Slide 1Clean Room Overview, NJ Chapter, Feb. 21, 2008
Clean Room OverviewClean Room OverviewComparison of FDA and EU RegulationsComparison of FDA and EU Regulations
Kumar GuptaVice President, Parsons
Slide 2Clean Room Overview, NJ Chapter, Feb. 21, 2008
AGENDA
IntroductionFDA Regulations EU RegulationsNIH Guidelines for BiologicsApplications/Examples
Slide 3Clean Room Overview, NJ Chapter, Feb. 21, 2008
Sources of Contamination
Slide 4Clean Room Overview, NJ Chapter, Feb. 21, 2008
Need for Clean rooms
Sixties saw several incidences of contamination in injectables resulting in deaths and injuryHigh level of cleanliness
Injectable drugs and devices inserted into body and implants - free of viable organisms and “large” particlesTerminal sterilization (SAL of 10-6 or higher)Aseptic processing (SAL of 10-3) requires highest
level of cleanlinessOpen manipulation of living organism –microbiology labs, seed preparation for biologics
Lower level of cleanlinessOral dosageTopical drugs
Slide 5Clean Room Overview, NJ Chapter, Feb. 21, 2008
Regulations don’t Tell MuchIt is the experience
FDA regulations mostly describe results to be obtained but not how to obtain themRegulations have terms like “suitable”, “appropriate”, “adequate”, “satisfactory”that require experience to interpret themThis gives industry the freedom to improve and “leapfrog” one another in raising the standards without FDA lifting a finger (“c” in cGMPs always changes)Parenterals have been the driving force for clean rooms
Slide 6Clean Room Overview, NJ Chapter, Feb. 21, 2008
History of Clean Room RegulationsThe first Federal Standard 209 published in 1963
Revised in 1966 (209A), 1973 (B), 1987 (C), 1988 (D) and 1992 (E), and withdrawn in 2001.
Followed by industry all over the worldUK published first “Orange Guide” (1971)Aseptic Processing Guide in 1987, first time describing class 100 and class100,000 EU issued more stringent GMPs in 1991Industry followed EU GMPs and raised the bar furtherISO standards adopted in 2001FDA issued revised guide in 2004mostly matching EU GMPs
Slide 7Clean Room Overview, NJ Chapter, Feb. 21, 2008
0.5
Slide 8Clean Room Overview, NJ Chapter, Feb. 21, 2008
Atlantic Divide
FDAEMEA
FDAEMEA
Slide 9Clean Room Overview, NJ Chapter, Feb. 21, 2008
FDA Regulations
Slide 10Clean Room Overview, NJ Chapter, Feb. 21, 2008
Umbrella GMPs, 21 CFR parts 210 & 211Biologics, 21 CFR, part 600 series Devices and Diagnostics, 21CFR, part 800 seriesElectronic Batch Records and Signatures 21 CFR part 11ISPE Baseline GuidelinesInternational GMPsFDA Guidelines for:
Aseptic ProcessingProcess Validation
FDA’s “Points to Consider”ISO Standards
Current Good Manufacturing Practices
Slide 11Clean Room Overview, NJ Chapter, Feb. 21, 2008
GuidelinesA guideline states principles and practices of general applicability that are not legal requirements but are acceptable to the Food and Drug Administration (FDA).A person may rely upon this guideline with the assurance of its acceptability to FDA, or may follow different procedures.When different procedures are chosen, burden of proof rests with that person.
