VALIDATION OF CLEAN ROOMS FOR

ASEPTIC MANUFACTURING
F.R.Smal
Pharmaceutical Director ICCE
ICCE a member of SNC-Lavalin Group
tel + 3226431600
E-Mail: francis.smal@be.snclavalin.com

VALIDATION OF CLEAN ROOMS

Proving that the environmental conditions of the clean

rooms that have been defined in the HVAC ORDER from
the USER PROCESS REQUIREMENTS are ALWAYS
reached in the clean rooms Installations

USER/PROCESS REQUIREMENTS FOR

CLEAN ROOMS

Layout and circulations (to avoid contamination and cross

contamination)
Environmental Conditions
Automation
Maintenance
Cleaning

V-MODEL

User Requirements
Specifications

Performance Qualification
Operations & Maintenance

Functional
Specifications

Operational
Qualification

Installation
Specifications

Installation
Qualification

CR HVAC As Built

URS HVAC
-

F.S

Automated
Fumigation

- Dedicated extractor
- Stopping HVAC in room
with Din 1946 Dampers
- Time sequences for Heating
plates
- Restarting HVAC

Maintenance of filling
line without stopping
the use of the other
clean rooms

- Access door from class D

- VAV Boxes

Absence of contamination
cross contamination

- Double HEPA filtration and

recirculation
- Air shower
- PAL and MAL











































 





















































 
























 


 
















































































 


DESIGN QUALIFICATION
Checking

URS

Checking

cGMP compliance

Approving
For
Execution

Schemes of Principes, P & ID

Data sheets

F.S

D.S

APPROVAL BEFORE CONSTRUCTION

SCHEMES OF PRINCIPLES
P & ID S
Ceiling Plan (supplies and returns)
Routing of Air ducts

FAT

Air Handling Units

Automation Acceptance tests
Electrical Acceptancce Tests

S A T (IQ+ OQ)

As built Documentation review

IQ
CAL + OQ

S T AN D AR D D O C UM E NT A T IO N L IST (SD L )
S ection

E ngineering file sections

1
2

TABL E O F CON TE N T
BID DIN G RE Q UIRE M E NT S

ORD E RIN G DO CUM E N TS

FO R EX E CU TION
AP PR OV E D DO CU M EN TS

FO R EX E CU TION
AP PR OV E D DR AW IN GS

AS BUIL T DRAW IN GS

AS BUIL T DO CUM E N TS

IN ST ALL ATIO N AND

IN SP E CTION DO CUM E N TS

OP E RAT IO NS AN D
M AIN TE N ANC E
DO CUM E N TAT IO N

10

SE T P OINT S, F UN CTION AL
PA RAM E TE RS

D ocum ent in file

S ections an d sub sections as m ention ed here
Bid ding specification s
Bid ding drawings
P urchase orders
L ist of supplier sub contractors
M ain components data sheets (Description/ specs)
D esign C alculation
Control system Specifications
P & ID s
GAD s
M echanical drawings
E lectrical drawings
Connectio n drawings
Control system drawings
O ther drawings
P & ID s
GAD s
M echanical drawings
E lectrical drawings
Connectio n drawings
Control system drawings
O ther drawings
General com ponents list an data sheets
Control system specs
O fficial control inspection reports
AIB Vinotte, Apave, TU V
Installation Instructions
Risk Analysis (E urop ean Directive)
O peration and maintenance m anuals
Consum ables list
S pare parts list
T raining D ocum entation
S et points, Alarm values, functional parameters
P ositio ns of dip switches, etc

STANDARD DOCUMENTATION LIST (SDL)

Section

Qualification file sections

1
2
3

TABLE OF CONTENT
PROJECT CHANGES
FACTORY ACCEPTANCE
TESTS (FAT)

