Clean Room Overview Comparison of FDA and EU Regulations

Kumar Gupta Vice President, Parsons

Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 1

AGENDA Introduction FDA Regulations EU Regulations NIH Guidelines for Biologics Applications/Examples

Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 2

Sources of Contamination

Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 3

NJ Chapter. Feb. seed preparation for biologics Lower level of cleanliness Oral dosage Topical drugs Clean Room Overview.free of viable organisms and “large” particles Terminal sterilization (SAL of 10-6 or higher) Aseptic processing (SAL of 10-3) requires highest level of cleanliness Open manipulation of living organism – microbiology labs.Need for Clean rooms Sixties saw several incidences of contamination in injectables resulting in deaths and injury High level of cleanliness Injectable drugs and devices inserted into body and implants . 2008 Slide 4 . 21.

Feb. “appropriate”. NJ Chapter. “adequate”.Regulations don’t Tell Much It is the experience FDA regulations mostly describe results to be obtained but not how to obtain them Regulations have terms like “suitable”. 2008 Slide 5 . 21. “satisfactory” that require experience to interpret them This 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 Clean Room Overview.

History of Clean Room Regulations The first Federal Standard 209 published in 1963 Revised in 1966 (209A). and withdrawn in 2001. 2008 Slide 6 . 1973 (B). 1988 (D) and 1992 (E).000 EU issued more stringent GMPs in 1991 Industry followed EU GMPs and raised the bar further ISO standards adopted in 2001 FDA issued revised guide in 2004 mostly matching EU GMPs Clean Room Overview. Feb. 1987 (C). NJ Chapter. 21. first time describing class 100 and class100. Followed by industry all over the world UK published first “Orange Guide” (1971) Aseptic Processing Guide in 1987.

Feb. 21.0. NJ Chapter. 2008 Slide 7 .5 Clean Room Overview.

2008 Slide 8 .Atlantic Divide FDA FDA EMEA EMEA Clean Room Overview. NJ Chapter. Feb. 21.

FDA Regulations Clean Room Overview. 21. Feb. 2008 Slide 9 . NJ Chapter.

part 800 series Electronic Batch Records and Signatures 21 CFR part 11 ISPE Baseline Guidelines International GMPs FDA Guidelines for: Aseptic Processing Process Validation FDA’s “Points to Consider” ISO Standards Clean Room Overview. 21 CFR parts 210 & 211 Biologics. 2008 Slide 10 . 21CFR. Feb.Current Good Manufacturing Practices Umbrella GMPs. 21. 21 CFR. part 600 series Devices and Diagnostics. NJ Chapter.

Clean Room Overview. A person may rely upon this guideline with the assurance of its acceptability to FDA. 2008 Slide 11 . 21. or may follow different procedures. NJ Chapter. When different procedures are chosen.Guidelines A guideline states principles and practices of general applicability that are not legal requirements but are acceptable to the Food and Drug Administration (FDA). burden of proof rests with that person. Feb.

NJ Chapter. General (2 pages) Describes status. or Holding of Drugs. Packing.FDA Regulation-21CFR Parts 210 & 211 Umbrella GMPs PART 210--Current Good Manufacturing Practice In Manufacturing. 21. Feb. applicability and definitions PART 211--Current Good Manufacturing Practice For Finished Pharmaceuticals for administration to humans or animals (20 pages) Clean Room Overview. 2008 Slide 12 . Processing.

2008 Slide 13 . which includes as appropriate: – (i) Floors.42 Design and construction features (c) • (10) Aseptic processing. walls. 21. Feb. NJ Chapter.FDA Regulations 211. and ceilings of smooth. hard surfaces that are easily cleanable – (ii) Temperature and humidity controls Clean Room Overview.

FDA Regulations 211. 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 Clean Room Overview. 2008 Slide 14 . Feb.) – (iii) An air supply filtered through highefficiency particulate air filters (HEPA) under positive pressure.42 Design and construction features (cont. 21. NJ Chapter.

21.FDA Regulations 211.46 Ventilation. Feb. dust. humidity. air heating and cooling (a) Adequate ventilation shall be provided (b) Control of air pressure. air filtration. microorganisms. NJ Chapter. and temperature when appropriate Clean Room Overview.44 Lighting • Adequate lighting shall be provided in all areas 211. 2008 Slide 15 .

