Clean Room Presentation ISPE

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 ƒ Introduction ƒ FDA Regulations ƒ EU Regulations ƒ NIH Guidelines for Biologics ƒ 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

Need for Clean rooms ƒ Sixties saw several incidences of contamination in injectables resulting in deaths and injury ƒ High level of cleanliness ¾ Injectable drugs and devices inserted into body and implants - free of viable organisms and “large” particles ¾ Terminal sterilization (SAL of 10-6 or higher) ¾ Aseptic processing (SAL of 10-3) requires highest level of cleanliness ¾ Open manipulation of living organism – microbiology labs, seed preparation for biologics ƒ Lower level of cleanliness ¾ Oral dosage ¾ Topical drugs Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 4

Regulations don’t Tell Much It is the experience ƒ FDA regulations mostly describe results to be obtained but not how to obtain them ƒ Regulations have terms like “suitable”, “appropriate”, “adequate”, “satisfactory” that require experience to interpret them ƒ 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) ƒ Parenterals have been the driving force for clean rooms Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 5

History of Clean Room Regulations ƒ The first Federal Standard 209 published in 1963 ¾ Revised in 1966 (209A), 1973 (B), 1987 (C), 1988 (D) and 1992 (E), and withdrawn in 2001.

ƒ Followed by industry all over the world ƒ UK published first “Orange Guide” (1971) ƒ Aseptic Processing Guide in 1987, first time describing class 100 and class100,000 ƒ EU issued more stringent GMPs in 1991 ƒ Industry followed EU GMPs and raised the bar further ƒ ISO standards adopted in 2001 ƒ FDA issued revised guide in 2004 mostly matching EU GMPs Clean Room Overview, NJ Chapter, Feb. 21, 2008

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0.5

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

Slide 7

Atlantic Divide

FDA FDA

EMEA EMEA

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

Slide 8

FDA Regulations

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

Slide 9

Current Good Manufacturing Practices ƒ ƒ ƒ ƒ

Umbrella GMPs, 21 CFR parts 210 & 211 Biologics, 21 CFR, part 600 series Devices and Diagnostics, 21CFR, part 800 series Electronic Batch Records and Signatures 21 CFR part 11 ƒ ISPE Baseline Guidelines ƒ International GMPs ƒ FDA Guidelines for: ¾ Aseptic Processing ¾ Process Validation

ƒ FDA’s “Points to Consider” ƒ ISO Standards

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

Slide 10

Guidelines ƒ A guideline states principles and

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

Slide 11

FDA Regulation-21CFR Parts 210 & 211 Umbrella GMPs ƒ PART 210--Current Good Manufacturing Practice In Manufacturing, Processing, Packing, or Holding of Drugs; General (2 pages) ¾ Describes status, applicability and definitions

ƒ PART 211--Current Good Manufacturing Practice For Finished Pharmaceuticals for administration to humans or animals (20 pages) Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 12

FDA Regulations ƒ 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 Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 13

FDA Regulations ƒ 211.42 Design and construction features (cont.) – (iii) An air supply filtered through highefficiency 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 Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 14

FDA Regulations ƒ 211.44 Lighting • Adequate lighting shall be provided in all areas ƒ 211.46 Ventilation, air filtration, air heating and cooling ¾(a) Adequate ventilation shall be provided ¾(b) Control of air pressure, microorganisms, dust, humidity, and temperature when appropriate

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

Slide 15

FDA Regulations ƒ 211.46 Ventilation, air filtration, air heating and cooling ¾(c) Pre-filters and HEPAs in air supply. For recirculated systems, adequate exhaust systems or other systems adequate to control contaminants ¾(d) Separate HVAC for manufacture, processing, and packing of penicillin

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

Slide 16

Summary of Clean Room Regulations ƒ Specification and control of the following: ¾Air quality – particle count (viable and nonviable) ¾Temperature ¾Humidity ¾Room pressurization ¾Air velocity or air changes ¾Directional flow pattern ¾Lighting ¾Room finishes Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 17

FDA Classifications Guideline (Sept. 2004) FDA Classification (0.5 micron particles/ft3)

ISO Designation (In Operation)

EU Class

100

5

Grade A

1,000

6

10,000

7

100,000

8

Particles/m3 = 0.5 micron or larger

Microbiological Active Air Action levels (cfu/m3)

Settling Plates Action Levels (diam. 90mm; cfu/4 hours

1

1

35,200

7

3

Grade B

352,000

10

5

Grade C

3,520,000

100

50

3,520

All classifications during period of activity

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

Slide 18

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, NJ Chapter, Feb. 21, 2008

Slide 19

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, NJ Chapter, Feb. 21, 2008

Slide 20

Class 100,000 Clean Rooms ƒ No more than 100,000 particles/cubic foot of air ƒ Particle size: 0.5 microns or larger ƒ Air circulation rate: 20 room volumes/hour(min) ƒ Temperature: 72°F ±5°F or as required ƒ Relative humidity: 30% to 50% ƒ Differential pressure: 0.05” of water (12.5 pascals) ƒ Bio-burden: 100 CFU/M3 (action level) Note: Regulation requires temperature and humidity control. However, no limits specified. Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 21

