CLEAN ROOM MONITORING – REGULATORY STANDARDS

Ø Air Classification as per Schedule M

Grade	Maximum permitted number of particles / m3 equal or above
	at rest		in operation
	0.5µm	5.0µm	0.5µm	5.0µm
A	3,520	29	3,500	29
B	35,200	293	3,52,000	2,930
C	3,52,000	2,930	35,20,000	29,300
D	35,20,000	29,300	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 7
Grade D correspond to with class 100000, M 6.5, ISO 8

Ø Air Classifications by US FDA guideline on Sterile Drug Products

Clean Area Classification	<0.5 µm Particles/ft3	<0.5 µm Particles/mt3	Microbiological Limit
Clean Area Classification	<0.5 µm Particles/ft3	<0.5 µm Particles/mt3	cfu/ft3	cfu/m3
100	100	3,500	<1	<3
1000	1000	35,000	<2	<7
10000	10000	350,000	<3	<18
100000	100000	3,500,000	<25	<88

Ø Air Classifications as per WHO 2002

Grade	Maximum Number Permitted / M3
	Particles		Microorganisms
	0.5µm	5.0µm	Microorganisms
A (LAF)	3,500	0	<1
B	3,500	0	5
C	3,50,000	2,000	100
D	3,500,000	20,000	500

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 7
Grade D correspond to with class 100000, M 6.5, ISO 8

Ø Airborne Classification in the European union guide to Good Manufacturing Practice

Grade	Maximum Permitted Number of Particles /m3 equal to or above
	at rest		in operation
	>= 0.5µm	>= 5.0µm	>= 0.5µm	>= 5.0µm
A	3500	0	3500	0
B	3500	0	350000	2000
C	350000	2000	3500000	20000
D	3500000	20000	not defined	not defined

Note :-

Grade A and B correspond to with class 100, M 3.5, ISO5
Grade C correspond to with class 10000, M 5.5, ISO 7
Grade D correspond to with class 100000, M 6.5, ISO 8

Ø Clean room Environmental Monitoring

Sr. No.	Test	Frequency
1	Particle Monitoring in air	6 monthly
2	HEPA Filter Integrity Testing	6 monthly
3	Air Changes Rate Calculation	6 monthly
4	Air Pressure Differentials	Daily
5	Temperature and Humidity	Daily
6	Microbiological monitoring by settle plates and / or swabs in aseptic areas	Daily, and at decreased frequency in other areas

Ø Clean room Industry Design Thumb Rule

ISO Class	Controls	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 – 15
8	Less Stringent	3 – 5	10 – 15	05- 10

Ø Comparison between selected equivalent class of federal standards 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 100 Class 1000 Class 10000 Class 100000

Ø Comparison of international standards

Country and Standard
USA 209D	USA 209E	Britain 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

Ø EUG GMP 2002 Recommended Limits for Microbial Contamination

Grade	Air Sample cfu/m3	Settle Plates Dia 90 mm cfu/m3	contact Plates Dia 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 :-

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 7
Grade D correspond to with class 100000, M 6.5, ISO 8

Ø Federal Standard 209D Class Limits

Class	Particles /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

Ø Federal Standard 209E Class Limits

Class Name		>= 0.1µm		>= 0.2µm		>= 0.3µm		>= 0.5µm		>=5.0µm
Volume Units		M³	Ft³	M³	Ft³	M³	Ft³	M³	Ft³	M³	Ft³
SI	English
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

Ø ISO Standard 14644-1 Class Limits

ISO Classification Number	Maximum concentration limits( Particles/m3 of air) for particles equal to and larger than the considered sizes shown below
ISO Classification Number	>= 0.1µm	>= 0.2µm	>= 0.3µm	>= 0.5µm	>= 1.0µm	>= 5.0µm
ISO 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	10200	3520	832	29
ISO Class 6	1000000	237000	102000	35200	8320	293
ISO Class 7				352000	83200	2930
ISO Class 8				3520000	832000	29300
ISO Class 9				35200000	8320000	293000

Ø Particles in Outdoor Air

	Number of Particles/m3 on Outdoor Air
Size in Microns	Dirty	Normal	Clean
>0.1	10000000000	3000000000	500000000
>0.3	300000000	90000000	20000000
>0.5	30000000	7000000	1000000

Ø Schedule of Mandatory Test to Demonstrate Continuing Compliance in Clean rooms

Test Parameter	Class	Maximum Time Interval
Particle Count Test	<= ISO 5	6 months
Particle Count Test	> ISO 5	12 months
Air Pressure Difference	All Classes	12 months
Airflow	All Classes	12 months

Ø Schedule of Optional Test to Demonstrate Continuing Compliance in Clean rooms

Test Parameter	Class	Maximum Time Interval
Installed Filter Leakage	All Classes	24 months
Containment Leakage	All Classes	24 months
Recovery	All Classes	24 months
Airflow Visualization	All Classes	24 months

Ø Special Requirements for ISO Class 3 Clean rooms

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	<0.1 µ ( Building); <0.01 µ ( Equipment) rms
Noise	< 55 dbA
Temperature	.1 degree C
Humidity	< 2%
Magnetic field var	< 1 mG
Static charge	< 50 v

Ø Types of Operations for Aseptic Preparations

Grade Types of Operations for Aseptic Preparations

A Aseptic preparation and filling

B Background room conditions for activities requiring Grade A

C Preparation of Solution to be filtered

D Handling of components after washing

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 7
Grade D correspond to with class 100000, M 6.5, ISO 8

PERMITTED DAILY EXPOSURE (PDE)

PERMITTED DAILY EXPOSURE (PDE) or ACCEPTANCE DAILY EXPOSURE Introduction During the manufacture of medicinal products accidental cross contamination can result from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms from active substances, other starting materials, and other products being processed concurrently, as well as from residues on equipment, and from operators ’ clothing. Due to the perceived risk, certain classes of medicinal product have previously been required to be manufactured in dedicated or segregated self contained facilities including, “certain antibiotics, certain hormones, certain cytotoxics and certain highly active drugs”. Until now no official guidance is available in order to assist manufacturers to differentiate between individual products within these specified classes. METHODS FOR ESTABLISHING EXPOSURE LIMITS The Gaylor-Kodell method of risk assessment (Gaylor, D. W. and Kodell, R. L.: Linea...

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