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

Sources of Contamination

Need for Clean rooms
Sixties saw several incidences of contamination in

injectables resulting in deaths and injury
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
Lower level of cleanliness
¾ Oral dosage
¾ Topical drugs

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”,
“appropriate”, “adequate”, “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

History of Clean Room Regulations
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1992 (E), and withdrawn in 2001.
Followed by industry all over the world
UK published first “Orange Guide” (1971)
Aseptic Processing Guide in 1987, first time
describing class 100 and class100,000
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

0.5

Atlantic Divide
FDA
FDA
EMEA
EMEA

FDA Regulations

Current Good Manufacturing Practices
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
ISPE Baseline Guidelines
International GMPs
FDA Guidelines for:
¾ Aseptic Processing
¾ Process Validation
FDA’s “Points to Consider”
ISO Standards

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

Manufacturing Practice For Finished
Pharmaceuticals for administration
to humans or animals (20 pages)
FDA Regulations
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
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
FDA Regulations
211.44 Lighting
• Adequate lighting shall be provided in all
areas
211.46 Ventilation, air filtration, air
heating and cooling
¾(a) Adequate ventilation shall be provided
¾(b) Control of air pressure, micro-
organisms, dust, humidity, and
temperature when appropriate

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

Summary of Clean Room Regulations
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

FDA Classifications Guideline (Sept. 2004)
FDA Classification (0.5 ISO EU Class Particles/m3 = 0.5 Microbiological Settling Plates
micron particles/ft3) Designation micron or larger Active Air Action Action Levels
(In Operation) levels (cfu/m3) (diam. 90mm; cfu/4
hours
100 5 Grade 3,520 1 1

A
All classifications during period of activity
1,000 6 35,200 7 3
10,000 7 Grade 352,000 10 5

B
100,000 8 Grade 3,520,000 100 50
C

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

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

Class 100,000 Clean Rooms
No more than 100,000 particles/cubic foot of
air
Particle size: 0.5 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: 0.05” 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 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)
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

Typical “Class 100” Clean Room
9ft

Clean Room Monitoring
Written monitoring program - sampling location, frequency
and timing
Sampling and testing includes air quality, floors, walls and
equipment surfaces
Settling plates (Petri type dishes containing nutrient agar)
in critical areas
“Active” samplers e.g. slit to agar,
centrifugal, liquid impingement
and membrane filtration
For surfaces, touch plates, swabs,
and contact plates
Test as a minimum once daily or once
a shift while in active use, normally
more frequently or after every upset
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 4/97
compliance with ISO14644-1
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- 10/97

contamination data.
ISO 14698-3 Bio-contamination control: Measuring the efficiency cleaning 9/98

and disinfect ion processes of inert surfaces.
ISO 14702 Terms, definitions and units 4/99

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 237 102 35 8
ISO 4 10,000 2370 1020 352 83
ISO 5 100,000 23,700 10,200 3,520 832 29
ISO 6 1,000,000 237,000 102,000 35,200 8320 293
ISO 7 352,000 83,200 2930
ISO 8 3,520,000 832,000 29,300
ISO 9 35,200,000 8,320,000 293,000

Guidance in Practice
ISO 14644 is the new US Federal Standard.

Classification should include both,ISO and
FS 209E designations
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)

AGENDA
Introduction
FDA Regulations
EU Regulations
NIH Guidelines
for Biologics

EU Regulations
The European Economic Community (EEC)
established in 1957 by 6 nations
Today it has 27 members and
500 million people in 1.7 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

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 radio-
pharmaceuticals
Directive 91/356/EEC for harmonization of
GMPs
Centralized, decentralized and single state
procedure

The rules governing medicinal products in
the European Union
Volume 4 of 9
Good Manufacturing Practices
Commission Directive 91/356/EEC of 1991, 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

International Conference on Harmonization (ICH)
Objective was to develop guidelines acceptable to
health authorities of USA, EU, and Japan (1990)
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)

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)
Maximum Permitted Number of Particles/m3 equal to or above
At Rest In Operation
0.5 µm 5 µm 0.5 µm 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 Not

defined defined

Comparison of EC & US Clean Rooms
Maximum number of 0.5 micron or larger particles/cubic meter*
EC In Operation At Rest
Classification
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
*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
Introduction
FDA Regulations
EU Regulations
NIH Guidelines for
Biologics

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

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)

Basis for the Classification of Biohazardous
Agents by Risk Group (RG)
Bacterial, Fungal, Parasitic, Viruses and Prions
Risk Group 1 (RG1) –

¾ asporogenic Bacillus subtilis or Bacillus licheniformis
¾ Hepatitis A, B, C, D, and E viruses
¾ Herpes viruses
¾ Measles and Mumps virus
¾ Polioviruses
¾ Yellow fever virus
¾ Prions-Transmissible spongioform encephalopathies (TME) agents
¾ Human immunodeficiency virus (HIV)
¾ Crimean-Congo hemorrhagic fever virus
¾ Filo viruses
¾ Ebola virus

