Air Classification as per Schedule M Maximum permitted number of particles/m3 equal or above Grade...

Air Classification as per Schedule M

Grade

Maximum permitted number of particles/m3 equal or above

at rest in operation

0.5 µm 5.0 µm 0.5 µm 5.0 µm

A 3520 29 3500 29

B 35200 293 352000 2930

C 352000 2930 3520000 29300

D 3520000 29300 not defined not defined

Note

Grade A and B correspond to with class 100, M 3.5, ISO 5 Grade C correspond to with class 10000, M 5.5, ISO 7Grade D correspond to with class 100000, M 6.5, ISO 8

Air Classifications by USFDA guideline on Sterile Drug Products

Clean Area Classification

0.5 < µm Particles/ft3

0.5 < µm Particles/mt3

Microbiological Limit

cfu/ft3 cfu/m3

100 100 3500 1 < 3 <

1000 1000 35000 2 < 7 <

10000 10000 350000 3 < 18 <

100000 100000 3500000 25 < 88 <

Air Classifications as per WHO 2002

Grade

Maximum Number Permitted / M3

Particles

Microorganisms0.5 µm 5.0 µm

A (LAF) 3500 0 1>

B 500 0 5

C 350000 2000 100

D 3500000 20000 500

Note


Airborne Classification in the European Union guide to Good Manufacturing Pratice

Maximum Permitted Number of Particles /m3 equal to or above

Grade at rest in operation

5.0>= µm 5.0 >= µm 0.5>= µm 5.0 >=µm

A 3500 0 3500 0

B 3500 0 350000 2000

C 350000 2000 3500000 20000

D 3500000 20000 not defined not defined

Note


Cleanroom Environmental Monitoring

Sl .NoTest Frequency

1 Particle Monitoring in air 6 monthly

2HEPA Filter Integrity Testing

Yearly

3Air Changes Rate Calculation

6 Monthly

4 Air Pressure Differentials Daily

5Temperature and Humidity

Daily

6

microbiological monitoring by settle plates and / or swabs in aseptic areas

Daily, and at decreased frequency in other areas

Cleanroom Contamination Classification

Substance Energy

Physical Chemical Biologic

DustOrganic Compounds

Bacteria Thermal

Dirt Inorganic Salts Fungus Light

Grit Vapour SporeElectromagnetic (EMI)

Fibre Mist Pollen Electrostatic(ESD)

