PhEn-602

Notes #5
J. Manfredi

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Clean Rooms and Controlled Environments
ISO vs FS209E: key differences
ISO limits are based strictly on a cubic meter
FS 209E has limits for both ft3 and m3
Three new classes were introduced ISO
Class 1 and Class 2, (both of which are
cleaner than FS 209E class 1), & ISO Class 9.
ISO added the 1.0 micron particle size

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Clean Rooms and Controlled Environments

ISO vs FS209E: key differences

ISO generally requires fewer sampling locations than

FS 209E
With ISO, number of sample locations is based on
clean room area, whereas with FS 209E it is based
on Class, size of clean room, and whether or not
unidirectional flow is present
ISO has a minimum 1 minute sample time, FS 209E
does not.

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Clean Rooms and Controlled Environments
European Union classifications (this list excludes
viable particulate limits)

At-Rest In-Operation
Max # particles per Max # particles per Max # particles per Max # particles
cubic meter (per cubic cubic meter (per cubic meter (per per cubic meter
ft.) cubic ft.) cubic ft.) (per cubic ft.)

0.5m 5m 0.5m 5m
Grade D 3,500,000 (100,000) 20,000 (570) No spec. No spec.

Grade C 350,000 (10,000) 2000 (57) 3,500,000 (100,000) 20,000 (570)

Grade B 3,500 (100) None 350,000 (10,000) 2000 (57)

Grade A 3,500* (100) None 3500 (100) None

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Clean Rooms and Controlled Environments
FDA vs. EU Requirements
QGrade A approximates Class 100 in U.S.,
but requires unidirectional flow.
Q Grade B in the at rest condition has
the same particle limit as Grade A at
rest, but does not require unidirectional
flow.
QGrade C is similar to Class 100,000 in
operation.
QGrade B in operation approximates Class
10,000 in operation.
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Clean Rooms and Controlled Environments

FDA Aseptic Guidelines:

Uses both the FS 209E classifications and
ISO classifications for aseptic manufacturing.
Non-viable particle levels must meet the FS
209E classes and ISO classes.
Mentions the as-built and dynamic state of
the cleanroom with more emphasis on the
dynamic (In-operation) condition.
Contains limits for viable particles
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Clean Rooms and Controlled Environments
FDA vs. EU Requirements
EU has requirements for At-Rest and In-
Operation
FDA Aseptic guidelines are based on In-
Operation condition only.
EU focuses on two particle sizes 0.5m and 5m
FDA Aseptic guidelines: 0.5m only
EU has limits for the 5 micron particle, FDA
Aseptic Guidelines do not.

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Clean Rooms and Controlled Environments

Useful cleanroom websites that cover some of

the material discussed:
www.s2c2.co.uk/docs/cccs.pdf
www.particle.com
www.clean-room.com
www.fda.gov/cder/guidance/5882fnl.htm
Website for FDA Aseptic guidelines
www.peakpureair.com/particlesize.htm

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Clean Rooms and Controlled Environments

Testing the Cleanroom for Particle Class

FS 209E
Number of sampling locations is a
function of area and classification
Different sampling location formula for
unidirectional and non-unidirectional
flow clean rooms
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Clean Rooms and Controlled Environments

FS 209E: For non-unidirectional flow clean rooms, the lesser of:

SI (metric) units: English units:

NL =Ax64/(10M)0.5 NL =A/(Nc)0.5
Where M=SI A= floor area of
description of class clean zone in ft2
A= floor area of Where Nc is English
clean zone in m2 class

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Clean Rooms and Controlled Environments

ISO number of sampling locations

Particulate Testing - Number of
sampling locations
NL= A

NL = minimum number of sampling locations

A= area of clean room in square meters

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Clean Rooms and Controlled Environments
Particle testing
Particle Size Cumulative # Differential #
(Microns) (Per Ft.3) (Per Ft.3)
0.3 200 70

0.5 130 30

1.0 100 80

5.0 20 20

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Clean Rooms and Controlled Environments