Containment for Biologics (BSL-3)
Fresh Air
Once Exhaust
Through HEPA Filter
BSL-3 A/L
+++ ++
++ 10,000 100,000
10,000
This concept can also be used for High Potency

Compounds
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, thermal oxidizer
A bag-in/bag-out (BIBO) filter or formaldehyde gas for
decontamination of filters
Exhaust air discharged away from supply air intakes

BL3-LS Design
General Considerations
All doors, HVAC, light fixtures etc. 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

Building Pressurization Concept
for Containment (e.g. BL3)
General Area 0.0”WG (slight +ve)
100K +++
Contained Area +
100K
++
100K +

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

AGENDA
Introduction
FDA Regulations
EU Regulations
NIH Guidelines for
Biologics

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

+ + + ++
10K
++++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
Intracellular Products
• Raw Materials Off-CAS Cell Lysis • Salt

Buffer Solution
• Water Containment & Recovery • WFI
Off-Gas
Media Fermentation Extracellular Sterile Filling

Purification
Preparation or Cell Culture Products & Lyophilization
Containment & Waste Treatment

Parenteral Plant
W FI ACTIVE ING REDIENTS
& E XCIPIENTS F
Figure 4-1: Filling and Lyophilization Operations

STERILE
SO LUTIO N
RECEIVER
Class 100,000
PREP TANK STERILE
PREFILTER FILTER with local HEPA
0.45 m m 0.22 m m
for exposed areas
F F
POLISH ING
S S
W FI S F
FILTER
0.45 mm
G LASS VIALS CLASS 100

FRO M STERILIZING FREEZE
W ASH RINSE FILLING STOPPERING TRAYING DRYING
W AREHO USE TUNNEL
W FI & CLEAN ST EAM

CLASS 100,000
RUBBER
STO PPERS W ASHER CLASS 10,000
STERILIZER
S OR
SILICO NE S CLASS 1,000
PARTS HO T AIR
& TRAYS W ASHER O VEN
S S S
TERMINAL
CARTO NER LABELER INSPECTIO N AUTOCLAVE CAPPING
LAM INAR FLOW

CLEAN STEAM
S
W FI
CASE PALLET ST RET CH TO W AREHO USE

PACKER W RAPPER

Terminal HEPA filters in Class 100 and

Class 10,000
Low returns in Class 100, Class 10,000 ,
gowning rooms and airlocks
In parenteral plants:
¾ With curtains and RABs, surrounding
area Class 10,000
¾ With isolators, surrounding area class
100,000
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
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
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, 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 market

All new facilities have to be world class
FDA, EU and WHO – big players
Objective is the translations of
confusing, often contradictory, and non-
specific regulations into a cost effective
facility that can be easily validated,
operated, and maintained

Clean Room Presentation ISPE

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Clean Room Overview

Comparison of FDA and EU Regulations

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 1

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 2

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 3

 Sixties saw several incidences of contamination in

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 4

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 5

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 6

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 7

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 8

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 9

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 10

 PART 211--Current Good

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 13

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 15

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 16

 Specification and control of the following:

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 17

100 5 Grade 3,520 1 1

10,000 7 Grade 352,000 10 5

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 18

Contamination moves towards the floor

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 19

Contamination moves from one wall to the other wall

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 20

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

 No more than 100 particles/cubic foot of air

 Undisturbed flow of air in a single direction

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 23

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 24

ISO 14644-1 Air Cleanliness Classification 3/96

ISO 14644-3 Metrology and test methods 4/98

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- 10/97

ISO 14698-3 Bio-contamination control: Measuring the efficiency cleaning 9/98

ISO 14702 Terms, definitions and units 4/99

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 26

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 27

 ISO 14644 is the new US Federal Standard.

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 28

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 29

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 30

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 31

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 32

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 33

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 Not

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 35

*No. of particles only, not class

 FDA’s 2004 guide does not specify velocity for

 All FDA requirements are for “in operation”

 Viable count: action level for FDA vs. limit for

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 37

 EU sampling more specific and more

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 38

Clean Room Overview, NJ Chapter, Feb. 21, 2008 Slide 39

BSL1 BSL1-LS Minimal Primary

BSL2 BSL2-LS Low Primary

Sixties saw several incidences of contamination in

PART 211--Current Good

Specification and control of the following:

No more than 100 particles/cubic foot of air

Undisturbed flow of air in a single direction

ISO 14644 is the new US Federal Standard.

FDA’s 2004 guide does not specify velocity for

All FDA requirements are for “in operation”

Viable count: action level for FDA vs. limit for

EU sampling more specific and more

Risk Group 1 (RG1) -Agents not associated with disease in healthy

Risk Group 1 (RG1) –

All doors, HVAC, light fixtures etc. carefully

Terminal HEPA filters in Class 100 and

Sufficient air change rates to dilute particulate

World is one market