For recirculated systems. air heating and cooling (c) Pre-filters and HEPAs in air supply. processing. and packing of penicillin Clean Room Overview. NJ Chapter. 21.FDA Regulations 211.46 Ventilation. air filtration. adequate exhaust systems or other systems adequate to control contaminants (d) Separate HVAC for manufacture. 2008 Slide 16 . Feb.

NJ Chapter.Summary of Clean Room Regulations Specification and control of the following: Air quality – particle count (viable and nonviable) Temperature Humidity Room pressurization Air velocity or air changes Directional flow pattern Lighting Room finishes Clean Room Overview. 21. 2008 Slide 17 . Feb.

200 1 7 10 100 1 3 5 50 All classifications during period of activity Grade B Grade C 352. 21.520 35.520.000 10.000 3. 2008 Slide 18 .5 micron particles/ft3) ISO Designation (In Operation) EU Class Particles/m3 = 0. cfu/4 hours 100 1. 2004) FDA Classification (0. 90mm.000 5 6 7 8 Grade A 3. NJ Chapter.5 micron or larger Microbiological Active Air Action levels (cfu/m3) Settling Plates Action Levels (diam.000 Clean Room Overview.000 100. Feb.FDA Classifications Guideline (Sept.

2008 Slide 19 . Feb. NJ Chapter.Down flow Laminar Concept Contamination moves towards the floor Class 100 achievable throughout the room This concept is most widely used in the pharmaceutical industry Clean Room Overview. 21.

Cross Flow Laminar Concept 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 Clean Room Overview. 2008 Slide 20 . Feb. 21. NJ Chapter.

5 microns or larger Air circulation rate: 20 room volumes/hour(min) Temperature: 72°F ±5°F or as required Relative humidity: 30% to 50% Differential pressure: 0. 2008 Slide 21 . Feb. no limits specified.000 Clean Rooms No more than 100.05” of water (12.000 particles/cubic foot of air Particle size: 0.5 pascals) Bio-burden: 100 CFU/M3 (action level) Note: Regulation requires temperature and humidity control. However. NJ Chapter. 21.Class 100. Clean Room Overview.

Class 100 Clean Rooms
No more than 100 particles/cubic foot of air Particle size: 0.5 micron or larger Temperature: 72°F ±5°F or as required Relative humidity: 30% to 50% Differential pressure: 0.05” of water(12.5 pascals) Terminal HEPA filter Laminar flow (undisturbed flow) Air velocity: 90 ft. ±18 ft./minute (1987 guide) Bio-burden: 1 CFU/M3 (action level)
Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 22

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 walls Only empty room approaches laminar condition Air velocity of 90 fpm (0.45m/s) For a room height of 9 feet = 600 air changes/hour
Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 23

Typical “Class 100” Clean Room

9ft

Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 24

liquid impingement and membrane filtration For surfaces.g. floors. touch plates. frequency and timing Sampling and testing includes air quality.sampling location. swabs.Clean Room Monitoring Written monitoring program . Feb. slit to agar. 2008 Slide 25 . walls and equipment surfaces Settling plates (Petri type dishes containing nutrient agar) in critical areas “Active” samplers e. normally more frequently or after every upset Clean Room Overview. 21. NJ Chapter. centrifugal. and contact plates Test as a minimum once daily or once a shift while in active use.

Bio-contamination control: Measuring the efficiency cleaning and disinfect ion processes of inert surfaces. NJ Chapter. Terms. Operation of clean room systems Isolators and transfer devices Bio-contamination control: General principles and measurement Bio-contamination control:Evaluation and interpretation of biocontamination data.ISO/TC209 Standard Adopted by FDA to Replace FS 209E Number Short Title Approved for DIS Circulation 3/96 4/97 4/98 10/97 9/98 4/99 10/97 10/97 9/98 4/99 ISO 14644-1 ISO 14644-2 ISO 14644-3 ISO 14644-4 ISO 14644-5 ISO 14644-6 ISO 14698-1 ISO 14698-2 ISO 14698-3 ISO 14702 Air Cleanliness Classification Specification for testing clean rooms to prove continued compliance with ISO14644-1 Metrology and test methods Design. 2008 Slide 26 . Feb. definitions and units Clean Room Overview. construction and start-up of clean room facilities. 21.