Class 100 Clean Rooms ƒ ƒ ƒ ƒ ƒ ƒ ƒ ƒ ƒ

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 ƒ Undisturbed flow of air in a single direction (parallel flow lines) ƒ Flow can be ceiling to floor (down flow) or across parallel walls (cross flow) ƒ Air supplied by whole ceiling or whole wall and returned through air walls ƒ Only empty room approaches laminar condition ƒ 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

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

Slide 25

ISO/TC209 Standard Adopted by FDA to Replace FS 209E 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 biocontamination 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

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

Slide 26

ISO Airborne Particulate Cleanliness Classes Maximum number of particles in each cubic meter class equal to or greater than the specified size 0.1 µm 0.2 µm 0.3 µm 0.5 µm 1 µm 5 µm ISO 1 10 2 4 ISO 2 100 24 10 ISO 3 1000 ISO 4 10,000 ISO 5 100,000 ISO 6 1,000,000 ISO 7 ISO 8

ISO 9

237 2370 23,700 237,000

102 1020 10,200 102,000

35 352 3,520 35,200 352,000 3,520,000 35,200,000

8 83 832 8320 83,200 832,000 8,320,000

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

29 293 2930 29,300 293,000

Slide 27

Guidance in Practice ƒ ISO 14644 is the new US Federal Standard. Classification should include both,ISO and FS 209E designations ƒ ISO 14644-1 requires ¾ ISO Class Number ¾ Specific Particle Size or Sizes ¾ Occupancy Status (as built, at rest or in operation; FDA always requires “in operation” Classification)

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

Slide 28

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

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

Slide 29

EU Regulations ƒ The European Economic Community (EEC) established in 1957 by 6 nations ƒ Today it has 27 members and 500 million people in 1.7 million sq miles ƒ The European Commission initiates new proposals and monitors compliance ƒ The Pharmaceutical Committee provides expert advice to the Commission ƒ European Medicines Evaluation Agency (EMEA) created in 1995 and located in London coordinates new licensing system Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 30

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

Slide 31

The rules governing medicinal products in the European Union Volume 4 of 9 Good Manufacturing Practices ƒ Commission Directive 91/356/EEC of 1991, GMPs for medicinal products for human use ƒ Commission Directive 91/412/EEC of 1991, GMPs for veterinary medicinal products ƒ 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, Feb. 21, 2008

Slide 32

International Conference on Harmonization (ICH) ƒ Objective was to develop guidelines acceptable to health authorities of USA, EU, and Japan (1990) ƒ Members ¾ FDA ¾ Pharmaceutical Research and Manufactures Association (PhRMA) ¾ European Union (EU) ¾ European Federation of Pharmaceutical Industries and Associations (EFPIA) ¾ Japan Ministry of Health, Labor, and Welfare (MHLW) ¾ Japan Pharmaceutical Manufactures Association (JPMA) Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 33

EU Clean Rooms- At Rest” and “In Operation” Condition ƒ 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. ƒ 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. ƒ 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, NJ Chapter, Feb. 21, 2008

Slide 34

Clean Room Classification (EU) Maximum Permitted Number of Particles/m3 equal to or above

At Rest 0.5 µm 5 µm

In Operation 5 µm 0.5 µm

Grade A

3,500

0

3,500

0

Grade B

3,500

0

350,000

2,000

Grade C

350,000

2,000 3,500,000

20,000

Grade D

3,500,000

20,000

Not defined

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

Not defined

Slide 35

Comparison of EC & US Clean Rooms Maximum number of 0.5 micron or larger particles/cubic meter* EC Classification

Grade A Grade B Grade C Grade D***

In Operation

At Rest

EC

Equivalent US EC

Equivalent US** 3,500 100 3,500 100 350,000 10,000 3,500,000 100,000

3,500 350,000 3,500,000 N/A

100 10,000 100,000 N/A

*No. of particles only, not class Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 36

FDA and EU Differences ƒ FDA does not have Grade D ƒ FDA’s 2004 guide does not specify velocity for class 100, EU does specify (0.45m/s+20%, leftover from FDA 1987 guide) ƒ All FDA requirements are for “in operation” ƒ Viable count: action level for FDA vs. limit for EU (FDA more stringent)

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

Slide 37

FDA and EU Differences ƒ EU classification at 0.5 micron and 5 micron, FDA only at 0.5 micron ƒ 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

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

Slide 38

AGENDA ƒ ƒ ƒ ƒ

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

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

Slide 39

NIH Contaminant Classifications Guidelines Labs

Production Plants Severity

Containment

BSL1

BSL1-LS

Minimal

Primary

BSL2

BSL2-LS

Low

Primary

BSL3

BSL3-LS

Moderate Primary + Secondary

BSL4

High

Primary + Secondary

Lab operations are carried in less then 10L fermentor Clean Room Overview, NJ Chapter, Feb. 21, 2008

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Basis for the Classification of Biohazardous Agents by Risk Group (RG) ƒ ƒ ƒ