Slide 12Clean Room Overview, NJ Chapter, Feb. 21, 2008
FDA Regulation-21CFR Parts 210 & 211Umbrella GMPs
PART 210--Current Good Manufacturing Practice In Manufacturing, Processing, Packing, or Holding of Drugs; General (2 pages)
Describes status, applicability and definitions
PART 211--Current Good Manufacturing Practice For Finished Pharmaceuticals for administration to humans or animals (20 pages)
Slide 13Clean Room Overview, NJ Chapter, Feb. 21, 2008
211.42 Design and construction features (c)
• (10) Aseptic processing, which includes as appropriate:
– (i) Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable
– (ii) Temperature and humidity controls
FDA Regulations
Slide 14Clean Room Overview, NJ Chapter, Feb. 21, 2008
FDA Regulations
211.42 Design and construction features (cont.)
– (iii) An air supply filtered through high-efficiency particulate air filters (HEPA) under positive pressure, regardless of whether flow is laminar or non-laminar
– (iv) Monitoring environmental conditions– (v) Cleaning and disinfecting the room
and equipment– (vi) System to maintain equipment used to
control aseptic conditions
Slide 15Clean Room Overview, NJ Chapter, Feb. 21, 2008
211.44 Lighting• Adequate lighting shall be provided in all
areas211.46 Ventilation, air filtration, air heating and cooling
(a) Adequate ventilation shall be provided(b) Control of air pressure, micro-organisms, dust, humidity, and temperature when appropriate
FDA Regulations
Slide 16Clean Room Overview, NJ Chapter, Feb. 21, 2008
211.46 Ventilation, air filtration, air heating and cooling
(c) Pre-filters and HEPAs in air supply. For re-circulated systems, adequate exhaust systems or other systems adequate to control contaminants(d) Separate HVAC for manufacture, processing, and packing of penicillin
FDA Regulations
Slide 17Clean Room Overview, NJ Chapter, Feb. 21, 2008
Summary of Clean Room Regulations
Specification and control of the following:Air quality – particle count (viable and nonviable)TemperatureHumidityRoom pressurizationAir velocity or air changesDirectional flow patternLightingRoom finishes
Slide 18Clean Room Overview, NJ Chapter, Feb. 21, 2008
All classifications during period of activity
501003,520,000Grade C
8100,000
510352,000Grade B
710,000
3735,20061,000
113,520Grade A
5100
Settling Plates Action Levels (diam. 90mm; cfu/4 hours
Microbiological Active Air Action levels (cfu/m3)
Particles/m3 = 0.5 micron or larger
EU ClassISO Designation(In Operation)
FDA Classification (0.5 micron particles/ft3)
FDA Classifications Guideline (Sept. 2004)
Slide 19Clean Room Overview, NJ Chapter, Feb. 21, 2008
Contamination moves towards the floor
Class 100 achievable throughout the room
This concept is most widely used in the pharmaceutical industry
Down flow Laminar Concept
Slide 20Clean Room Overview, NJ Chapter, Feb. 21, 2008
Contamination moves from one wall to the other wall
Cleanest work area in the beginning
Suitable where work area is near the supply wall and a large number of people present
Cross Flow Laminar Concept
Slide 21Clean Room Overview, NJ Chapter, Feb. 21, 2008
No more than 100,000 particles/cubic foot of airParticle size: 0.5 microns or largerAir circulation rate: 20 room volumes/hour(min)Temperature: 72°F ±5°F or as required Relative humidity: 30% to 50% Differential pressure: 0.05” of water (12.5 pascals)Bio-burden: 100 CFU/M3 (action level)
Note: Regulation requires temperature and humidity control. However, no limits specified.