Particle Size Cumulative # Differential #

(Microns) (Per Ft.3) (Per Ft.3)
0.3 175 70
0.5 105 95
1.0 10 8
5.0 2 2
Does the above data show that the room meets Class 100
conditions at 0.5 micron? NO
Does the above room pass for ISO Class 5 at 1.0 micron? YES
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Clean Rooms and Controlled Environments

ISO ISO 14644-1 FED Std 209E

vs ISO Class English Metric
1
FS209E:
2
3 1 M1.5
4 10 M2.5
5 100 M3.5
6 1,000 M4.5
7 10,000 M5.5
8 100,000 M6.5
9

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Clean Rooms and Controlled Environments
ISO
ISO 14644-1
FED Std 209E
vs ISO Class English Metric
1
FS209E:
2
3 1 M1.5
4 10 M2.5
5 100 M3.5
6 1,000 M4.5
7 10,000 M5.5
8 100,000 M6.5
9

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Clean Rooms and Controlled Environments

0.5 Microns
Other
25 Microns
contaminants
Dust
100
Microns
Human Hair

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Clean Rooms and Controlled Environments

Particle counting
The particle count limits are for the particular
size and larger
The particle counter can distinguish between
different particle sizes
The counter typically prints out data that
provides actual counts at the specific particle
size (differential) and the cumulative count

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Continuous Particle Monitoring Systems

Particle counting: continuous sampling

two types
Sequential monitoring system (manifold
system)

Simultaneous monitoring system

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Clean Rooms and Controlled Environments
Typical Particle Counter

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Controlled Environments-Cleanroom Standards

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 Continuous Particle Monitoring
Sequential (manifold) Simultaneous remote
particle counters

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Continuous Particle Monitoring Systems
Particle counting: continuous sampling
Sequential monitoring system:
Single particle counter sequences through sample
locations
Disadvantage: particle loss from long sampling tube
lengths
Rotate thru sensors, can miss a potential high-reading

Simultaneous monitoring system

Multiple particle counters
Every location has a particle counter
More expensive than sequential

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 Clean Rooms and Controlled Environments
Other important notes

Particle counting: continuous sampling

Sequential monitoring system (centralized manifold
system):
Sample ports connected to central vacuum source
Air taken from each port in rotational fashion
Central vacuum pump and particle counter
Simultaneous monitoring system
Particle sensors connected via cabling to a central
computer
Both allow auto notification if particle levels exceed alert
and action levels
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 Sequential Particulate Monitoring

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 PhEn602 Pharmaceutical Facility
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 Sequential Particle
Monitoring System

Sequential
Particle
Counter
Vacuum
Pump

Particle Manifold

Monitoring Manifold
controller Other
locations

System an Air

alternate
look at it.. Tubing

Sensor Sensor Sensor

Room 1 Room 2 Room 3

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 Simultaneous Particle
Monitoring System
Input board

Electrical signal
4 - 20 mA to PC

Simultaneous
Particle
Counting

Particle Particle Particle

Counter Counter Counter

Room 1 Room 2 Room 3

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Clean Rooms and Controlled Environments
Common items - ISO Standard 14644-1 & 2 and FS 209E

No fewer than two sample locations

Minimum sample volume and time is also dictated
in each standard
For the most part, ISO Class 3 through 8 are very
similar to FS 209E Class 1 through 100,000.
The particle limits are for the particle size stated
and larger

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Clean Rooms and Controlled Environments
FS 209E & ISO Standard 14644-1 & 2

Note that the number of sampling locations is the minimum

required.

Its often easier to sample a room at 10 or more locations,

rather than going through the statistical analysis

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Clean Rooms and Controlled Environments

Important note regarding FDA Aseptic Guidelines:

FDA Aseptic guidelines do not allow averaging at a
sampling site!

Each discrete sample must be below the class limit.

This is important, since you can pass ISO and FS 209E, and
not meet FDA requirement.

FDA aseptic guidelines still reference the FS 209E classes.

