example, in an eight foot high room, a particle in the 50 micron range might take, in an eight foot high room, a particle in the 50 micron range might take 60 seconds to settle, while a 1 micron particle might take 15 hours to settle.60 seconds to settle, while a 1 micron particle might take 15 hours to settle. x x
  28. 28. Mechanism of Filtration through HEPA (1)Mechanism of Filtration through HEPA (1) HEPA filters are designed to target much smaller pollutants and particles.HEPA filters are designed to target much smaller pollutants and particles. These particles are trapped (they stick to a fiber) through a combination of theThese particles are trapped (they stick to a fiber) through a combination of the following three mechanisms:following three mechanisms: InterceptionInterception,, where particles following a line of flow in the air stream comewhere particles following a line of flow in the air stream come within one radius of a fiber and adhere to it.within one radius of a fiber and adhere to it. Impaction (Inertial Impaction)Impaction (Inertial Impaction),, where larger particles are unable to avoidwhere larger particles are unable to avoid fibers (as so large that it is unable to quickly adjust to the abrupt changes infibers (as so large that it is unable to quickly adjust to the abrupt changes in streamline direction near a filter fiber) while following the curving contours ofstreamline direction near a filter fiber) while following the curving contours of the air stream and are forced to embed in one of them directly; this effectthe air stream and are forced to embed in one of them directly; this effect increases with diminishing fiber separation and higher air flow velocity.increases with diminishing fiber separation and higher air flow velocity. DiffusionDiffusion,, an enhancing mechanism that is a result of the collision with gasan enhancing mechanism that is a result of the collision with gas molecules by the smallest particles, especially those below 0.1 micrometer inmolecules by the smallest particles, especially those below 0.1 micrometer in diameter, which are thereby impeded and delayed in their path through thediameter, which are thereby impeded and delayed in their path through the filter ; this behavior is similar to Brownian motion and raises the probability thatfilter ; this behavior is similar to Brownian motion and raises the probability that a particle will be stopped by either of the two mechanisms above; it becomesa particle will be stopped by either of the two mechanisms above; it becomes dominant at lower air flow velocities. Diffusion predominates below the 0.1dominant at lower air flow velocities. Diffusion predominates below the 0.1 micrometer diameter particle size. Impaction and interception predominatemicrometer diameter particle size. Impaction and interception predominate above 0.4 micrometer. In between, near the Most Penetrating Particle Sizeabove 0.4 micrometer. In between, near the Most Penetrating Particle Size (MPPS) 0.3 micrometer, both diffusion and interception are comparatively(MPPS) 0.3 micrometer, both diffusion and interception are comparatively inefficient. Therefore, the HEPA specifications use the retention of theseinefficient. Therefore, the HEPA specifications use the retention of these particles to define the filter.particles to define the filter.
  29. 29. Mechanism of Filtration through HEPA (2)Mechanism of Filtration through HEPA (2) Diffusion :Diffusion : Very small “particles” are bombarded by gas molecules causingVery small “particles” are bombarded by gas molecules causing them to move erratically (Brownian motion) and contact the filter fibers.them to move erratically (Brownian motion) and contact the filter fibers. OROR Diffusion :Diffusion : Particles are collected as they travel from areas of high airflow toParticles are collected as they travel from areas of high airflow to areas of low airflow, where other particles may already be trapped.areas of low airflow, where other particles may already be trapped. So, conclusion is:So, conclusion is: A HEPA filter that is 99.97% efficient at 0.3 microns is 99.97% effective atA HEPA filter that is 99.97% efficient at 0.3 microns is 99.97% effective at trapping particles at its most vulnerable size of 0.3 microns. For particles thattrapping particles at its most vulnerable size of 0.3 microns. For particles that either larger or smaller than 0.3 microns, the filter is actually more efficienteither larger or smaller than 0.3 microns, the filter is actually more efficient than 99.97%. 0.3 microns is considered the filter’s most penetrating particlethan 99.97%. 0.3 microns is considered the filter’s most penetrating particle size (MPPS), in other words, 0.3 microns is the size particle at whichsize (MPPS), in other words, 0.3 microns is the size particle at which penetration of particles through the filter is highest.penetration of particles through the filter is highest. HEPA filters are tested by challenging the filters with an aerosolized product ofHEPA filters are tested by challenging the filters with an aerosolized product of known size to determine the filter’s efficiency at that specific size. For example,known size to determine the filter’s efficiency at that specific size. For example, D.O.P or P.A.O. is forced through the filter using an aerosol generator. TheD.O.P or P.A.O. is forced through the filter using an aerosol generator. The filter is then scanned at downstream side using a photometer, or aerosolfilter is then scanned at downstream side using a photometer, or aerosol detection device.detection device.