Class 100,000 Clean Rooms
Slide 22Clean Room Overview, NJ Chapter, Feb. 21, 2008
Class 100 Clean Rooms
No more than 100 particles/cubic foot of airParticle size: 0.5 micron or largerTemperature: 72°F ±5°F or as requiredRelative humidity: 30% to 50%Differential pressure: 0.05” of water(12.5 pascals)Terminal HEPA filterLaminar flow (undisturbed flow)Air velocity: 90 ft. ±18 ft./minute (1987 guide)Bio-burden: 1 CFU/M3 (action level)
Slide 23Clean Room Overview, NJ Chapter, Feb. 21, 2008
Laminar Flow Rooms
Undisturbed flow of air in a single direction (parallel flow lines)Flow can be ceiling to floor (down flow) or across parallel walls (cross flow)Air supplied by whole ceiling or whole wall and returned through air wallsOnly empty room approaches laminar conditionAir velocity of 90 fpm (0.45m/s) For a room height of 9 feet = 600 air changes/hour
Slide 24Clean Room Overview, NJ Chapter, Feb. 21, 2008
Typical “Class 100” Clean Room
9ft
Slide 25Clean Room Overview, NJ Chapter, Feb. 21, 2008
Clean Room MonitoringWritten monitoring program - sampling location, frequency and timingSampling and testing includes air quality, floors, walls and equipment surfacesSettling plates (Petri type dishes containing nutrient agar) in critical areas“Active” samplers e.g. slit to agar, centrifugal, liquid impingement and membrane filtrationFor surfaces, touch plates, swabs,and contact platesTest as a minimum once daily or once a shift while in active use, normally more frequently or after every upset
Slide 26Clean Room Overview, NJ Chapter, Feb. 21, 2008
Adopted by FDA to Replace FS 209E
ISO/TC209 Standard
Number Short Title Approved for DIS Circulation
ISO 14644-1 Air Cleanliness Classification 3/96
ISO 14644-2 Specification for testing clean rooms to prove continued compliance with ISO14644-1
4/97
ISO 14644-3 Metrology and test methods 4/98
ISO 14644-4 Design, construction and start-up of clean room facilities. 10/97
ISO 14644-5 Operation of clean room systems 9/98
ISO 14644-6 Isolators and transfer devices 4/99
ISO 14698-1 Bio-contamination control: General principles and measurement 10/97
ISO 14698-2 Bio-contamination control:Evaluation and interpretation of bio-contamination data.
10/97
ISO 14698-3 Bio-contamination control: Measuring the efficiency cleaning and disinfect ion processes of inert surfaces.
9/98
ISO 14702 Terms, definitions and units 4/99
Number Short Title Approved for DIS Circulation
ISO 14644-1 Air Cleanliness Classification 3/96
ISO 14644-2 Specification for testing clean rooms to prove continued compliance with ISO14644-1
4/97
ISO 14644-3 Metrology and test methods 4/98
ISO 14644-4 Design, construction and start-up of clean room facilities. 10/97
ISO 14644-5 Operation of clean room systems 9/98
ISO 14644-6 Isolators and transfer devices 4/99
ISO 14698-1 Bio-contamination control: General principles and measurement 10/97
ISO 14698-2 Bio-contamination control:Evaluation and interpretation of bio-contamination data.
10/97
ISO 14698-3 Bio-contamination control: Measuring the efficiency cleaning and disinfect ion processes of inert surfaces.
9/98
ISO 14702 Terms, definitions and units 4/99
Slide 27Clean Room Overview, NJ Chapter, Feb. 21, 2008
classMaximum number of particles in each cubic meterequal to or greater than the specified size0.1 µm 0.2 µm 0.3 µm 0.5 µm 1 µm 5 µm
ISO 1 10 2
ISO 2 100 24 10 4
ISO 3 1000 237 102 35 8ISO 4 10,000 2370 1020 352 83ISO 5 100,000 23,700 10,200 3,520 832 29ISO 6 1,000,000 237,000 102,000 35,200 8320 293ISO 7 352,000 83,200 2930ISO 8 3,520,000 832,000 29,300ISO 9 35,200,000 8,320,000 293,000
ISO Airborne Particulate Cleanliness Classes
Slide 28Clean Room Overview, NJ Chapter, Feb. 21, 2008