FDA has no formal position regarding the ISO standards
impact on pharmaceutical manufacturers

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Clean Rooms and Controlled Environments
European Union Guide to GMP (EU cGMP)
Formal title:The Rules Governing Medicinal
Products in the European Union. Volume 4.
Good Manufacturing Practices Medicinal
Products for Human and Veterinary Use
Establishes four grades: Grade A, B, C, D
Grade A is cleanest, Grade D is least clean
Each grade has limits for viable and non-viable
particulates
Refers to ISO standard for more details
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Clean Rooms and Controlled Environments
European Union Guide to GMP (EU cGMP)
Grade A: The local zone for high-risk operations, e.g.
filling zone, stopper bowls, open ampoules and vials,
making aseptic connections. Normally such conditions
are provided by a laminar flow work station. Laminar
flow air systems should provide a homogeneous air
speed
Grade B: For aseptic preparation and filling, this is the
background environment for Grade A zone.
Grade C and D: Clean areas for carrying out less
critical stages of the manufacture of sterile products.

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Clean Rooms and Controlled Environments
EU Classifications (excludes viable particulate limits)

At-Rest In-Operation
At-Rest Max # At-Rest Max # In-Operation Max # In-Operation
particles per cubic particles per cubic particles per cubic Max # particles
meter meter meter per cubic meter

0.5 m 5 m 0.5 m 5 m
Grade D 3,500,000 20,000 No spec. No spec.

Grade C 350,000 2000 3,500,000 20,000

Grade B 3,500 None 350,000 2000

Grade A 3,500* None 3500* None

*EU Grade A requires unidirectional flow
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Clean Rooms and Controlled Environments
EU Classifications (excludes viable particulate limits)
(per cubic foot numbers in parenthesis)

At-Rest In-Operation
Max # particles per Max # particles per Max # particles per Max # particles
cubic meter (per cubic cubic meter (per cubic meter (per per cubic meter
ft.) cubic ft.) cubic ft.) (per cubic ft.)

0.5 m 5 m 0.5 m 5 m
Grade D 3,500,000 (100,000) 20,000 (570) No spec. No spec.

Grade C 350,000 (10,000) 2000 (57) 3,500,000 (100,000) 20,000 (570)

Grade B 3,500 (100) None 350,000 (10,000) 2000 (57)

Grade A 3,500* (100) None 3500 (100) None

*EU Grade A requires unidirectional flow

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Clean Rooms and Controlled Environments

Manufacturing Operation and Clean

Room Class EU Requirements
Aseptic Preparation:
Washing of components - Grade D
environment
Compounding - Grade C if later filtered.
Filling: Grade A with Grade B
background

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Clean Rooms and Controlled Environments
Manufacturing Operation and Clean Room Class
FDA/US Requirements Aseptic processes

Typical Process Step Background Product/container

environment closure exposure
area
Dispensing Class 100,000 Local protection
specific enclosures
Compounding Class 100,000 Class 10,000
Filtration Class 10,000 Class 100
Initial prep/washing Pharmaceutical - Pharmaceutical -
components Class 100,000 Class 100,000
at rest at rest
Final rinse of Class 100,000 Class 100,000
components/containers
From ISPE Baseline Guide Volume 3 Sterile Manufacturing Facilities
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Clean Rooms and Controlled Environments
Manufacturing Operation and Clean Room Class
FDA/US Requirements Terminally sterilized processes

Typical Process step Background Product/container

environment /closure exposure
area
Dispensing Class 100,000 Class 100,000

Compounding Class 100,000 Class 100,000

Filtration Class 100,000 Class 100

Initial prep/washing Pharmaceutical Pharmaceutical -

components -Class 100,000 Class 100,000 at
at rest rest
Final rinse of Pharmaceutical Class 100,000
components/containers -Class 100,000
at rest
From ISPE Baseline Guide Volume 3 Sterile Manufacturing Facilities
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Clean Rooms and Controlled Environments
Manufacturing Operation and Clean Room Class
FDA/US Requirements Aseptic processes