INSTALLATION
QUALIFICATION TESTS

CALIBRATION

SITE ACCEPTANCE TESTS

(SAT)
OPERATIONAL
QUALIFICATION (OQ)
EXTENDED QUALITY
DOCUMENTATION
PIPING/WELDING
DOCUMENTATION

EQUIPMENT/SUPPLIER
CERTIFICATES

Document in file
Quality Documentation File contents
Change (control) documents and related documents
Supplier pre FAT test reports,
FAT Protocols, Report, Raw Data, Punch list
Electro-mechanical IQ Protocol, Report, Raw data, Punch list
Control system IQ Protocol, Report, Raw data, Punch list
IQ certificate
Calibration certificates
Calibration Protocols, Report, Raw data, Punch list
Calibration certificate
Electro-mechanical OQ Protocol, Report, Raw data, Punch list
Control system OQ Protocol, Report, Raw data, Punch list
OQ certificate
Slopes verification
Welding procedure and Qualification including Isometric
drawings
Welders Qualification
Cleaning/passivation procedures and reports
Pressure leak test reports
Quality Plan, Quality Manual
Supplier ISO certificates
CE compliance
Material certificates
Pressure/safety valves certificates
Other certificates

INSTALLATION QUALIFICATION
A T T A C H M E NT #

T IT L E

# 01

Test form : P ersonnel perform ing IQ

# 02

IQ D eviation Form

# 03

IQ Inform ation, O bservation, C om m ent Form

# 04

# 06

Test Form : D ocum entation V erification

Test form : P iping & Instrum entation D iagram (P& ID )
Verification
Test Form : G eneral A rrangem ent V erification

# 07

Test form : T rolleys, S helves and other ancillary system s

verification

# 08

Test form : P ower, E lectrical utilities verification

# 09

T est form : No n-electrical utilities verification

# 10

Test form : C ritical Instrum ent List and Verification

# 11

Test form : F ilters and other C onsum ables list

# 12

Test form : S pare part list

# 13

Environm ental and Safety review

# 14

System associated S O Ps list and Log-book verification

# 15

Installation Q ualification C om pletion and A pproval

# 05

OPERATIONAL
QUALIFICATION TESTS

AIR HANDLING UNITS (AHUS)

OPERATIONAL TESTS

Frequency Variator Setting

Motor Speed
Absorbed current Intensity
DP AHU in out
Calculation of Air Flow
Supply and Exhaust Fan Interlocks

OTHER OPERATIONAL TESTS

Heating and cooling Batteries

Steam Humidifier
CAV VAV Box
Dampers

OPERATIONAL TESTS CONTINUED

Temperature and Humidity

Noise levels
Formolation tests

Operational Qualification
Testing of Automation System
Testing of HVAC Operation against Functional
Specifications
Filter Integrity tests
Air speeds and air flow measurements
Pressure differentials measurements
Air flow patterns
Decontamination time

EN / ISO 14644 and IN SITU HEPA TESTING

14644-3 will allow EMERY 9004 / DURASIN 164, ONDINA EL

and other oil aerosol

P 0,01%

Annex B6: particle counter method satisfies the FDA

Aseptic processing guide 87 that requires an adequate
challenge level be established for a valid test.

THE EN 1822-1: 1998 Table 1: Classification of HEPA and ULPA

Filters
Filter class Overall value
Efficiency (%)

H
E
P
A

U
L
P
A

Local value 1) 2)
Penetration (%)

Efficiency (%)

Penetration (%)

H10 85

15

---

---

H11 95

---

---

H12 99,5

0,5

---

---

H13 99,95

0,05

99,75

0,25

H14 99,995

0,005

99,975

0,025

U15 99,999 5

0,000 5

99,997 5

0,002 5

U16 99,999 95

0,000 05

99,999 75

0,000 25

U17 99,999 995

0,000 005

99,999 9

0,000 1

1) see 6.5.2 and prEN 1822-4

2) local values low er than those given in the table may be agreed betw een supplier and
purchaser

EN / ISO 14644 and AIR EXCHANGE RATES

14644
14644--44does
doesnot
notspecify
specifyany
anyrequirement
requirement

Pharma
Pharmaguides:
guides: minimum
minimum20
20air
airchanges
changes//h.
h.