Guidance in Practice
ISO 14644 is the new US Federal Standard. Classification should include both,ISO and FS 209E designationsISO 14644-1 requires
ISO Class NumberSpecific Particle Size or SizesOccupancy Status (as built, at rest or in operation; FDA always requires “in operation”Classification)
Slide 29Clean Room Overview, NJ Chapter, Feb. 21, 2008
AGENDA
IntroductionFDA Regulations EU RegulationsNIH Guidelines for BiologicsApplications/Examples
Slide 30Clean Room Overview, NJ Chapter, Feb. 21, 2008
EU Regulations
The European Economic Community (EEC) established in 1957 by 6 nationsToday it has 27 members and500 million people in 1.7 million sq miles The European Commission initiates new proposals and monitors complianceThe Pharmaceutical Committee provides expert advice to the CommissionEuropean Medicines Evaluation Agency (EMEA) created in 1995 and located in London coordinates new licensing system
Slide 31Clean Room Overview, NJ Chapter, Feb. 21, 2008
EU RegulationsDirective 65/65/EEC set EC-wide requirements for medicine control and still remains the basis of controlDirective 89/342/EEC for vaccinesDirective 89/381/EEC for blood productsDirective 89/343/EEC for radio-pharmaceuticalsDirective 91/356/EEC for harmonization of GMPsCentralized, decentralized and single state procedure
Slide 32Clean Room Overview, NJ Chapter, Feb. 21, 2008
Volume 4 of 9Good Manufacturing Practices
Commission Directive 91/356/EEC of 1991, GMPs for medicinal products for human useCommission Directive 91/412/EEC of 1991, GMPs for veterinary medicinal productsRelevant Annexes
• Annex 1 Manufacture of sterile drug products• Annex 2 Manufacture of biological medicinal
products for human use• Annex 14 Manufacture of products derived from
blood or human plasma• Annex 18 GMPs for active pharmaceutical
ingredients
The rules governing medicinal products in the European Union
Slide 33Clean Room Overview, NJ Chapter, Feb. 21, 2008
International Conference on Harmonization (ICH)
Objective was to develop guidelines acceptable to health authorities of USA, EU, and Japan (1990)Members
FDAPharmaceutical Research and Manufactures Association (PhRMA)European Union (EU)European Federation of Pharmaceutical Industries and Associations (EFPIA)Japan Ministry of Health, Labor, and Welfare (MHLW)Japan Pharmaceutical Manufactures Association (JPMA)
Slide 34Clean Room Overview, NJ Chapter, Feb. 21, 2008
EU Clean Rooms- At Rest” and “In Operation” Condition
In order to meet “in operations” conditions, these areas should be designed to reach certain specified air-cleanliness levels in the “at rest” occupancy state.The “at-rest” state is the condition where the installation is installed and operational, complete with production equipment but with no operating personnel present. “At Rest”condition achieved in 15 to 20 minutes after operation ceased.The “in-operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.
Slide 35Clean Room Overview, NJ Chapter, Feb. 21, 2008
Clean Room Classification (EU)
Not defined
Not defined
20,0003,500,000Grade D
20,0003,500,0002,000350,000Grade C
2,000350,00003,500Grade B
03,50003,500Grade A
5 µm0.5 µm5 µm0.5 µmIn OperationAt Rest
Maximum Permitted Number of Particles/m3 equal to or above
Slide 36Clean Room Overview, NJ Chapter, Feb. 21, 2008
Maximum number of 0.5 micron or larger particles/cubic meter*
EC Classification
In Operation At Rest
EC Equivalent US EC Equivalent US**
Grade A 3,500 100 3,500 100 Grade B 350,000 10,000 3,500 100 Grade C 3,500,000 100,000 350,000 10,000 Grade D*** N/A N/A 3,500,000 100,000
Comparison of EC & US Clean Rooms
*No. of particles only, not class
Slide 37Clean Room Overview, NJ Chapter, Feb. 21, 2008