Lint Fume Virus Radiation

Fly ash Smoke Human Skin Electrical

Cells

Cleanroom Industry Design Thumb Rule

ISO ClassControls

Air Velocity at table level

in FPM

Air Changes Rate per

Hour

HEPA Coverage as % of Ceiling

1 Stringent 70-130 750 < 100

2 Stringent 70-130 750 < 100

3 Stringent 70-130 750 < 100

4 Stringent 70-110 500-600 100

5 Stringent 70-90 150-400 100

6 Intermediate 25-40 60-100 33-40

7 Intermediate 10-15 25-40 10-50

8 Less Stringent 3-5 10-15 05 -10

Comparison between selected equivalent classes of Federal

Standard 209 and ISO 14644-1

ISO 14644-1 Classes

Class 3 Class 4 Class 5 Class 6 Class 7 Class 8

Federal Standard

Class 1 Class 10 Class 100Class 1000

Class 10000

Class 100000

Comparison of International Standards

Country and Standard

USA 209D USA 209EBritain BS 5295

Australia AS 1386

France AFNOR NFX 44-101

Germany VDI 2083

ISO

Date of Current Issue

1988 1992 1989 1989 1981 1990 1999

1 M 1.5 C 0.035 - 1 3

10 M 2.5 D 0.35 - 2 4

100 M 3.5 E or F 3.5 4000 3 5

1000 M 4.5 G or H 35 - 4 6

10000 M 5.5 J 350 400000 5 7

100000 M 6.5 K 3500 4000000 6 8

EUGGMP 2002 Recommended Limits for Microbial Contamination

GradeAir Sample

cfu/m3

Settle Plates Diam 90 mm

cfu/m3

contact Plates Diam 55 mm

cfu/m3

Glove Print 5 fingers

cfu/glove

A 1> 1> 1> 1>

B 10 5 5 5

C 100 50 25 -

D 200 100 50 -

Note


Federal Standard 209D Class Limits

ClassParticles /ft3

Size 0.1>=µm 0.2>=µm 0.3>=µm 0.5>=µm 5.0>=µm

1 35 7.5 3 1 NA

10 350 75 30 10 NA

100 NA 750 300 100 NA

1000 NA NA NA 1000 7

10000 NA NA NA 10000 70

100000 NA NA NA 100000 700

Federal Standard 209E Class Limits

Class Limits

Class Name >=0.1µm >=0.2 >=0.3 >=0.5 >=0.5

Volume UnitsSI English m3 ft3 m3 ft3 m3 ft3 m3 ft3 m3 ft3

M 1 350 9.91 75.7 2.14 30.9 0.875 10.0 0.283 -- --

M 1.5 1 1240 35 265 7.50 106 3.00 35.3 1.00 -- --

M 2 3500 99.1 757 21.4 309 8.75 100 2.83 -- --

M 2.5 10 12400 350 2650 75.0 1060 30.0 353 10.0 -- --

M 3 35000 991 7570 214 3090 87.5 1000 28.3 -- --

M 3.5 100 -- -- 26500 750 10600 300 3530 100 -- --

M 4 -- -- 75700 2140 30900 875 10000 283 -- --

M 4.5 1000 -- -- -- -- -- -- 35300 1000 247 7.00

M 5 -- -- -- -- -- -- 100000 2830 618 17.5

M 5.5 10000 -- -- -- -- -- -- 353000 10000 2470 70.0

M 6 -- -- -- -- -- -- 1000000 28300 6180 175

M 6.5 100000 -- -- -- -- -- -- 3350000 100000 24700 700

M 7 -- -- -- -- -- -- 10000000 283000 61800 1750

ISO Standard 14644-1 Class Limits

ISO Classificati

on Number

Maximum concentration limits( Particles/m3 of air) for particles equal to and larger than the considered sizes shown below

>=0.1µm >=0.2m >=0.3µm >=0.5µm >=1µm >=5.0µmISO Class 1 10 2 ISO Class 2 100 24 10 4 ISO Class 3 1000 237 102 35 8 ISO Class 4 10000 2370 1020 352 83 ISO Class 5 100000 23700 1020 3520 832 29ISO Class 6 100000 273000 102000 35200 830 293ISO Class 7 352000 83200 2930ISO Class 8 3520000 832000 29300ISO Class 9 35200000 8320000 293000

Particles in Outdoor Air

Number of Particles/m3 on Outdoor Air

Size in Microns Dirty Normal Clean

> 0.1 10000000000 3000000000 500000000

> 0.3 3000000000 90000000 20000000

> 0.5 30000000 7000000 1000000

Schedule of Mandatory Tests to Demonstrate Continuing Compliance in Cleanrooms

Test ParameterClass

Maximum Time Interval

Particle Count Test

<= ISO 5> ISO 5

6 Months12 Months

Air Pressure Difference

All Classes 12 Months

Airflow All Classes 12 months

Schedule of Optional Tests to Demonstrate Continuing Compliance in Cleanrooms

Test ParameterClass

Maximum Time Interval

Installed Filter Leakage


Containment Leakage


Recovery All Classes 24 Months

Airflow Visualization


Special Requirements for ISO Class 3 Cleanrooms

Special Requirements for ISO Class 3 Cleanrooms

Air Quality Total Hydrocarbons <1 ppm; Na <0.1 µg/m3

Fresh Air Intake 0.5 m3 /min per sqm of cleanroom floor area

Vibration< 0.1µ ( Building); <0.01 µ ( Equipment)

rms

Noise < 55 dbA

Temperature 0.1 degree C

Humidity < 2%

Magnetic field var < 1mG

Static charge < 50 v

Types of Operations for Aseptic Preparations

GradeTypes of Opeartions for Aseptic

Preparations

A Aseptic preparation and filling

BBackground room conditions for activities requiring Grade A

C Preparation of Solution to be filtered

D Handling of components after washing

Note


Types of Operations for Terminally Sterilised Products

GradeTypes of Opeartions for Terminally

Sterilised Products

A Filling fo products, when unusually at risk

C

Placement of filling and sealing machines, preparation of solutions, when unusually at risk. Filling of products when unusually at risk

Dmoulding, blowing (pre-forming) opearions of plastic containers, Preparation of solutions and components for subsequent filling

Note


Outdoor Design Conditions

a. Summer:

1) Dry-Bulb Temperature = 89°F (31C)

2) Wet-Bulb Temperature = 80°F (26C)

(Based on 0.4% wet-bulb and mean coincident dry-

bulb temperature for Gainesville,Florida as published

by 2001 ASHRAE Fundamentals.)

b. Winter:

1) Dry-Bulb Temperature = 30°F(-1C)