Typical Process step Background Product/container/

environment closure exposure
area
Loading of components and Class 100,000 Class 100,000
containers for
sterilization/depyrogenation
Sterilization of Class 10,000 Class 100
components/depyrogenation (or
of containers - unloading wrapped/sealed)
Filling and stoppering Class 10,000 Class 100
Lyophilization Operation N/A Closed system
Lyophilization transfer Class 10,000 Class 100
From ISPE Baseline Guide Volume 3 Sterile Manufacturing Facilities
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Clean Rooms and Controlled Environments
Manufacturing Operation and Clean Room Class FDA/US
Requirements Terminal Sterilized processes

Typical Process step Background Product/container/

environment closure exposure
area
Sterilization of Pharmaceutical Class 100,000
components/depyrogenation Class 100,000 (or
of containers - loading at rest wrapped/sealed)
Sterilization of Class 100
components/depyrogenation Class 100,000 (or
of containers - unloading wrapped/sealed)
Filling and stoppering Class 100,000 Class 100
Capping Pharmaceutical Local protection
Terminal sterilization Pharmaceutical N/A
From ISPE Baseline Guide Volume 3 Sterile Manufacturing Facilities

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Clean Rooms and Controlled Environments
Manufacturing Operation and Clean Room Class
FDA/US Requirements Aseptic processes

Typical Process step Background Product/container/

environment closure exposure
area
Capping and Crimping Pharmaceutical Local protection
-Class 100,000 laminar flow or
at rest enclosure
Inspection Pharmaceutical N/A

Label and Package Pharmaceutical N/A

From ISPE Baseline Guide Volume 3 Sterile Manufacturing Facilities

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Clean Rooms and Controlled Environments
Manufacturing Operation and Clean Room Class
FDA/US Requirements Aseptic processes

Typical Process step Background Product/containe

environment r/closure
exposure area
Inspection Pharmaceutical N/A

Label and Package Pharmaceutical N/A

From ISPE Baseline Guide Volume 3 Sterile Manufacturing Facilities

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Clean Rooms and Controlled Environments
Manufacturing Operation and Clean
Room Class EU Requirements
Aseptically produced products
Grade Examples of operations
A Aseptic Preparation and filling

C Preparation of solutions to be filled.

D Handling of components after washing

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Clean Rooms and Controlled Environments
Manufacturing Operation and Clean
Room Class EU Requirements
Terminally sterilized products
Grade Examples of operations
A Filling of products, when unusually at
risk
C Preparation of solutions, when unusually at
risk. Filling of less susceptible products.

D Preparation of solutions and

components for subsequent filling

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Clean Rooms and Controlled Environments

Manufacturing Operation and Clean

Room Class EU & FDA Requirements

With terminally sterilized products, you

can scale back on the cleanliness of
many of the clean rooms.

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Summary of Grades and Classes vs. Process

Type of Process Step/Activity Nearest US GMP EU GMP

Processing equivalent ISO expectation in Grade
14644-1 class operation
in operation
Aseptic Aseptic formulation and filling 5 100/M3.5 A
operations
Aseptic Background to the above activities 7 10,000/M5.5 B
Aseptic Preparation of solutions to be 8 100,000/M6.5 C
filtered
Aseptic Component handling after washing 8 100,000/M6.5 C
when exposed to the environment
Terminally Filling of unusually at risk products 5 100/M3.5 A
sterilised
Terminally Filling of products, unusually at 8 100,000/M6.5 C
sterilised risk solution preparation
Terminally Preparation of products and unclassified/ Pharmaceutical D
sterilised solutions controlled

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 Gowning
Typical Flow Diagram
Packaging
Materials
Aseptically Produced Products
Vials
Actives Caps

Pharmaceutical
Stoppers
Staging Vials
Outgoing Reciepts/Incoming
Warehouse Warehouse Actives
and
Excipients

Pharmaceutical + Local
To/From
Dispensing Monitoring Class 100,000
Plant At-Rest
Laundry Class
Unclassified 100,000 In- PW PW PW
Areas Operation Wash Wash Wash
To/From
Plant
Process Compounding
Stage,
services
Quarantine,
WFI, PS, CA, Class 10,000 In Operation
Analyze WFI WFI WFI
N2 when product is exposed Rinse Rinse Rinse

