You are on page 1of 9

Journal Code

Q A J

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61

Article ID
Dispatch: 11.09.11
4 8 5 No. of Pages: 9

CE:
ME:

A Risk Assessment Approach:


Qualication of HVAC System in
Aseptic Processing Area Using Building
Management System
Anil K. Shukla1,*, Ashutosh Katole2, Nilesh Jain1, C. Karthikeyan1, Farhad Mehta1 and
Piyush Trivedi1
1

School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, Madhya


Pradesh, India
2
Ranbaxy Laboratories Limited, Industrial Area 3, Dewas, Madhya Pradesh, India

Q1

Abstract

Q2

Q3

Q4

Q5

Q6

In the pharmaceutical industry qualication of HVAC systems is done by using a risk based
approach. FMEA concept was used for risk assessment in HVAC system to determine
scope and extent of qualication and validation in this present work. The level of risk was
assessed, based on the impact and severity on the aseptic practice in sterile
manufacturing because the HVAC system is the direct impact system in the aseptic
practice expected to have a direct impact on product quality and regulatory compliance.
On completion of the risk assessment, existing controls, measures and recommended
action were identied required for the better cGMP and upgradation of the system.
After completion of the risk assessment the recommended actions were extended and
veried against the qualication stages of the HVAC system. Finally, the HVAC system
was subjected to PQ study. All of the tests were performed and a report was generated.
On evaluation of the data collected during PQ, it was found that the HVAC system met all
the specied design criteria and complied with the entire cGMP requirement. Hence the
system stands validated for PQ. Copyright 2011 John Wiley & Sons, Ltd.
Key Words: HVAC; UAF; PQ; ICH; FMEA

Introduction
Quality risk management is an important part of
science based decision making which is essential
*Correspondence to: Anil Shukla, School of PharmaceuticalSciences,RajivGandhiProudyogikiVishwavidyalaya,
Bhopal,MadhyaPradesh,India.E-mail:aksqargpv@gmail.
com

Copyright 2011 John Wiley & Sons, Ltd.

for quality management of pharmaceutical


manufacturing. The ICH Q9 guideline, quality
risk management and other literature provide
guidance on the principal of quality risk management. The FMEA model can be used to facilitate
risk assessment for any system in the aseptic
processing area of sterile products. It provides a

Qual Assur J (2011)


DOI: 10.1002/qaj

62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122

2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61

A. K. Shukla et al.

62
63
Qualitative
Risk factor
64
ranking
65
Severity
Occurrence
Detection
66
High
Impact of unwanted event is
Occurrence is
The process failure will almost certainly
67
severe
often
escape detection
68
Medium
Impact of unwanted event is
Occurrence is
Control may detect the existence of a
69
moderate
periodic
process failure
70
Low
Impact of unwanted event is
Occurrence is
The process failure is obvious and
71
low
seldom
readily detected
72
73
74
75
tool to assess and evaluate different activities and
extended to qualication stages of HVAC system
76
conditions. Risk in sterile product manufacturing
to have a high level of assurance and if the test
77
and aseptic processing is relatively high when
result are not acceptable, carry out corrective
78
compared to other pharmaceutical process,
action that may include modication in the
79
T2 Q11 80
making risk assessment particularly important.
existing controls and the system. Table 2
81
The European Union GMP requirements
82
place specic obligations on manufacturers of
Performance Qualication for HVAC
83
medicinal products to implement risk based
Q12
and UAF System
84
qualication, validation and change control
85
programs. In pharmaceutical manufacturing,
86
Air Velocity and Air Changes
87
validation is an important part of QA and is a
88
requirement of cGMP and other guidelines.
Velocity at the inlet air grills was measured at 5 points in a
89
In the air handling system, special attention
plane parallel to lter face plane and at a distance of
90
must be made to keep the environment clean and
91
about 6 inches (~ 150mm) from the lter/opening face.
prevent product contamination. From a techni92
The velocity was measuredforat least 10 seconds from
cal perspective, the role of the HVAC system is
93
each point. It is performed by thermal anemometer
94
paramount in achieving and maintaining an
and vane type anemometer and calculated by
95
Q8 T1 acceptable manufacturing environment. Table 1
formula where, D is no. of air changes, B is air
96
supply volume (CFM), R is volume of the room
97
3
98
(ft ), 60 is factor (for air change per hour).
Experimental
99
P
100
B  60
Risk assessment (FMEA model)
D
101
R
102
Evaluate the overall risk of the qualication and
103
Differential Pressure Test
validation steps by combining individual risk
104
values. For the most of the direct impact system,
105
Measure and record the pressure difference
Q9 the severity will always be high. The RPR then
106
between the room to be tested and any
107
becomes a combination of an occurrence and
surrounding ancillary environment.
108
detection. If the level of risk is not acceptable, a
109
recommendation must be made to modify the
110
HEPA Filter Leakage Test
qualication and validation step to reduce the risk
111
Position the aerosol generator to introduce an
to an acceptable level or enhance the method of
112
aerosol challenge upstream of the HEPA lter to a
113
detection to reduce the risk to an acceptable level.
114
concentration
of
20-100mg/m
(20100
mg/lit.)
of
Preference should be given to reducing the
115
air by opening appropriate number of nozzles.
occurrence rather than increasing the level of
116
Measure upstream concentration of aerosol by
detection. After completion of the risk assessment,
117
using upstream port. Adjust the photometers gain
the recommended action of unacceptable risk
118
119
120
Copyright 2011 John Wiley & Sons, Ltd.
Qual Assur J (2011)
121
DOI: 10.1002/qaj
122