  30. 30. Mechanism of Filtration through HEPA (3)Mechanism of Filtration through HEPA (3) HEPA filters are composed of a mat of randomly arranged fibres. The fibres are typicallyHEPA filters are composed of a mat of randomly arranged fibres. The fibres are typically composed of fiberglass and possess diameters between 0.5 and 2.0 micron. Key factors affectingcomposed of fiberglass and possess diameters between 0.5 and 2.0 micron. Key factors affecting function are fibre diameter, filter thickness, and face velocity. The air space between HEPA filterfunction are fibre diameter, filter thickness, and face velocity. The air space between HEPA filter fibres is much greater than 0.3 µm. The common assumption that a HEPA filter acts like a sievefibres is much greater than 0.3 µm. The common assumption that a HEPA filter acts like a sieve where particles smaller than the largest opening can pass through is incorrect. Unlike membranewhere particles smaller than the largest opening can pass through is incorrect. Unlike membrane filters, where particles as wide as the largest opening or distance between fibres cannot pass infilters, where particles as wide as the largest opening or distance between fibres cannot pass in between them at all, HEPA filters are designed to target much smaller pollutants and particles.between them at all, HEPA filters are designed to target much smaller pollutants and particles. These particles are trapped (they stick to a fibre) through a combination of the three mechanisms-These particles are trapped (they stick to a fibre) through a combination of the three mechanisms- Interception, Impaction and DiffusionInterception, Impaction and Diffusion
  31. 31. Removal of MicrobesRemoval of Microbes • As dust is a carrier, dust must be controlled.As dust is a carrier, dust must be controlled. • Ambient microbe is removed by filtration.Ambient microbe is removed by filtration. • Internal microbe distribution can be controlled byInternal microbe distribution can be controlled by directional air flow and air flushing or dilution.directional air flow and air flushing or dilution. • Surface microbe is controlled by adhering strictly toSurface microbe is controlled by adhering strictly to cleaning SOPs.cleaning SOPs.
  32. 32. States/Conditions of Clean roomStates/Conditions of Clean room air as built air air at rest in operation
  33. 33. How Are Cleanrooms Classified ?How Are Cleanrooms Classified ?
  34. 34. Classification of Clean AreasClassification of Clean Areas Comparison of classificationsComparison of classifications WHO GMP US 209E US Customary ISO/TC (209) ISO 14644 EEC GMP Grade A M 3.5 Class 100 ISO 5 Grade A Grade B M 3.5 Class 100 ISO 5 Grade B Grade C M 5.5 Class 10 000 ISO 7 Grade C Grade D M 6.5 Class 100 000 ISO 8 Grade D
  35. 35. Manufacturing Environment (1)Manufacturing Environment (1) Two operation states of Clean AreasTwo operation states of Clean Areas – Classified in terms of airborne particlesClassified in terms of airborne particles Grade At rest In operation maximum permitted number of particles/m3 0.5 - 5.0 µm > 5 µm 0.5 - 5.0 µm > 5 µ A 3 500 0 3 500 0 B 3 500 0 350 000 2 000 C 350 000 2 000 3 500 000 20 000 D 3 500 000 20 000 not defined not defined “At rest” - production equipment installed and operating “In operation” - Installed equipment functioning in defined operating mode and specified number of personnel present
  36. 36. 36 Manufacturing Environment (2)Manufacturing Environment (2) Four grades of clean areas:Four grades of clean areas: • Grade D (equivalent to Class 100,000, ISO 8):Grade D (equivalent to Class 100,000, ISO 8): – Clean area for carrying out less critical stages in manufacture ofClean area for carrying out less critical stages in manufacture of aseptically prepared products e.g., handling of components afteraseptically prepared products e.g., handling of components after washing.washing. • Grade C (equivalent to Class 10,000, ISO 7):Grade C (equivalent to Class 10,000, ISO 7): – Clean area for carrying out less critical stages in manufacture ofClean area for carrying out less critical stages in manufacture of aseptically prepared products e.g., preparation of solutions to beaseptically prepared products e.g., preparation of solutions to be filtered.filtered. • Grade B (equivalent to Class 100, ISO 5):Grade B (equivalent to Class 100, ISO 5): – For aseptic preparation & filling, Background environment for GradeFor aseptic preparation & filling, Background environment for Grade A zone, e.g., clean room in which laminar flow workstation isA zone, e.g., clean room in which laminar flow workstation is housed.housed.