Sterile Depyro Stopper Components Pass Back

Filtration Tunnel Processor Autoclave

Filling and
Stoppering
Pharmaceutical Machine

Class 100 In-

Operation,
Class 10,000 In-
Label and
Inspect Cap & Crimp Lyophilizer Operation
Package
Background
Pharma + local
monitoring
Class 100,000 at rest

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 High Efficiency Air Filtration

HEPA filters
Typically 99.97% efficient at 0.3 micron
Used for Clean Room Classes 100,000 thru 100
For Class 10 and better, use ULPA filters, Ultra
Low Penetration Air filters
ULPA Filters
Have an efficiency greater than 99.999% against
0.1 0.2 micron particles.

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 High Efficiency Air Filtration

ULPA Filters
Typically used in the micro-electronics industry.
Some Pharmaceutical firms are using ULPAs
in their Class 10,000 (Grade B) and Class 100
(Grade A) clean rooms
Care is required due to the increased pressure
drop with ULPAs vs. HEPAs. This can impact
overall airflow if filters switched in an existing
system system resistance changes
(increases).

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 High Efficiency Air Filtration

Methods of sealing HEPA and ULPA filters

Gasketed method typically neoprene
rubber gasket
AIRFLOW
Housing

HEPA FILTER

Gasket
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 High Efficiency Air Filtration
Methods of sealing HEPA and ULPA filters
Fluid Seal method

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 High Efficiency Air Filtration

Areas where leakage can occur:

Housing to filter seal
Very important potential leak source
Filter paper
Filter paper to case cement area
Frame joints
Gasket

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 High Efficiency Air Filtration

Typical sizes of HEPA filters

2 x 4 (2 ft. wide by 4 ft. long)
2 x 2 (2 ft. wide by 2 ft. long)
Typical height is 6

48"

HEPA
6"
Filter

24"

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 High Efficiency Air Filtration

Other points about HEPA Filtration:

When replacing, should be fitted so
that replacement can be made from
the Aseptic room side thus keeping
integrity of room
Efficiencies of 99.97% at 0.3 micron
and 99.99% at 0.3 micron often used.

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 Clean Rooms and Controlled Environments
Summary of Tests for Cleanroom Certification

Quantity of air: sufficient quantity to

ensure removal of contaminants
For turbulent or non-unidirectional flow
clean room, the volume of air and air
change rate is important

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 Clean Rooms and Controlled Environments
Summary of Tests for Cleanroom Certification
Seven primary tests:
1. Airflow Volume
2. Air Change Rate Calculations
3. Air Velocity Testing:
(For a unidirectional flow clean room, it is velocity that is critical)
Airflow direction between clean rooms: air should travel from
cleaner room to less-clean room
4. Room to Room DP Testing
5. Filter Installation Leak Testing:
To ensure no contaminants from the air system enter the clean
room
6. Airflow pattern test (smoke test):
Airflow direction within the clean room: air should flow from
clean portion of room to dirty portion and then be extracted
7. Particle count testing
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 Frequency of HEPA filter leak testing

Depends on use of area. For for critical (Class

100 and sub-critical (Class 10,000) areas:
twice per year per FDA Aseptic guidelines.
Class 100,000 areas typically every 6
months or every year depends on
manufacturer. PDA recommends annually.
Many pharmaceutical manufacturers shutdown
their facilities every six months for the
certification
Conduct major maintenance activities during
the same time

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 Clean Rooms and Controlled Environments
Summary of Tests for Cleanroom Certification

Additional tests that may be performed:

Temperature and relative humidity
testing
Lighting
Sound levels
Vibration levels

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Clean Rooms and Controlled Environments
Clean Room Design Principles

Displacement Design

Dilution Design

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Clean Rooms and Controlled Environments
Clean Room Design Principles

Displacement Design:
Dirty air is displaced by clean air,
travelling at a relatively high velocity
Typical of unidirectional flow clean
rooms (Class 100 rooms, EU Grade A
rooms).