FDA and EU Differences
FDA does not have Grade D
FDA’s 2004 guide does not specify velocity for class 100, EU does specify (0.45m/s+20%, leftover from FDA 1987 guide)
All FDA requirements are for “in operation”
Viable count: action level for FDA vs. limit for EU (FDA more stringent)
Slide 38Clean Room Overview, NJ Chapter, Feb. 21, 2008
FDA and EU Differences
EU classification at 0.5 micron and 5 micron, FDA only at 0.5 micron
EU sampling more specific and more extensive, EU: air sample (0.5 and 5 micron), settling plates, contact plates, glove print; FDA: air sample (0.5 micron) and settling plates
Slide 39Clean Room Overview, NJ Chapter, Feb. 21, 2008
AGENDA
IntroductionFDA Regulations EU RegulationsNIH Guidelines for BiologicsApplications/Examples
Slide 40Clean Room Overview, NJ Chapter, Feb. 21, 2008
NIH Contaminant ClassificationsGuidelines
Primary + Secondary
HighBSL4
Primary + Secondary
ModerateBSL3-LSBSL3
PrimaryLowBSL2-LSBSL2
PrimaryMinimalBSL1-LSBSL1
ContainmentSeverityProduction PlantsLabs
Lab operations are carried in less then 10L fermentor
Slide 41Clean Room Overview, NJ Chapter, Feb. 21, 2008
Basis for the Classification of BiohazardousAgents by Risk Group (RG)
Risk Group 1 (RG1) -Agents not associated with disease in healthy adult humans Risk Group 2 (RG2) -Agents associated with human disease but rarely serious and for which preventive or therapeutic interventions availableRisk Group 3 (RG3) -Agents associated with serious or lethal human disease for which preventive or therapeutic interventions may beavailable (high individual risk but low community risk)Risk Group 4 (RG4) -Agents likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usuallyavailable (high individual risk and high community risk)
Slide 42Clean Room Overview, NJ Chapter, Feb. 21, 2008
Basis for the Classification of BiohazardousAgents by Risk Group (RG)
Risk Group 1 (RG1) –asporogenic Bacillus subtilis or Bacillus licheniformis
Risk Group 2 (RG2) –Hepatitis A, B, C, D, and E virusesHerpes virusesMeasles and Mumps virusPolioviruses
Risk Group 3 (RG3) –Yellow fever virusPrions-Transmissible spongioform encephalopathies (TME) agents Human immunodeficiency virus (HIV)
Risk Group 4 (RG4) –Crimean-Congo hemorrhagic fever virusFilo viruses Ebola virus
Bacterial, Fungal, Parasitic, Viruses and Prions
Slide 43Clean Room Overview, NJ Chapter, Feb. 21, 2008
Containment for Biologics (BSL-3)
++10,000
+++10,000
++100,000
HEPA Filter
Fresh Air
A/L
ExhaustOnce Through
This concept can also be used for High Potency Compounds
BSL-3
Slide 44Clean Room Overview, NJ Chapter, Feb. 21, 2008
NIH Containment Guidelines
Exhaust air not re-circulated to other areas of facilityRecommend once through air (dedicated single-pass exhaust system) Discharge through HEPA filters, thermal oxidizerA bag-in/bag-out (BIBO) filter or formaldehyde gas for decontamination of filtersExhaust air discharged away from supply air intakes
Ventilation – movement of air and filtration of air(BL3)
Slide 45Clean Room Overview, NJ Chapter, Feb. 21, 2008
BL3-LS DesignGeneral Considerations
All doors, HVAC, light fixtures etc. carefully sealed and room leak testedAll pipe and other services through walls welded to a plate or sealed properlyProvide spare openings and seal them for future use to avoid temptation to make holesStrictly control all future work in the roomSpill containment dikes and room decontamination provision
Slide 46Clean Room Overview, NJ Chapter, Feb. 21, 2008
General Area 0.0”WG (slight +ve)
100K +++
Contained Area +100K
Building Pressurization Conceptfor Containment (e.g. BL3)
++
+100K
Slide 47Clean Room Overview, NJ Chapter, Feb. 21, 2008
General Area 0.0”WG (slight +ve)
