Clean Room Presentation ISPE

Clean 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


AGENDA

IntroductionFDA Regulations EU RegulationsNIH Guidelines for BiologicsApplications/Examples


Sources of Contamination


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


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


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Revised in 1966 (209A), 1973 (B), 1987 (C), 1988 (D) and 1992 (E), and withdrawn in 2001.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


0.5


Atlantic Divide

FDAEMEA

FDAEMEA


FDA Regulations


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


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.


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)


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


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


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


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


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


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)


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


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


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


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)


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


Typical “Class 100” Clean Room

9ft


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


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


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


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)


AGENDA



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


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


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


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)


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.


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


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


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)


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


AGENDA



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


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)


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


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


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)


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


General Area 0.0”WG (slight +ve)

100K +++

Contained Area +100K

Building Pressurization Conceptfor Containment (e.g. BL3)

++

+100K


General Area 0.0”WG (slight +ve)

100K ++

Contained Area +10K

Building Pressurization Conceptfor Containment

Cleaner Contained Area

+10K +++


AGENDA



General Corridor +

Controlled Environment Area + + +100K

Highest Cleanliness Area + + + ++

10K

Building Pressurization Concept

++++10K

++100K


Gowning Room

At rest level of A/L should be the same as the at rest level of higher class i.e. class 100


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


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



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



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


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


•Smooth•Minimal ledges•Minimal joints•Radius corners•Non-shedding•Non-porous•Resistant to growth•Withstand repeated cleaning/sanitization


Modular Airwall Systems


Media Makeup, Grade C


20K Bioreactor, Grade C


Chromatography Column Grade B/C


Purification Suite with UF Skids Grade B/C


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

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