Table 1. Risk ranking system

Q7

Q10

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61

Qualication of HVAC System in Aseptic Processing Area

Table 2. Determination of RPR


Risk related to probability of detection
Low
Occurrence High

This is likely to occur, but when


it does, it will be detected. If
we are certain it will be
detected, it is Low Risk, but if
we are not certain then it
should be a Medium Risk.
Medium This could occur but if it did, it
would be detected.
Depending on the frequency
of occurrence and the
confidence in the detection, it
is a Low or a Medium Risk.
Low
This is not likely to occur and
if it does occur it will be
detected. This is a Low Risk.

/ span control for a full-scale deection on 100%


range. Scan the downstream side of the HEPA
lter. The photometer probe should be about 1
inch from the surface and at a transverse rate not
more than 10ft/minute with a sample ow rate of
1cft/min  10%.

Air Flow Visualization (Non-unidirectional


ow)
Q13 Generate

the tracer particles by WFI fogger.


Position the tracer at the appropriate place,
such as at the downstream of supply air and the
return air risers as well as at the doors opening
and check for the indication of the airow
direction. Record the airow pattern using
photography/videography.

Airborne Particle Count


Derive the number of sampling point locations
by using the equation where, NL is the minimum
number of sampling locations and A is Area of
the room in square meter.
NL A
Volume of sample (for grade A at rest and
operation,gradeBatrest)-1m3 equivalentto35.3ft3
Copyright 2011 John Wiley & Sons, Ltd.

Medium

High

This is likely to occur and the


detection is not certain. It is a
High Risk.

This is likely to occur and


the detection is not certain.
It is a High Risk.

This could occur and it could


be detected. Depending on
our confidence in the
detection, its risk would be
Medium or High Risk.

This may occur and it will


not be detected The Risk is
High.

The cause is not likely to occur


and if it did, it may be detected.
Depending on the frequency of
occurrence and the confidence
in detection method, it would
be a Low or Medium Risk.

The cause is not likely to


occur but if it did occur, it
probably would not be
detected. The Risk is
Medium.

Volume of sample (for grade B at operation


and other grades at both conditions) -1 ft3

Recovery/decontamination rate test


Take the particle count in the area before aerosol
generation at rest condition. The sampling rate
should be 1 CFM. Articially generate DOP/PAO
aerosol in the classied area and check the count
(1000 times more than classied area at rest).
Record the particle count and time. Stop the
aerosol generator. The time at which the aerosol
generator is stopped should be the starting time
for establishing the recovery rate. Start the
particle counting at the specied location at a
sampling rate of 1 CFM. Establish the time
required for attaining the at rest condition.

Environmental Conditions Temperature and Relative Humidity


It was performed by digital hygrometers and
Sling hygrometer and performed the test for 5
consecutive days for category A1 AHUs and for
3 consecutive days for AHUs of other categories. Readings should be for minimum 16
hours/day at 2 hour interval.
Qual Assur J (2011)
DOI: 10.1002/qaj

62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122

Copyright 2011 John Wiley & Sons, Ltd.

Risk no.

New equipment facility or system


or any major change in the
existing equipment may affect
the product requirement safety
feature and environment.