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 Displacement Design

VERTICAL
UNIDIRECTIONAL
FLOW

Displacement
Design

EXTRACTS EXTRACTS

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 Displacement design: Unidirectional Flow:
Also called Laminar Flow airflow having
generally parallel streamlines, operating in a
single direction, and with uniform velocity
over its cross section.

VERTICAL
UNIDIRECTIONAL
FLOW

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 HVAC Design Principles
Dilution Design:
Dirty air is mixed continuously with clean
air.
Turbulent air mixing reduces the particulate
load in the room.
Typical of Class 10,000 and Class 100,000
rooms
Dilution rooms are called mixed flow rooms
Often have local regions in the room with
displacement features
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 Dilution Design: Non-unidirectional Flow:
Also called mixed-flow or turbulent flow
- airflow which is not unidirectional.

s u p p ly s u p p ly

N O N -U N ID IR E C T IO N A L
FLO W

E x a m p le o f a
D ilu tio n D e s ig n
ro o m

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 Dilution Design Room

s u p p ly s u p p ly

N O N -U N ID IR E C T IO N A L
FLO W

E x a m p le o f a
D ilu tio n D e s ig n
ro o m

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 Dilution with Local Unidirectional Zone

s u p p ly s u p p ly

N O N -U N ID IR E C T IO N A L
FLO W LO CAL
U N ID IR E C T IO N A L
FLOW
(D IS P L A C E M E N T )

C R IT IC A L
P O IN T

E x a m p le o f a
D ilu tio n D e s ig n
ro o m

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 HVAC Design Principles

Dilution Design:
Local regions with unidirectional
flow assist with the dilution effect
(they add to the overall room air
change rate).

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 HVAC Design Principles

Unidirectional Flow (Displacement) Cleanrooms

vs. Non-unidirectional Flow (Dilution) Cleanrooms
Can generally achieve Class 10,000 with dilution
design. In some cases even Class 1,000 is
achievable.
Higher cleanliness classes (i.e. cleaner than Class
1,000) requires unidirectional flow.
Unidirectional Flow Cleanrooms have higher flow
rates and as a result are more expensive to build
Many more HEPA filters used with higher material
costs
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 HVAC Design Principles

Vertical unidirectional flow clean rooms

Return can be through floor. The ideal
case ensures uniform unidirectional flow
throughout width of room. This provides
very effective sweeping of contaminants
OR
Return through low mount extracts
either room mounted grills or return air
walls very common but less effective
than raised floor

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 HVAC Design Principles

With vertical unidirectional flow clean

rooms:
Desirable to minimize the width of the
room. Maximum width is generally 6
meters (20 ft).
Difficult to achieve good unidirectional
flow in center of room

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Clean Rooms:
Airflows and Air Change Rates

CFM per HEPA Filter: Qf

Qf = Vavg Af
Average Face Velocity x Filter Area
Room Total Flow = #HEPA Filters x
CFM per HEPA
Qr=NFQf

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Clean Rooms:
Airflows and Air Change Rates

Alternate Formula:
Room Total Flow = Sum of flow
through each HEPA filter in room
(CFM per HEPA)

Qr= Qf i
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Clean Rooms:
Airflows and Air Change Rates
Air Change Rate: Air changes per
minute
ACR = Total room flow / room volume
ACR = Qr / Vr
Room Volume Vr = H x W x L
Requirements are based on air
changes per hour
ACPH = ACR x 60 or (Qr/Vr) x 60
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Clean Rooms:
Airflows and Air Change Rates
Qf = Vavg x Af
Qr = NFQf or Qf i
ACR= Qr / Vr
ACPH= ACR x 60 or (Qr/Vr) x 60
Units:
Af in square feet (Ft2)
Vavg in Ft/Min
Vr in cubic feet (Ft3)
Qr and Qf in cubic feet per minute (CFM)
ACR in air changes per minute
ACPH in air changes per hour