  37. 37. Manufacturing Environment (3)Manufacturing Environment (3) • Grade A (equivalent to Class 100 (US Federal Standard 209E),Grade A (equivalent to Class 100 (US Federal Standard 209E), ISO 5 (ISO 14644-1):ISO 5 (ISO 14644-1): – Local zone for high risk operations e.g., product filling, stopper bowls,Local zone for high risk operations e.g., product filling, stopper bowls, open vials, handling sterile materials, aseptic connections, transfer ofopen vials, handling sterile materials, aseptic connections, transfer of partially stoppered containers to be lyophilized.partially stoppered containers to be lyophilized. – Conditions usually provided by laminar air flow workstation.Conditions usually provided by laminar air flow workstation. • Each grade of cleanroom has specifications for viable and non-viableEach grade of cleanroom has specifications for viable and non-viable particlesparticles
  38. 38. Manufacturing Environment (4)Manufacturing Environment (4) • Limits for microbiological monitoring (In Operation)Limits for microbiological monitoring (In Operation) Grade Air sample (CFU/m3) Settle plates (90mm diameter) (CFU/4hours) Contact plates (55mm diameter) (CFU/plate) Glove print (5 fingers) (CFU/glove) A < 1 < 1 < 1 < 1 B 10 5 5 5 C 100 50 25 - D 200 100 50 - – These are average values – Individual settle plates may be exposed for Not less than 4 hours • Values are for guidance only - not intended to represent specifications • Levels (limits) of detection of microbiological contamination should be established for alert and action purposes and for monitoring trends of air quality in the facility
  39. 39. air Sampling point Cleanroom monitoring programCleanroom monitoring program Cleanrooms should be monitored for micro-organisms & particles
  40. 40. Other parameters that need to be regulatedOther parameters that need to be regulated && monitored in Clean roomsmonitored in Clean rooms  TemperatureTemperature  Relative HumidityRelative Humidity  Room PressureRoom Pressure  Air movementAir movement  LightingLighting
  41. 41. ISO Standard 14644ISO Standard 14644 The ISO Standard 14644 is an internationally accepted standard ofThe ISO Standard 14644 is an internationally accepted standard of Cleanroom and the associated controlled environments.Cleanroom and the associated controlled environments. •This standard is used since its introduction of the First Edition in 1999.This standard is used since its introduction of the First Edition in 1999. •ISO 14644 consists of the following parts:ISO 14644 consists of the following parts: Part 1Part 1 :: Classification of air cleanlinessClassification of air cleanliness Part 2Part 2 :: Specifications for testing and monitoring to prove continuedSpecifications for testing and monitoring to prove continued compliance with ISO 14644-1compliance with ISO 14644-1 Part 3Part 3 :: Metrology and test methodsMetrology and test methods Part 4Part 4 :: Design, construction and start-upDesign, construction and start-up Part 5Part 5 :: OperationsOperations Part 6Part 6 :: Terms and definitionsTerms and definitions Part 7Part 7 :: Enhanced clean devices (Microenvironments and Isolators)Enhanced clean devices (Microenvironments and Isolators) Part 8Part 8 :: Molecular ContaminationMolecular Contamination