700 237.3 µm 0. 21.200 102.000 29 293 2930 29.000 8 83 832 8320 83.000 35.000 ISO 5 100.1 µm 0.000. 2008 Slide 27 .000 ISO 6 1.200 832.000 ISO 7 ISO 8 237 2370 23.000 3.200 352.520.000 8. Feb.300 293.000 Clean Room Overview.200.000 ISO 9 35 352 3.320.2 µm 0.000 102 1020 10.ISO Airborne Particulate Cleanliness Classes Maximum number of particles in each cubic meter class equal to or greater than the specified size 0. NJ Chapter.520 35.5 µm 1 µm 5 µm ISO 1 10 2 4 ISO 2 100 24 10 ISO 3 1000 ISO 4 10.

Feb. 2008 Slide 28 .Guidance in Practice ISO 14644 is the new US Federal Standard. at rest or in operation. 21. NJ Chapter.ISO and FS 209E designations ISO 14644-1 requires ISO Class Number Specific Particle Size or Sizes Occupancy Status (as built. FDA always requires “in operation” Classification) Clean Room Overview. Classification should include both.

NJ Chapter. 2008 Slide 29 .AGENDA Introduction FDA Regulations EU Regulations NIH Guidelines for Biologics Applications/Examples Clean Room Overview. Feb. 21.

EU Regulations The European Economic Community (EEC) established in 1957 by 6 nations Today it has 27 members and 500 million people in 1. 21.7 million sq miles The European Commission initiates new proposals and monitors compliance The Pharmaceutical Committee provides expert advice to the Commission European Medicines Evaluation Agency (EMEA) created in 1995 and located in London coordinates new licensing system Clean Room Overview. 2008 Slide 30 . NJ Chapter. Feb.

Feb.EU Regulations Directive 65/65/EEC set EC-wide requirements for medicine control and still remains the basis of control Directive 89/342/EEC for vaccines Directive 89/381/EEC for blood products Directive 89/343/EEC for radiopharmaceuticals Directive 91/356/EEC for harmonization of GMPs Centralized. NJ Chapter. 21. decentralized and single state procedure Clean Room Overview. 2008 Slide 31 .

The rules governing medicinal products in the European Union Volume 4 of 9 Good Manufacturing Practices Commission Directive 91/356/EEC of 1991. Feb. GMPs for medicinal products for human use Commission Directive 91/412/EEC of 1991. GMPs for veterinary medicinal products Relevant 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 Clean Room Overview. NJ Chapter. 2008 Slide 32 . 21.

2008 Slide 33 . and Welfare (MHLW) Japan Pharmaceutical Manufactures Association (JPMA) Clean Room Overview. 21. Feb. and Japan (1990) Members FDA Pharmaceutical Research and Manufactures Association (PhRMA) European Union (EU) European Federation of Pharmaceutical Industries and Associations (EFPIA) Japan Ministry of Health. NJ Chapter. Labor.International Conference on Harmonization (ICH) Objective was to develop guidelines acceptable to health authorities of USA. EU.

these areas should be designed to reach certain specified air-cleanliness levels in the “at rest” occupancy state. The “in-operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working. Clean Room Overview. The “at-rest” state is the condition where the installation is installed and operational. 2008 Slide 34 .At Rest” and “In Operation” Condition In order to meet “in operations” conditions. NJ Chapter.EU Clean Rooms. complete with production equipment but with no operating personnel present. “At Rest” condition achieved in 15 to 20 minutes after operation ceased. 21. Feb.

500.5 µm 5 µm Grade A Grade B Grade C Grade D 3.000 Not defined 2.000 3.000 20.Clean Room Classification (EU) Maximum Permitted Number of Particles/m3 equal to or above At Rest 0.500. 2008 Slide 35 .000 0 0 In Operation 5 µm 0.000 Not defined Clean Room Overview.500 3. 21. NJ Chapter.500 350.5 µm 3. Feb.000 20.500 350.000 3.000 0 2.