AIR FLOW SPECIFICATIONS

Per supply

- 10 %, + 30% of specified Air Flow

Per room

- 5 %, + 25 % of specified Air Flow

EN / ISO 14644 and AIRFLOW VELOCITY

14644
14644--44suggests
suggests0,2
0,2--0,7
0,7m/s
m/s
with
withefficiency
efficiencydemonstrated
demonstratedby
byperformance
performance
testing.
testing.
Pharmacy
Pharmacyexpectations:
expectations: 0,45
0,45 20%
20%
Not
Notalways
alwaysapplicable.
applicable.

AIR SPEED MEASUREMENTS

LAF
HOOD

0.45 m/s + 20 % at working level

LAF
with air curtains
Or
LAF
over filling machine

measurement of speeds:
-10 cm under filter
- at working level (bottom of curtain)
No specs : For information ONLY

EN / ISO 14644 and ROOM PRESSURE

14644
14644--44suggests
suggestsdp
dp55-- 20
20Pa
Pa
gives
givesguidance
guidanceon
onrisks
riskson
onvery
veryhigh
highpressure
pressure
very
verylow
lowpressure
pressure

ItItaccepts
accepts
low
lowpressure
pressuredifferential
differential++Flow
Flowthrough
throughopenings
openings

PRESSURE DIFFERENTIAL

Dp 10 Pa (15 Pa)

with + 5 Pa tolerance around set point

no overlap

AIR FLOW PATTERNS

Difficulties of performance linked to

- Smoke generation and initial velocity
- Talents of cameraman and film mounting

DECONTAMINATION TIMES
MEASUREMENTS

Decontamination Time Procedure

-

- Place the probe of the particle counter at a place which is representative for the air flow

pattern outside the flow of the HEPA filter (mostly near an extract duct or a place which is poorly
ventilated) (particle counting in Worst case conditions).
- Create an artificial contamination in the room using a Drger smoke generator (along
walls, near machine frames, under HEPA filtered air inlets) in order to obtain a contamination
level:
> 10000 particles 0.5 m per ft (class B)
> 100000 particles 0.5 m per ft (class C)
> 106 particles (class D)
- Start the particle counter : sampling time = 1 minute ; delay between the samples 1 sec.,
program the particle counter printer with limits 0.5 and 5 m. Check that the number of
particles 0.5 m is greater than 10000/ft (or 100000, or106/ft3 as applicable).
- Leave the room and allow to auto-decontaminate until steady conditions are obtained, this
is when the contamination level is stable and the possible anomalies have been observed (see BH
77/2 for example where one or more ondulations in the particle counts are obtained).
-

- The number of sampling points per area is calculated with the following principle :

1 point per 25 m2 of floor surface with a minimum of 1 per room.

for areas of more than 3 m high : 1 point for each 75 m3.

Operational tests Conclusions

PUNCH LIST (List of Deviations)

Accepted without remarks
Accepted with remarks
Not accepted

PL
Nber

PL
Nber

Description

Action By

Critical Y/N

Retest

Verified By Closing Date

Description

Action By

Retest

Verified By Closing Date

Critical Y/N

PERFORMANCE QUALIFICATION

PARTICULATE COUNTINGS
CONTAMINATION CURVES












 




NOTICE OF CANCELLATION
FED-STD-209NOTICE 1




















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THE EU GMP 5 Particle Number Problem

Nber of Particles EC EC

EC

EC

ISO ISO
5

ISO

0 2,000 20,000 29 2,930 29,300

PROCEDURE, PARTICLE COUNTS

-

D e te r m in e th e n u m b e r o f p a r tic le c o u n tin g p o in ts w ith

(lo c a tio n s ) r e s p e c t to th e r e c o m m e n d a tio n s o f th e

E N IS O 1 4 6 4 4 - 1 : 1 9 9 9 (E )

" T h e ru le s g o v e rn in g m e d ic in a l p r o d u c ts in th e
E u r o p e a n C o m m u n ity ( E u d r a le x V o lu m e IV , A n n e x 1 ,
1 9 9 8 )"