  42. 42. Cleanroom maintenance program (1)Cleanroom maintenance program (1) Schedule of Tests to Demonstrate Continuing Compliance Test Parameter Class MaximumTime Interval TestProcedure A,B <=ISO5 6Months ISO14644-1AnnexAParticle Count Test C,D >ISO5 12Months ISO14644-1AnnexA Air Pressure Difference AllClasses 12Months ISO14644-1AnnexB5 Air Flow AllClasses 12Months ISO14644-1AnnexB4
  43. 43. Cleanroom maintenance program (2)Cleanroom maintenance program (2) Schedule of Additional Optional Tests Test Parameter Class Maximum Time Interval Test Procedure Installed Filter Leakage All Classes 24 Months ISO 14644-1 Annex B6 Containment Leakage All Classes 24 Months ISO 14644-1 Annex B4 Recovery All Classes 24 Months ISO 14644-1 Annex B13 Air Flow Visualisation All Classes 24 Months ISO 14644-1 Annex B7
  44. 44. ISO Classifications (ISO 4 – ISO 1) used in following industriesISO Classifications (ISO 4 – ISO 1) used in following industries ISO 4:ISO 4: • High speed video duplicationHigh speed video duplication • Glass laminationGlass lamination ISO 3:ISO 3: • Compact disk manufacturingCompact disk manufacturing • Optical manufacturingOptical manufacturing ISO 2:ISO 2: • Semi-conductor manufacturingSemi-conductor manufacturing ISO 1:ISO 1: • Latest wafer and chip manufacturingLatest wafer and chip manufacturing • Hard disk manufacturingHard disk manufacturing
  45. 45. <USP> 797, the sequence for gowning<USP> 797, the sequence for gowning Personnel must don garb in the following order:Personnel must don garb in the following order: • Dedicated shoes or shoe covers.Dedicated shoes or shoe covers. • Head and facial hair covers and facemasks.Head and facial hair covers and facemasks. • Eye shields are optional unless working with irritants.Eye shields are optional unless working with irritants. • After this garb, personnel must clean their nails and wash theirAfter this garb, personnel must clean their nails and wash their hands.hands. • Then they must dry with lint-free disposable towels or an electricThen they must dry with lint-free disposable towels or an electric hand dryer.hand dryer. • After hands are dry, personnel must don a non-shedding gown.After hands are dry, personnel must don a non-shedding gown. • Once inside the buffer room, prior to donning sterile, powder freeOnce inside the buffer room, prior to donning sterile, powder free gloves, personnel must clean their hands with an alcohol basedgloves, personnel must clean their hands with an alcohol based surgical hand scrub as per mfg. recommendations.surgical hand scrub as per mfg. recommendations.