(Based on 99.6% dry-bulb conditions for Gainesville,

Florida as published by 2001ASHRAE Fundamentals)

Indoor Design Conditions a. Office, Conference, Administrative Support Areas, Laboratory and Laboratory

Support,Raw Storage, and Shipping/Receiving

1) Dry-Bulb Temperature

a) Summer = 76°F ± 3°F(24C)

b) Winter = 72°F ± 3°F(22C) 2) Relative Humidity

a) Summer = 50% maximum ± 5%

b) Winter = No Control

b. Clean Rooms

1) Dry-Bulb Temperature = 67°F(19C) ± 2°F (year round)

2) Relative Humidity

a) Summer = 50% maximum ± 5%

b) Winter = No Control

c. Mechanical and Electrical Rooms

1) Dry-Bulb Temperature

a) Summer = 90°F(32C) Maximum

b) Winter = 60°F(15C) Minimum

2) Relative Humidity = No control

Heating and Cooling Loads a. Electrical

1) Offices

a) Lighting = 2 watts per sq ft

b) Equipment = 1.0 watts per sq ft

2) Laboratory

a) Lighting = 2 watts per sq ft

b) Equipment = (to be determined by actual equipment load,

but not less than 10 watts per sq ft)

3) Corridor

a) Lighting = 0.5 watts per sq ft

b) Equipment = 0 watts per sq ft

4) Clean Rooms

a) Lighting = 2.5 watts per sq ft

b) Equipment = (to be determined by actual equipment, but not less

than 10 watts per sq ft)

b. Occupants

1) The occupancy heat rejection will be as follows:

a) Sensible = 250 Btuh/person

b) Latent = 200 Btuh/person

2) The number of occupants in each space will be

based on the actual occupant density listed in the

facility program.

3) Occupancy Density = 40-50 people

4) Occupancy Schedule = The mechanical systems will

be designed to operate 24 hours per day, 365 days

per year.

Ventilation Rates a. The minimum ventilation (outdoor air) rates will be as follows: 1) Offices, Conference and Administrative Support Area. a) 20 cfm per occupant to meet the requirements of ASHRAE 62 Standard. 2) Laboratories and Laboratory Support Areas. a) Occupied = 12 air changes per hour, minimum b) Unoccupied = 6 air changes per hour, minimum 3) Cleanrooms: a) Class 100,000 = 20 air changes per hour b) Class 10,000 = 45-50 air changes per hour c) Class 1000 = 120 air changes per hour

Fume Hood Exhaust Rate

a. The exhaust air requirements for general-purpose

chemical fume hoods will be based on maintaining a

face velocity of 100 fpm through the open sash with the

sash stop at 18” above the sill.

b. Description/Exhaust Requirement

1) 6’-0” restricted sash (horizontal) bench hood: 900

CFM @ 0.22” WC. Current programming indicates

approximately 5 total fume hoods

2) 6’-0” class II, type B3 (30% exhaust) Biological

Safety Cabinet: 587 CFM minimum @ 0.22" WC

with thimble connection. Current programming indicates

approximately 14 total BSCs.

Building Pressure Relationships Criteria

a. The laboratories, toilet rooms and janitor’s closet will be at

a negative pressure with respect to adjacent spaces. The

corridors and office area will be at a positive pressure with

respect to laboratories. . Refer to Air Flow Diagram for

pressure relationships within the manufacturing suites.

Office Area Air Handling System a. System Description 1) It is anticipated that an existing Trane 15-ton rooftop heat pump will serve the office area. 2) System will be a single duct variable air volume reheat system, providing heating and cooling, to the spaces. Humidification will not be provided. A unit bypass duct will be provided to maintain constant airflow across the evaporator. 3) Air handling system will operate 24 hours per day, 365 days

per year. 4) Ductwork will not be lined Sound attenuating flexible duct up to 6 ft in total length will be provided at the supply diffusers to control noise. 5) Ductwork will be constructed in accordance with SMACNA Standards for appropriate pressure class. Ductwork will be sealed to meet SMACNA Seal Class A as a minimum and to limit ductwork leakage not exceeding 1% of the design flow rate for high pressure ductwork and 2% for low pressure ductwork.

b.Design Criteria 1) Duct System Distribution Criteria: a) Supply Ductwork Sizing From Air Handling Unit to Air terminal (AT) Device: 0.15"/100 ft when ≤ 10,000 cfm; 2,000 fpm when > 10,000 cfm. Air Terminal Device to Supply Diffuser: 0.1"/100 ft when ≤ 8,000 cfm; 1,600 fpm when > 8,000 cfm b) Return/Exhaust Ductwork Sizing: 0.1"/100 ft when ≤ 8,000 cfm; 1,600 fpm when > 8,000 cfm. 2) Reserve Capacity and Redundant Systems a) There will be no redundancy. b) The air handling system will be on normal power. 3) The supply air terminals (ATs) will be damper blade type and will have internal liner with aluminum foil protection similar to Titus Steri-Loc units. ATs will be variable air volume and will be provided with system pressure independent DDC type actuators.