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Clean Rooms:
Airflows and Air Change Rates
Minimum airchange rate for Class
100,000 clean rooms: 20 ACPH
What dictates this?
1987 FDA Aseptic Manufacturing Guidelines
2004 FDA Aseptic Manufacturing Guidelines
There is no clear criteria for minimum
air change rates for Class 1,000,
10,000 or Class 100
There are targets however, from IEST.
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 Clean Rooms:
Airflows and Air Change Rates
IEST recommended air change rates
RP-CC-012.1:
Targeted airchange rates:
Class 100,000 5 481 ACPH ISO Class 8
Class 10,000 60-90 ACPH ISO Class 7
Class 1,000 150-240 ACPH ISO Class 6
Class 100 240 4802 ACPH ISO Class 5
Important Notes:
1. Minimum air change rate for Class 100,000 rooms is 20 ACPH
per 2004 FDA Aseptic Guidelines.
2. Air change rates for Class 100 rooms typically exceed 480
ACPH.
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Clean Rooms:
Airflows and Air Change Rates

Airflow Velocity Specifications

No spec for Class 100,000, 10,000 or
1,000
Target for Class 100 Rooms:
90 Ft/min +/- 20%
Where does this requirement come from?
1987 FDA Aseptic Manufacturing
Guidelines
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 Clean Rooms:
Airflows and Air Change Rates
Air change rate should be based on satisfying
the maximum particle load, based on the
specific operation performed.
Varies depending on:
1. Operation: Amount of particles generated
in the space
2. Heat gain within the space
3. Required recovery time
Any of the above can determine the minimum air
change rate.
Calculating air volume to offset heat gain is a
standard HVAC system design issue.
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Clean Rooms:
Air Change Rates per FDA

2004 FDA Aseptic Guidelines, section 4, part c:

Air change rate is another important cleanroom design
parameter. For Class 100,000 (ISO 8) supporting
rooms, airflow sufficient to achieve at least 20 air
changes per hour is typically acceptable.
Significantly higher air change rates are normally
needed for Class 10,000 and Class 100 areas.

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Air Change Rates:
EU Guideline Expectations
In order to reach the B, C and D air grades, the
number of air changes should be related to the size of
the room and the equipment and personnel present in
the room. The air system should be provided with
terminal filters such as HEPA for grades A, B and C.
Re: Room recovery: The particulate conditions
given in the table for the at rest state should be
achieved after a short cleanup period of 15-20
minutes (guidance value) after completion of operations

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Clean Rooms and Controlled Environments
Room Recovery Time vs. Air Change Rates
Particle Concentration

106

10 airchanges
per hour

100
30 airchanges
50 airchanges per hour
per hour

30 50
Time in minutes

Graph illustrating increases in airchange rates

reduces room recovery time

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 Unidirectional Flow Clean Rooms
and air velocity

Air velocity in unidirectional clean rooms:

Generally maintained between 60 fpm and 120 fpm
For critical area: In the 1987 Aseptic Guide, FDA
used to suggest 90 fpm +/- 20%.
New FDA Aseptic Guide in 2004 changed this they
do not specify a target velocity or range.
EU guidelines indicate 0.45 m/sec velocity, +/- 20%
(guidance value). This equates to 0.36 0.54 m/s, or
70 fpm 105 fpm.

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Unidirectional Flow Clean Rooms
and air velocity
Parenteral Drug Association: Guidance
on air velocity
Topic A: Airflow Velocity How often tested?
Problem Statement: When do velocity measurements
have to be taken?
Recommendation
Airflow velocity measurements should be taken during
operational and performance qualification studies.
Frequency of routine monitoring should be at least
annually. HEPA filters in critical areas should be tested
semi-annually. More frequent measurements may be
appropriate if other measures of clean room quality
indicate a significant deviation.
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Unidirectional Clean Rooms:
Velocity Testing
Airflow pattern studies should be repeated when any changes
are made that might have an impact on the velocity
measurements outside validated acceptance criteria (i.e.,
changes to air handling systems, aseptic processing
equipment, HEPA filters). Evaluation of such impact should
be made following applicable change management
procedures. Airflow measurements can be area or line-
specific.
Rationale for Recommendation
Airflow velocity is measured to ensure adequate airflow to
protect exposed product, product contact packaging
components, and product contact surfaces. It is also
measured to ensure there have been no significant changes to
the HVAC system. Airflow criteria are established during
qualification studies.