500 100 350. not class Clean Room Overview. NJ Chapter.500 350.500.000 N/A At Rest Equivalent US** 3.500.000 100.000 3.000 100.5 micron or larger particles/cubic meter* EC Classification EC Grade A Grade B Grade C Grade D*** 3.000 10.500 100 3. Feb. 2008 Slide 36 .000 3.Comparison of EC & US Clean Rooms Maximum number of 0. of particles only.000 N/A In Operation Equivalent US EC 100 10. 21.000 *No.

limit for EU (FDA more stringent) Clean Room Overview. Feb. leftover from FDA 1987 guide) All FDA requirements are for “in operation” Viable count: action level for FDA vs. EU does specify (0.45m/s+20%. NJ Chapter.FDA and EU Differences FDA does not have Grade D FDA’s 2004 guide does not specify velocity for class 100. 2008 Slide 37 . 21.

Feb. contact plates. 2008 Slide 38 . EU: air sample (0. settling plates. 21. glove print. FDA: air sample (0.5 and 5 micron).5 micron) and settling plates Clean Room Overview. FDA only at 0.5 micron and 5 micron.FDA and EU Differences EU classification at 0. NJ Chapter.5 micron EU sampling more specific and more extensive.

AGENDA Introduction FDA Regulations EU Regulations NIH Guidelines for Biologics Applications/Examples Clean Room Overview. NJ Chapter. 21. Feb. 2008 Slide 39 .

NJ Chapter. Feb. 2008 Slide 40 .NIH Contaminant Classifications Guidelines Labs BSL1 BSL2 BSL3 BSL4 Production Plants Severity BSL1-LS BSL2-LS BSL3-LS Minimal Low Containment Primary Primary Moderate Primary + Secondary High Primary + Secondary Lab operations are carried in less then 10L fermentor Clean Room Overview. 21.

Feb. 21. NJ Chapter. 2008 Slide 41 .Basis for the Classification of Biohazardous Agents 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 available Risk Group 3 (RG3) -Agents associated with serious or lethal human disease for which preventive or therapeutic interventions may be available (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 usually available (high individual risk and high community risk) Clean Room Overview.

Viruses and Prions Risk Group 1 (RG1) – asporogenic Bacillus subtilis or Bacillus licheniformis Risk Group 2 (RG2) – Hepatitis A.Basis for the Classification of Biohazardous Agents by Risk Group (RG) Bacterial. D. 2008 Slide 42 . Parasitic. 21. C. NJ Chapter. B. and E viruses Herpes viruses Measles and Mumps virus Polioviruses Risk Group 3 (RG3) – Yellow fever virus Prions-Transmissible spongioform encephalopathies (TME) agents Human immunodeficiency virus (HIV) Risk Group 4 (RG4) – Crimean-Congo hemorrhagic fever virus Filo viruses Ebola virus Clean Room Overview. Feb. Fungal.

NJ Chapter. Feb.000 This concept can also be used for High Potency Compounds Clean Room Overview. 21.000 ++ 100.000 +++ 10. 2008 Slide 43 .Containment for Biologics (BSL-3) Fresh Air Once Through Exhaust HEPA Filter BSL-3 A/L ++ 10.

NIH Containment Guidelines Ventilation – movement of air and filtration of air (BL3) Exhaust air not re-circulated to other areas of facility Recommend once through air (dedicated single-pass exhaust system) Discharge through HEPA filters. Feb. thermal oxidizer A bag-in/bag-out (BIBO) filter or formaldehyde gas for decontamination of filters Exhaust air discharged away from supply air intakes Clean Room Overview. NJ Chapter. 2008 Slide 44 . 21.

HVAC. carefully sealed and room leak tested All pipe and other services through walls welded to a plate or sealed properly Provide spare openings and seal them for future use to avoid temptation to make holes Strictly control all future work in the room Spill containment dikes and room decontamination provision Clean Room Overview. 2008 Slide 45 . light fixtures etc. Feb.BL3-LS Design General Considerations All doors. NJ Chapter. 21.

21. 2008 Slide 46 .Building Pressurization Concept for Containment (e.0”WG (slight +ve) 100K +++ Contained Area + 100K + + 100K + Clean Room Overview.g. NJ Chapter. Feb. BL3) General Area 0.

Building Pressurization Concept for Containment Cleaner Contained Area General Area 0. 21. NJ Chapter. 2008 Slide 47 . Feb.0”WG (slight +ve) 100K ++ Contained Area + 10K 10K +++ + Clean Room Overview.

Feb. 2008 Slide 48 .AGENDA Introduction FDA Regulations EU Regulations NIH Guidelines for Biologics Applications/Examples Clean Room Overview. NJ Chapter. 21.