Types of water used in pharmaceutical processes

Purified water Water for Injections – PFW & WFI Softened Water Water for Final Rinse Pure, or clean Steam Water for cooling Autoclaves

Contaminants of water:

Problem minerals Calcium and magnesium Iron and manganeseSilicatesCarbon dioxideHydrogen sulfidePhosphates

Contaminants of waterFurther problem minerals

CopperAluminiumHeavy metals

Arsenic, lead, cadmiumNitrates

Sampling location Target

Alert Action

Raw water 200 300 500

Post multimedia filter

100 300 500

Post softener 100 300 500

Post activated carbon filter

50 300 500

Feed to RO 20 200 500

RO permeate 10 50 100

Points of Use 1 10 100

Suggested bacterial limits (CFU /mL)

Cationic column Anionic column

Hygienic pump

Outlets or storage.

Ozone generator

UV light

HCl NaOH

Eluates toneutralization

plant

Air break to sewer

Drain line

from water softener

Water must be kept circulating

Typical de-ionizer schematic

12345

6

12345

6

Return to de-ioniser

Cartridgefilter 5 µm


Branch

Branch

2nd stage buffer tank


Second stage RO cartridge

First stage filtrate feeds second stage RO with excess back to 1st stage buffer tank.

1st

stag

e re

ject

co

nce

ntr

ate

Air breakto sewer

Second stage reject water goes back to first stage buffer tank

Second stage RO watermeets Pharmacopoeia

standards Outlets or storage

1st stage buffer tank

Water from softener or de-ioniser

Water returns to 1st stage buffer tank

Typical 2-stage RO schematic

Hygienic pump

First stage RO cartridge

High pressure pump

raw water

High pressure

Feedwater

underpressure

Re

jec

tw

ate

r

Se

mi-p

erm

ea

ble

me

mb

ran

e

Pe

rme

ate

wa

ter

drain or recycle

Low pressure

Purified water

Reverseosmosis (RO) theory

+

Production Room

Exhaust air treatment

Central air handling unit

Terminal air treatmentat production room level

Fresh air treatment (make-up air)

FilterSilencer

Terminal filter

Weather louvre Control damper

FanFlow rate controller

Humidifier

Heating coil

Cooling coil with droplet

separator

Production Room

Overview components

+

Prefilter

Filter classesDust filters

Standard Aerosol

FineCoarse ULPAHEPA

10 µ m > Dp > 1 µ mDp > 10 µ m Dp < 1 µ m

F5 - F9G1 - G4 U 14- 17H 11 - 13

EN 1822 StandardEN 779 Standard

Average EfficiencyIntegral Value

Peak ArrestanceLocal Value

Retention in%

Penetration Efficiency Penetration

F9 85 0.15

H11 95 0.05

H12 99.5 5x10-3 97.5 25x10-3

H13 99.95 5x10-4 99.75 25x10-4

U14 99.995 5x10-5 99.975 25x10-5

Classification of filters according to their efficiency

HEPA or tertiaary filterSecondary filter

1 Filter2 Tightening frame3 Register outlet4 Screw fixation for register

1

2

3

44

High induction office type diffusor(avoid)

Low induction swirl diffusor(preferred)

Turbulent dilution of dirty air

Uni-directional / laminardisplacement of dirty air

N ote : D irection of door opening relative to room pressure

15 Pa

0 PaA ir

Lock30 Pa PassageD

C

A

B

D LF

A ir LockA ir Lock

45 Pa

Room 3 Room 2 Room 1

45 Pa60 Pa30 Pa


15 Pa

15 Pa15 Pa

E30 Pa

Passage0 Pa

A irLock


15 Pa

A ir LockA ir Lock

Pressure cascade solidsProtection from cross-contamination


15 Pa

0 PaA ir

Lock30 Pa PassageD

C

A

B

D LF

A ir LockA ir Lock

45 Pa


45 Pa60 Pa30 Pa

Protection from micro-organisms and particles

Air Classification as per Schedule M Maximum permitted number of particles/m3 equal or above Grade...

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