" F D A g u id e lin e o n s te r ile d ru g p r o d u c ts p r o d u c e d b y

a s e p tic p r o c e s s in g " ,1 9 8 7

M a k e a d r a w in g o f th e r o o m a n d lo c a te th e m e a s u r in g
p o in ts ( p r e fe r a b ly a t th e m o s t c r itic a l p o in ts ).
A t e a c h p o in t, p la c e th e p r o b e o f th e p a r tic le c o u n te r
p a ra lle l to th e flo w ( v e r tic a lly o r h o r iz o n ta lly ) w ith th e
o p e n in g to w a r d s th e H E P A filte r ( is o a x ia l s a m p lin g ) .

T h e p a rtic le c o u n te r is u s e d f o llo w in g th e
re c o m m e n d a tio n s o f th e m a n u f a c tu r e r . E a c h tim e th e
c o u n te r p r o b e is m o v e d in th e r o o m , th e in itia l d e la y
m u s t b e p r o g ra m m e d w ith a tim e a p p ro p r ia te fo r th e
c le a n in g o f th e tu b e . T h e tim e b e tw e e n tw o s u c c e s s iv e
re a d in g s w ith o u t tr a n s fe r r in g th e p r o b e is p r o g ra m m e d a t
1 s e c . ( d e la y tim e ) .

S a m p le th e a ir a t th e h e ig h t o f th e w o r k a c tiv ity ( q u ite

o fte n b e tw e e n 0 ,8 to 1 .2 m ), u n le s s im p o s s ib le d u e to th e
p re s e n c e o f e q u ip m e n t .

PROCEDURE, PARTICLE COUNTS

-

Sample the air once at each location except if :

There is only 1 sampling point in the room : sample the air
thrice at the same location
The result of the 1st sampling is out of the specifications
range.
Then confirm or refute the reading by 3 successive
readings

For class C and D at rest or operational, sample time is 1 min and

sampling volume is 1ft

For class A at rest or operational or B at rest the sampling time will be at

least 5 min and could be more if the results are in between Pass and
Failed values of the Table F.1 of the Annex F of the EN ISO 14644-1 :
1999, describing the sequential sampling procedure (see next page)

The statistical calculations of classification are performed in accordance

with the recommendations of the "EN ISO 14644-1" at the upper confidenc
level of 95 %.

EN ISO 14644-1
EN ISO 14644-1 : 1999 (E) Sequential sampling procedure
Table F.1 upper and lower limits for time at which C observed counts
should arrive

FAILS IF COUNT, C, COMES

EARLIER THAN EXPECTED
Fractional time, t
0,001 9
0,050 5
0,099 2
0,147 6
0,196 1
0,244 7
0,293 2
0,341 7
0,390 2
0,438 8
0,487 3
0,535 9
0,584 4
0,633 0
0,681 5
0,730 0
0,778 6
1,000 0

Observed Count
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21

PASSES IF COUNT, C, COMES

LATER THAN EXPECTED
Fractional time, t
0,192 2
0,240 7
0,289 3
0,337 8
0,386 4
0,434 9
0,483 4
0,532 0
0,580 5
0,629 1
0,667 6
0,726 2
0,774 7
0,823 3
0,871 8
0,920 3
0,968 9
1,000 0

Observed Count
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

NOTE Fractional times are given as the fraction of total times (t = 1,000 0 at the class limit)
Total times t = 1,000 0 at the class limit represents 24,3 minutes at the limit of class A,B (class A
at rest or operational, class B at rest) for particles 5 microns

PASS AND FAIL CONDITIONS FOR CLASS

A/B 5 PARTICLE COUNTINGS

Pass and Fail Conditions for class A/B 5 particle countings

CONTINUE
COUNTING

F
A
IL

M
i
n
u
t
e
s

P
A
S
S

25
24
23
22
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0

10 11
12
# Pa rticle s

13

14

15

16

17

18

19

20

21

ACCEPTANCE CRITERIA
P a rtic le c o u n tin g , c la s s ific a tio n o f ro o m s
-

P artic le co u n ts a re w ith in spe cifica tio n s at a u p pe r co n fid en c e lev el o f 9 5 % fo llo w ing th e sta tistica l
ca lc u la tio n o f the "E N IS O 1 4 6 4 4 -1 : 1 9 9 9 E " .
T h e s pe cifica tio ns fo r the airb orn e p a rticu late c la ssifica tio n o f cle an ro om s, a s d efine d in th e E u dra le x
V o lu m e IV , A n n ex 1 , 19 9 8
.