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Velocity Testing in Unidirectional
Flow Clean Rooms

During qualification, airflow pattern

tests/smoke studies should be
performed to establish the acceptable
velocity range.
Where do we take our velocity
readings?
At filter face, 6 down? Or at Work level?

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TABLE 1 - Air
Classifications CDER Aseptic Guidelines - 2004

We will discuss Micro levels later in

FDA Aseptic Guidelines course
Cleanroom Class

Microbiological
Settling Plates
Clean Area G.T. or equal to Microbiological Action Levels
Classification (0.5 ISO 0.5 micron Active Air Action (diam. 90mm,
3 3 3
micron particles/ft ) Designation (particles/m ) Levels (cfu/m ) cfu/4 hours)

100 5 3,520 1 1
1,000 6 35,200 7 3
10,000 7 352,000 10 5
100,000 8 3,520,000 100 50

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 Summary of Grades and Classes vs. Process
Type of Process Step/Activity Nearest US GMP EU GMP
Processing equivalent ISO expectation in Grade
14644-1 class operation
in operation
Aseptic Aseptic formulation and filling 5 100/M3.5 A
operations
Aseptic Background to the above activities 7 10,000/M5.5 B
Aseptic Preparation of solutions to be 8 100,000/M6.5 C
filtered
Aseptic Component handling after washing 8 100,000/M6.5 C
when exposed to the environment
Terminally Filling of unusually at risk products 5 100/M3.5 A
sterilised
Terminally Filling of products, unusually at 8 100,000/M6.5 C
sterilised risk solution preparation
Terminally Preparation of products and unclassified/ Pharmaceutical D
sterilised solutions controlled

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 Vials Product Flow Stoppers Pharmaceutical
Pharmaceutical Sterilize Class 100,000
Wash Vessels
With Local Mon. and Stoppers
Vials Sterilized parts are Caps
Class 100K at rest Change discharged into a - wash
Parts Class 10,000 area, Class
Vials
with local Class 100 100,000
Caps
Class
100,000
Depyro- Com- Class 100,000
genate po und Stoppers
Vials Product Class 10,000 - Sterilize

(Local)
Class 100 Class 10,000
Class 10,000 Sterile Class 10,000 Discharge into
Background Filter Class 100
Bulk Local
Class 100
Solution
(Local)

Class 100 Fill Vials

Class 10,000
Background

Partially
Class 100 Stopper
Vials
Class 10,000
Background

Load Vials
into
Typical Class 100 Lyophili-
zer
Process Class 10,000
Background
Flow for
Lyophilized Freeze Cap Label
Product with dry and and Inspect and
stopper Crimp Pack
Room
Classes Within Pharmaceutical Pharmaceutical Pharmaceutical
Equipment
With Local Mon.
Class 100K at rest

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Example Number of particles per location, per cubic meter.

Particle size, in microns

Location 0.3 0.5 5.0
1 98 90 1
2 103 50 0
3 120 45 0
4 80 70 0
5 90 40 0
6 60 20 1

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 Sample Problem
1. A firm is interested in determining whether the room meets ISO
Class 3 requirements for the 0.3 micron particle size.
2. Is it necessary to perform statistical analysis to make this
determination?
3. What is the 95% UCL?
4. Does the room meet ISO Class 3 conditions at 0.3 micron?
5. If the room dimensions were 5 m by 5 m, were the minimum
number of sample locations per ISO met?
6. Does the room meet ISO Class 3 conditions for the 5 micron
particle?
7. Does the room meet ISO Class 5 conditions for the 5 micron
particle?
8. If the entire room was desired to be maintained at the required
class for filling operations, and the readings were actually taken in
the in-operation state, would the room meet EU requirements for
filling operations for an aseptically produced product? (Assume
unidirectional flow is provided).
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