ƒ

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, NJ Chapter, Feb. 21, 2008

Slide 41

Basis for the Classification of Biohazardous Agents by Risk Group (RG) Bacterial, Fungal, Parasitic, Viruses and Prions ƒ ƒ

ƒ

ƒ

Risk Group 1 (RG1) – ¾ asporogenic Bacillus subtilis or Bacillus licheniformis Risk Group 2 (RG2) – ¾ Hepatitis A, B, C, D, and E viruses ¾ Herpes viruses ¾ Measles and Mumps virus ¾ Polioviruses Risk Group 3 (RG3) – ¾ Yellow fever virus ¾ Prions-Transmissible spongioform encephalopathies (TME) agents ¾ Human immunodeficiency virus (HIV) Risk Group 4 (RG4) – ¾ Crimean-Congo hemorrhagic fever virus ¾ Filo viruses ¾ Ebola virus

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

Slide 42

Containment for Biologics (BSL-3)

Fresh Air Once Through

Exhaust HEPA Filter

BSL-3

++ 10,000

A/L

+++ 10,000

++ 100,000

This concept can also be used for High Potency Compounds Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 43

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

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

Slide 44

BL3-LS Design General Considerations

ƒ All doors, HVAC, light fixtures etc. carefully sealed and room leak tested ƒ All pipe and other services through walls welded to a plate or sealed properly ƒ Provide spare openings and seal them for future use to avoid temptation to make holes ƒ Strictly control all future work in the room ƒ Spill containment dikes and room decontamination provision

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

Slide 45

Building Pressurization Concept for Containment (e.g. BL3)

General Area 0.0”WG (slight +ve) 100K +++ Contained Area + 100K

++ 100K

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

+

Slide 46

Building Pressurization Concept for Containment Cleaner Contained Area General Area 0.0”WG (slight +ve) 100K ++ Contained Area + 10K

10K +++

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

+

Slide 47

AGENDA ƒ ƒ ƒ ƒ

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

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

Slide 48

Building Pressurization Concept

General Corridor + Controlled Environment Area + + +100K Highest Cleanliness Area + + + ++ 10K

++++10K

++100K

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

Slide 49

Gowning Room

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

Slide 50

Typical Biologics Unit Operations

Intracellular Products • Raw Materials • Water

Media Preparation

Off-CAS Containment Off-Gas

Cell Lysis & Recovery

Buffer Solution

Fermentation or Cell Culture

Extracellular Products

Purification

• Salt • WFI

Sterile Filling & Lyophilization

Containment & Waste Treatment

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

Slide 51

Parenteral Plant ACTIVE ING REDIENTS & E XCIPIENTS

W FI

F

Figure 4-1: Filling and Lyophilization Operations SO LUTIO N PREP TANK

STERILE RECEIVER

STERILE FILTER 0.22 m m

PREFILTER 0.45 m m F

F

S

W FI G LASS VIALS FRO M W AREHO USE

CLASS 100,000

F

POLISH ING FILTER 0.45 mm

S

S CLASS 100

W ASH RINSE

STERILIZING TUNNEL

FILLING

STOPPERING

TRAYING

FREEZE DRYING

W FI & CLEAN ST EAM RUBBER STO PPERS

W ASHER STERILIZER

PARTS & TRAYS

S

S

SILICO NE

LABELER

CLASS 10,000 OR CLASS 1,000

HO T AIR O VEN

W ASHER

S CARTO NER

Class 100,000 with local HEPA for exposed areas

INSPECTIO N

TERMINAL AUTOCLAVE

S

S

CAPPING LAM INAR FLOW

CLEAN STEAM

S

W FI CASE PACKER

PALLET ST RET CH W RAPPER

TO W AREHO USE

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

Slide 52

Guidance in Practice ƒ Terminal HEPA filters in Class 100 and Class 10,000 ƒ Low returns in Class 100, Class 10,000 , gowning rooms and airlocks ƒ In parenteral plants: ¾ With curtains and RABs, surrounding area Class 10,000 ¾ With isolators, surrounding area class 100,000 Clean Room Overview, NJ Chapter, Feb. 21, 2008

Slide 53

Guidance in Practice ƒ Sufficient air change rates to dilute particulate Class 10,000 40 to 50 air changes Class 100,000 20 to 25 air changes Airlocks 60 air changes ƒ Infiltration/Ex-filtration Allowance (consistent with pressurization) Single door 370 CFM double door 520 CFM

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

Slide 54

Clean Room Construction ƒ Stick built - more flexible, late design input possible ƒ Prefabricated panels - superior finishes ƒ Prefabricated modules with HVAC system – superior construction – may be more expensive – parallel construction – great in low tech geographical areas ƒ Modular Plant with all HVAC, piping and equipment – similar to above

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

Slide 55

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

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

Slide 56

Modular Airwall Systems

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

Slide 57

Media Makeup, Grade C

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

Slide 58

20K Bioreactor, Grade C

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

Slide 59

Chromatography Column Grade B/C

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

Slide 60

Purification Suite with UF Skids Grade B/C

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

Slide 61

International cGMP Compliance ƒ ƒ ƒ ƒ

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

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