  46. 46. Sources of Contamination in Clean room (1)Sources of Contamination in Clean room (1) 1.1. PersonnelPersonnel • Skin flakes and oilSkin flakes and oil • Cosmetics and perfumeCosmetics and perfume • SpittleSpittle • Clothing debris (lint, fibers etc.)Clothing debris (lint, fibers etc.) • HairHair 2.2. FacilitiesFacilities • Walls, floors and ceilingsWalls, floors and ceilings • Paint and coatingsPaint and coatings • Construction material (sheet rock, saw dust etc.)Construction material (sheet rock, saw dust etc.) • Air conditioning debrisAir conditioning debris • Room air and vaporsRoom air and vapors • Spills and leaksSpills and leaks 3.3. Equipment / Tool GeneratedEquipment / Tool Generated • Friction and wear particlesFriction and wear particles • Lubricants and emissionsLubricants and emissions • VibrationsVibrations • Mops and dustersMops and dusters 44.. FluidsFluids • Cleaning chemicalsCleaning chemicals 55.. ProductProduct
  47. 47. Sources of Contamination in Clean room (2)Sources of Contamination in Clean room (2) Among the Several sources (Area ceilings, walls; materials, Equipment) the largest cause ofAmong the Several sources (Area ceilings, walls; materials, Equipment) the largest cause of contamination in a clean room are personnel.contamination in a clean room are personnel. 1.1. Standing or sitting with no movementStanding or sitting with no movement results in sheddingresults in shedding 100,000 particles/minute100,000 particles/minute 0.30.3 microns or larger.microns or larger. 2.2. Sitting or standing, light head, hand and forearm movementSitting or standing, light head, hand and forearm movement results in sheddingresults in shedding 500,000500,000 particles/minuteparticles/minute, 0.3 microns & larger., 0.3 microns & larger. 3.3. Sitting or standing, average body and arm movement , toe tappingSitting or standing, average body and arm movement , toe tapping, results in shedding, results in shedding 1,000,000 particles / minute1,000,000 particles / minute, 0.3 microns & larger., 0.3 microns & larger. 5.5. WalkingWalking 5a.5a. Slow walkingSlow walking (2 mph), results in shedding(2 mph), results in shedding 5,000,000 particles/minute5,000,000 particles/minute, 0.3 microns &, 0.3 microns & larger.larger. 5b.5b. Average walkingAverage walking (3.57 mph), results in shedding(3.57 mph), results in shedding 7,500,000 particles/minute7,500,000 particles/minute, 0.3 micron &, 0.3 micron & larger.larger. 5c.5c. Fast walkingFast walking (5 mph), results in shedding(5 mph), results in shedding 10,000,000 particles/minute10,000,000 particles/minute, 0.3 microns and, 0.3 microns and largerlarger 6.6. Climbing stairsClimbing stairs, results in shedding, results in shedding 10,000,000 particles/minute10,000,000 particles/minute, 0.3 microns and larger., 0.3 microns and larger. It is important that each of us understand how our personal hygiene and habits affect theIt is important that each of us understand how our personal hygiene and habits affect the Cleanroom’s cleanliness.Cleanroom’s cleanliness.
  48. 48. CLEANROOM DOs & DON’TsCLEANROOM DOs & DON’Ts DOs, before entering the Cleanroom:DOs, before entering the Cleanroom: • Enter only through the ante-room – no shortcuts.Enter only through the ante-room – no shortcuts. • Walk across tacky mat to clean soles of your shoes.Walk across tacky mat to clean soles of your shoes. • Wear shoe covers.Wear shoe covers. • Wear Cleanroom garments (bunny suit).Wear Cleanroom garments (bunny suit). • Wear a bouffant cap & beard cover, as per requirement.Wear a bouffant cap & beard cover, as per requirement. • Wear gloves, as per requirement.Wear gloves, as per requirement. • Wipe down any hand tools carrying.Wipe down any hand tools carrying. • Wipe down any other items brought into the area.Wipe down any other items brought into the area. DON’Ts, inside the Cleanroom:DON’Ts, inside the Cleanroom: • No wooden pallets, ladders or wood-handled tools.No wooden pallets, ladders or wood-handled tools. • No cardboard boxes.No cardboard boxes. • No pencils or erasers – pens only.No pencils or erasers – pens only. • Never bring in unclean or rusty tools.Never bring in unclean or rusty tools. • No Food, No Drink, No Chewing Gum – ever.No Food, No Drink, No Chewing Gum – ever. • No cosmetics and jewellery.No cosmetics and jewellery. DOs, Whenever leaving the CleanroomDOs, Whenever leaving the Cleanroom:: • Exit only through the ante-room/personnel Air Lock – no shortcuts.Exit only through the ante-room/personnel Air Lock – no shortcuts. • Remove Cleanroom garments within the ante-room.Remove Cleanroom garments within the ante-room. • Discard garments properly in bin only.Discard garments properly in bin only. • Take your time – haste does make waste.Take your time – haste does make waste.
  49. 49. Clean areas: Play a major role in the quality of pharmaceuticals. Design requires careful consideration of its intended use. Must be designed meticulously, by professionals. Must be treated as a critical system. ConclusionConclusion
  50. 50. THANK YOUTHANK YOU

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