2008 Slide 49 . Feb. NJ Chapter. 21.Building Pressurization Concept General Corridor + Controlled Environment Area + + +100K Highest Cleanliness Area + + + ++ 10K ++++10K ++100K Clean Room Overview.

class 100 Clean Room Overview.Gowning Room At rest level of A/L should be the same as the at rest level of higher class i. 2008 Slide 50 . Feb. 21. NJ Chapter.e.

21. NJ Chapter.Typical Biologics Unit Operations Intracellular Products • Raw Materials • Water Off-CAS Containment Off-Gas Cell Lysis & Recovery • Salt • WFI Buffer Solution Media Preparation Fermentation or Cell Culture Extracellular Products Purification Sterile Filling & Lyophilization Containment & Waste Treatment Clean Room Overview. 2008 Slide 51 . Feb.

21. Feb.22 m m F Class 100.45 mm FILLING STOPPERING TRAYING FREEZE DRYING CLASS 100.000 S CARTO NER LABELER INSPECTIO N TERMINAL AUTOCLAVE S CAPPING LAM INAR FLOW S CLEAN STEAM W FI CASE PACKER PALLET ST RET CH W RAPPER TO W AREHO USE S Clean Room Overview. 2008 Slide 52 . NJ Chapter.Parenteral Plant W FI ACTIVE ING REDIENTS & E XCIPIENTS F Figure 4-1: Filling and Lyophilization Operations SO LUTIO N PREP TANK PREFILTER 0.000 with local HEPA for exposed areas S S CLASS 100 W FI G LASS VIALS FRO M W AREHO USE S W ASH RINSE STERILIZING TUNNEL F POLISH ING FILTER 0.000 OR CLASS 1.000 W FI & CLEAN ST EAM RUBBER STO PPERS W ASHER STERILIZER SILICO NE PARTS & TRAYS W ASHER S HO T AIR O VEN S CLASS 10.45 m m F STERILE RECEIVER STERILE FILTER 0.

000 Clean Room Overview. NJ Chapter. Feb.000 With isolators. 2008 Slide 53 . surrounding area class 100. 21.000 Low returns in Class 100. surrounding area Class 10.Guidance in Practice Terminal HEPA filters in Class 100 and Class 10. gowning rooms and airlocks In parenteral plants: With curtains and RABs. Class 10.000 .

21. Feb. 2008 Slide 54 . NJ Chapter.000 20 to 25 air changes Airlocks 60 air changes Infiltration/Ex-filtration Allowance (consistent with pressurization) Single door 370 CFM double door 520 CFM Clean Room Overview.Guidance in Practice Sufficient air change rates to dilute particulate Class 10.000 40 to 50 air changes Class 100.

Clean Room Construction Stick built . 2008 Slide 55 . NJ Chapter.more flexible. late design input possible Prefabricated panels .superior finishes Prefabricated modules with HVAC system – superior construction – may be more expensive – parallel construction – great in low tech geographical areas Modular Plant with all HVAC. Feb. piping and equipment – similar to above Clean Room Overview. 21.

Feb.•Smooth •Minimal ledges •Minimal joints •Radius corners •Non-shedding •Non-porous •Resistant to growth •Withstand repeated cleaning/sanitization Clean Room Overview. 2008 Slide 56 . NJ Chapter. 21.

21.Modular Airwall Systems Clean Room Overview. NJ Chapter. Feb. 2008 Slide 57 .

Media Makeup. 2008 Slide 58 . Feb. 21. NJ Chapter. Grade C Clean Room Overview.

2008 Slide 59 . 21. NJ Chapter. Grade C Clean Room Overview.20K Bioreactor. Feb.

NJ Chapter. 2008 Slide 60 . 21. Feb.Chromatography Column Grade B/C Clean Room Overview.

2008 Slide 61 . Feb. 21.Purification Suite with UF Skids Grade B/C Clean Room Overview. NJ Chapter.

operated. and maintained Clean Room Overview. 21.International cGMP Compliance World is one market All new facilities have to be world class FDA. Feb. and nonspecific regulations into a cost effective facility that can be easily validated. 2008 Slide 62 . often contradictory. NJ Chapter. EU and WHO – big players Objective is the translations of confusing.

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