100K ++
Contained Area +10K
Building Pressurization Conceptfor Containment
Cleaner Contained Area
+10K +++
Slide 48Clean Room Overview, NJ Chapter, Feb. 21, 2008
AGENDA
IntroductionFDA Regulations EU RegulationsNIH Guidelines for BiologicsApplications/Examples
Slide 49Clean Room Overview, NJ Chapter, Feb. 21, 2008
General Corridor +
Controlled Environment Area + + +100K
Highest Cleanliness Area + + + ++
10K
Building Pressurization Concept
++++10K
++100K
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Gowning Room
At rest level of A/L should be the same as the at rest level of higher class i.e. class 100
Slide 51Clean Room Overview, NJ Chapter, Feb. 21, 2008
Typical Biologics Unit Operations
Cell Lysis& Recovery Buffer Solution
Purification Sterile Filling& Lyophilization
Media Preparation
Fermentationor Cell Culture
Containment & Waste Treatment
• Salt• WFI
Off-CASContainment
• Raw Materials• Water
Intracellular Products
ExtracellularProducts
Off-Gas
Slide 52Clean Room Overview, NJ Chapter, Feb. 21, 2008
Figure 4-1: Filling and Lyophilization Operations
S S
S SS
W ASHERSTERILIZER
HOT AIROVEN
CASEPACKER
S
W FI ACTIVE INGREDIENTS& EXCIPIENTS
F F
F
F
SOLUTION PREP TANK
STERILE RECEIVER
PREFILTER 0.45 mm
STERILEFILTER
0.22 mm
GLASS VIALS FROM
W AREHOUSE
W FI
W ASH RINSE STERILIZINGTUNNEL
FILLING STOPPERING TRAYING FREEZEDRYING
CLASS 100
CLASS 10,000OR
CLASS 1,000
W FI & CLEAN STEAM
RUBBER STOPPERS
SILICONE
CLASS 100,000
CLEAN STEAM
W FI
TO W AREHOUSE
LAMINAR FLOW
W ASHERPARTS
& TRAYS
LABELER INSPECTIONTERMINAL
AUTOCLAVE CAPPING
PALLET STRETCHW RAPPER
POLISHING FILTER 0.45 mm
CARTONER
S
S
S
Parenteral Plant
Class 100,000 with local HEPAfor exposed areas
Slide 53Clean Room Overview, NJ Chapter, Feb. 21, 2008
Guidance in Practice
Terminal HEPA filters in Class 100 and Class 10,000Low returns in Class 100, Class 10,000 , gowning rooms and airlocksIn parenteral plants:
With curtains and RABs, surrounding area Class 10,000With isolators, surrounding area class 100,000
Slide 54Clean Room Overview, NJ Chapter, Feb. 21, 2008
Guidance in Practice
Sufficient air change rates to dilute particulateClass 10,000 40 to 50 air changesClass 100,000 20 to 25 air changesAirlocks 60 air changes
Infiltration/Ex-filtration Allowance (consistent with pressurization)
Single door 370 CFM double door 520 CFM
Slide 55Clean Room Overview, NJ Chapter, Feb. 21, 2008
Clean Room Construction
Stick built - more flexible, late design input possiblePrefabricated panels - superior finishesPrefabricated modules with HVAC system – superior construction– may be more expensive– parallel construction– great in low tech geographical areas
Modular Plant with all HVAC, piping and equipment – similar to above
Slide 56Clean Room Overview, NJ Chapter, Feb. 21, 2008
•Smooth•Minimal ledges•Minimal joints•Radius corners•Non-shedding•Non-porous•Resistant to growth•Withstand repeated cleaning/sanitization
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Modular Airwall Systems
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Media Makeup, Grade C
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20K Bioreactor, Grade C
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Chromatography Column Grade B/C
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Purification Suite with UF Skids Grade B/C
Slide 62Clean Room Overview, NJ Chapter, Feb. 21, 2008
International cGMP Compliance
World is one marketAll new facilities have to be world class FDA, EU and WHO – big playersObjective is the translations of confusing, often contradictory, and non-specific regulations into a cost effective facility that can be easily validated, operated, and maintained