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 Performance Qualification

Specifications Operations & Maintenance

Functional Operational
Specifications Qualification

Installation Installation
Specifications Qualification

CR HVAC As Built
 URS HVAC F.S

- Automated - Dedicated extractor

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

Maintenance of filling - Access door from class D

line without stopping - VAV Boxes
the use of the other
clean rooms

- Absence of contamination - Double HEPA filtration and

cross contamination recirculation
- Air shower
- PAL and MAL



 


 










 




 






 









 









 









 





 












 


 







 









 










 

 











 

 DESIGN QUALIFICATION

Checking URS F.S D.S

Checking cGMP compliance

Approving Schemes of Principes, P & ID

For
Execution Data sheets
 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 D ocum ent in file
1 TABL E O F CON TE N T S ections an d sub sections as m ention ed here
2 BID DIN G RE Q UIRE M E NT S Bid ding specification s
Bid ding drawings
3 ORD E RIN G DO CUM E N TS P urchase orders
L ist of supplier sub contractors
4 “FO R EX E CU TION ” M ain components data sheets (Description/ specs)
AP PR OV E D DO CU M EN TS D esign C alculation
Control system Specifications
5 “FO R EX E CU TION ” P & ID ’s
AP PR OV E D DR AW IN GS GAD ’s
M echanical drawings
E lectrical drawings
Connectio n drawings
Control system drawings
O ther drawings
6 AS BUIL T DRAW IN GS P & ID ’s
GAD ’s
M echanical drawings
E lectrical drawings
Connectio n drawings
Control system drawings
O ther drawings
7 AS BUIL T DO CUM E N TS General com ponents list an data sheets
Control system specs
8 IN ST ALL ATIO N AND O fficial control inspection reports
IN SP E CTION DO CUM E N TS AIB Vinçotte, Apave, TU V
Installation Instructions
Risk Analysis (E urop ean Directive)
9 OP E RAT IO NS AN D O peration and maintenance m anuals
M AIN TE N ANC E Consum ables list
DO CUM E N TAT IO N S pare parts list
T raining D ocum entation
10 SE T P OINT S, F UN CTION AL S et points, Alarm values, functional parameters
PA RAM E TE RS P ositio ns of dip switches, etc…
 STANDARD DOCUMENTATION LIST (SDL)
Section Qualification file sections
1 TABLE OF CONTENT
2 PROJECT CHANGES
3 FACTORY ACCEPTANCE
TESTS (FAT)
4 INSTALLATION
QUALIFICATION TESTS
5 CALIBRATION
6 SITE ACCEPTANCE TESTS
(SAT)
OPERATIONAL
QUALIFICATION (OQ)
7 EXTENDED QUALITY
DOCUMENTATION
PIPING/WELDING
DOCUMENTATION
8 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 Test Form : D ocum entation V erification
Test form : P iping & Instrum entation D iagram (P& ID )
# 05
Verification
# 06 Test Form : G eneral A rrangem ent V erification
Test form : T rolleys, S helves and other ancillary system s
# 07
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 P’s list and Log-book verification
# 15 Installation Q ualification C om pletion and A pproval
 OPERATIONAL
QUALIFICATION TESTS
 AIR HANDLING UNITS (AHU’S)
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 Local value 1) 2)
Efficiency (%) Penetration (%) Efficiency (%) Penetration (%)
H10 85 15 --- ---

H H11 95 5 --- ---

E
H12 99,5 0,5 --- ---
P
A H13 99,95 0,05 99,75 0,25

H14 99,995 0,005 99,975 0,025

U U15 99,999 5 0,000 5 99,997 5 0,002 5
L
U16 99,999 95 0,000 05 99,999 75 0,000 25
P
A 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: 0,45±± 20%
expectations: 0,45 20%
Not
Notalways
alwaysapplicable.
applicable.
 AIR SPEED MEASUREMENTS

LAF 0.45 m/s + 20 % at working level

HOOD

LAF measurement of speeds:

with air curtains -10 cm under filter
Or - at working level (bottom of curtain)
LAF
over filling machine 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 Dräger smoke generator (along
walls, near machine frames, under HEPA filtered air inlets) in order to obtain a contamination
level:
• > 10’000 particles 0.5 ≥ µm per ft³ (class B)
• > 100’000 particles 0.5 ≥ µm per ft³ (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 µm. Check that the number of
particles ≥ 0.5 µm is greater than 10’000/ft³ (or 100’000, 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 Description Action By Critical Y/N
Nber

Retest Verified By Closing Date

PL Description Action By Critical Y/N

Nber

Retest Verified By Closing Date

 PERFORMANCE QUALIFICATION

• PARTICULATE COUNTINGS

• CONTAMINATION CURVES











 




NOTICE OF CANCELLATION
FED-STD-209NOTICE 1





















 !
" # 


 "
$"



%&
' (
) #)!