A t rest
GR ADE

In o p e ra tio n

M a xim u m p e rm itte d n u m b er o f p a r tic le s/m e q u a l to o r a b o ve

0.5 m

5 m

0 .5 m

5 m

A
IS O C lass 5

3 .5 0 0
3 .5 2 0

0
29

3.5 00
3.5 20

0
29

B
IS O C lass 5

3 .5 0 0
3 .5 2 0

0
29

3 50 .0 0 0
3 52 .0 0 0

2.0 00
2.9 30

IS O class 6

3 5 .2 0 0

293

3 52 .0 0 0

2.9 30

C
IS O C lass 7

3 5 0.0 00
3 5 2.0 00

2 .00 0
2 .93 0

D
IS O C lass 8

3.5 00 .00 0
3.5 20 .00 0

2 0.0 00
2 9.3 00

3 .5 0 0 .0 0 0
2 0 .0 0 0
3 .5 2 0 .0 0 0
2 9 .3 0 0
N o t d e fin ed ,
d e pe nd s on n a ture of o p era tio n s

A n y ch a n g e o f h er ea b o v e a cc ep ta n c e c riter ia m u st b e m u tu a lly ag r ee d u p on b y IC C E a n d (se e

A n ne x 1: S h ee t fo r ch an g e o f ac ce pta nc e c riteria).
N o te th e d isc re p a n cy b etw ee n E u d r ale x a n d E N IS O 14 6 4 4-1 : 1 99 9 fo r c la ss A , B
p a rticle s 5 w h ere E u d ra le x a d m its 0/m an d E N IS O a d m its u p to 2 9 .
2 9 s h ou ld b e co n sid er ed b e ca u se of th e elec tro n ic n o ise o f th e c o u n ter a n d o th er co n sid e ra tio n s.

TEST RESULTS : PARTICLE COUNTINGS

ACCORDING EN ISO 14644-1 : 1999(E)
TEST RESU LTS: PARTICLE CO U N TING S AC CO RD IN G EN ISO 14644-1 : 1999 (E)
Particle coun tings class A,B (ISO 5) : A at rest or operation al
B at rest on ly
Sam plin g tim e 5 m in
Sam p lin g Volum e 5 ft
N um ber o f sam plin g p oin t (SP)/roo m = 1
Sequen tial sam plin g
Ro om ID :
Class B at rest

Samp ling Po int ID

1

Particle cou nts 0 .5 /ft

Particle cou nts/ft
2

A vg 0.5

Part 0 .5
A cceptance criteria
In co mp liance Y/N
Particle coun ts 5
Cou nting time :
Particle co unts
Acceptance criteria
(min utes)
(ob served)
5
0
6
1
7
2
* (1)
* (1)
(2)
In co mp liance with acceptance criteria of table F1 Y/N

<100

Fails
8
9
10
(3)

(1) En ter first value w hich is in com p lian ce w ith co unts of table F1 o r which fails
(2) En ter relevan t acceptance criteria (from table F)
(3) En ter relevan t fail valu e (from table F1)

REFERENCES
- The Rules governing Medicinal Products in the
European Community
(Eudralex Volume IV Annex 1, 1998)
- EN ISO 14644-1-7 on Clean Room Standards
- ISPE Baseline Pharmaceutical Guide :
Sterile Manufacturing Facilities
- ISPE Baseline Pharmaceutical Guide :
Commissioning and Validation

CONCLUSIONS

All the validation steps are important

(start well to finish well)
It is not possible to validate a poor Design
It is not possible to validate a poor Field Installation