#
&*$ &
(
#" # "%# !
 + #%, "%#
-
" # %, "%#
./

" # &
#" # "%# !
" # &
-
! # &
#
&&)% "

)#" !!
#% ##"&

01002
 "
3
! &&%-%) "%#
-
%

)! #!%#&&4
#

01002

 "

3
$)%-%) "%#&
-
"&"%#+
#

#%" %#+
"
$ 
)#"%#*
)$!% #)
5%"'

01002

$$!%) "%#
-
)$%&
-

" # &
01002
 "

#
01002

 "


4
 (

 &&
"
"'
#&"%"*"
-
#% ##" !
)%#)&
#

 THE EU GMP 5µ Particle Number Problem

Nber of Particles EC EC EC EC ISO ISO ISO

A B C D 5 7 8

≥ 5µ 0 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 1ft³

- 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 PASSES IF COUNT, C, COMES

EARLIER THAN EXPECTED LATER THAN EXPECTED

Fractional time, t Observed Count Fractional time, t Observed Count

0,001 9 4 0,192 2 0
0,050 5 5 0,240 7 1
0,099 2 6 0,289 3 2
0,147 6 7 0,337 8 3
0,386 4 4
0,196 1 8
0,434 9 5
0,244 7 9 0,483 4 6
0,293 2 10 0,532 0 7
0,341 7 11 0,580 5 8
0,390 2 12 0,629 1 9
0,438 8 13 0,667 6 10
0,487 3 14 0,726 2 11
0,535 9 15 0,774 7 12
0,584 4 16 0,823 3 13
0,633 0 17 0,871 8 14
0,681 5 18 0,920 3 15
0,968 9 16
0,730 0 19
1,000 0 17
0,778 6 20
1,000 0 21

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 5µ PARTICLE COUNTINGS

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

25
24
23
22
21
20
19
S

18
S
A

# 17
P

16
M 15
i 14
n 13
u 12 CONTINUE
t 11
e 10 COUNTING
s 9
8
7
6
5

IL
A
4

F
3
2
1
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
# Pa rticle s
 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 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 ³ e q u a l to o r a b o ve

GR ADE
0.5 µ m 5 µm 0 .5 µ m 5 µm

A 3 .5 0 0 0 3.5 00 0
IS O C lass 5 3 .5 2 0 29 3.5 20 29
B 3 .5 0 0 0 3 50 .0 0 0 2.0 00
IS O C lass 5 3 .5 2 0 29 3 52 .0 0 0 2.9 30

IS O class 6 3 5 .2 0 0 293 3 52 .0 0 0 2.9 30

C 3 5 0.0 00 2 .00 0 3 .5 0 0 .0 0 0 2 0 .0 0 0
IS O C lass 7 3 5 2.0 00 2 .93 0 3 .5 2 0 .0 0 0 2 9 .3 0 0
D 3.5 00 .00 0 2 0.0 00 N o t d e fin ed ,
IS O C lass 8 3.5 20 .00 0 2 9.3 00 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 µ w h ere E u d ra le x a d m its 0/m ³ 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 ft³
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

Particle cou nts ≥ 0 .5 µ /ft³

Samp ling Po int ID Particle cou nts/ft³
1 2 3 A vg 0.5
Part ≥ 0 .5 µ
A cceptance criteria <100
In co mp liance Y/N

Particle coun ts ≥ 5 µ
Cou nting time : Particle co unts Acceptance criteria Fails
(min utes) (ob served)
5 0 ≥8
6 ≤1 ≥9
7 ≤2 ≥ 10
* (1) * (1) (2) (3)
In co mp liance with acceptance criteria of table F1 Y/N

(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