High

Impact
(severity)
Description of
identied risk
(unwanted
events)

High
If any mismatch observed
between user and supplier
specication.

Air/energy losses may


occur during air
distribution through
ducts.
Contamination due to
air leakage when AHU
is shutdown. (negative
pressure may lead to
contamination)
2

lock. Insulation
thermocole.
Cladding- aluminum.
Medium

Low
Sheets are lock forming
quality.

High
If there is no check
done to verify the duct
leakage.

High

Low
URS and vendor DQ are in place.

Medium

No

Risk accepted?
(yes/no)
Risk priority
rank
Risk related to
Probability of
detection

Likelihood of
occurrence
(probability
and frequency)

No

User and supplier specifications and


drawings are evaluated for their
compliance to the intended use and
cGMP during DQ.

Recommended
action
Duct leakage should be
checked through smoke
test and reports
addressed in the IQ.

Installation of
component at
inappropriate places
leading to
inadequate
performance of
AHU.

High

Low
Vendor installed
component as per
approved drawing.

High
If drawings are not
available.

High

No

Schematic, P&ID, GA
drawings should be
verified in IQ.

(Continues)

Chocking of the filter


affected the differential
pressure level and may lead
to contamination in area at
higher cleanliness class.
Inappropriate operation of
AHU may lead to noncompliance with respect to
performance requirement
and frequent maintenance.

High

Low
Differential pressure
monitoring switches are
placed across the filter.
Pre filter are in place.

High
If the sensors are fail to
generate alarms.

High

DP switches are provided across


HEPA filter for monitoring the
chocking of the filter and
feedback given to DDC which
generates an alarm.
No

High

High
If the operating and
maintenance person are not
trained with respect to the
related SOP.
Medium
Instrument is runing as per
approved SOP with control
parameter.

High

No

Identify and verify the SOP


during OQ.

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61

Table 3. Risk assessment for HVAC system

4
A. K. Shukla et al.

Qual Assur J (2011)


DOI: 10.1002/qaj

62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122

High
Air velocity and air changes
may affect the cleanliness
class, heat load and recovery
from contamination.

No
High
High
If the alarms are not
generated during the
excursion in temp./RH/DP
beyond the set limit.

Medium
List of all alarms are
verified and classified in
critical/ non critical on the
basis of impact on
product quality/purity.

High
Failure of Audio/ visual
indication of alarms may
not alert the personnel and
will continue to operate in
non-complying conditions.

No
High
High
If the instrument are
not calibrated as per
frequency.

Medium
Instrument/
component are
identified for
calibration with tag
no.

Copyright 2011 John Wiley & Sons, Ltd.

High
Uncalibrated
instrument affected
the monitoring and
controlling the desired
product environment
condition.
6

Medium
Supply and return air volume
(CFM) of AHU are as per
requirement of area and
occupancy.

No
High
High
If there is no check done to
verify the air velocity air
changes per hour (ACPH).

All alarms should be


checked, verified and set
the parameters related to
safety of product/person/
environment during OQ.

Instrument/ component
should be calibrated
(temp., RH, DP) and
report addressed in the
OQ.
The air velocity and ACPH should
be checked by anemometer to
ensure that adequate amount of
air is supplied in the room and
report addressed in the PQ.

High
Differential pressure is critical for
maintaining cleanliness class and
cross contamination.

Low
DP gauge continuous monitor the
pressure difference between
different class room (one for each
room separately).

DP should be checked through


magnehelic gauge to verify the
capability of complete installation
to maintain the specified pressure
difference and report addressed in
PQ.
No
High
High
If differential pressure value less
than alarm limit and greater than
specified time between similar and
non similar classes.

10

Low
The change in
HEPA filter at
regular interval
and as required.
The HEPA filter
installed by the
certified
supplier.
High
The validation
status with
respect to the
filter integrity
may be affected.

The integrity
should be
checked through
DOP test and
report addressed
in the PQ.
No
High
High
If there is no
check done to
verify the
integrity of filter.

11

(Continues)

High
Air flow pattern may
affect the effective
cleanliness of the area.

Dampers maintain the


desired differential
pressure in the room.

No
High
High
If differential pressure
value less than alarm
limit and greater than
specified time between
similar and non similar
classes.
Low
Rooms are designed from
positively to negatively
pressurized zone.

Non unidirectional air


flow should be checked
through WFI fogger and
report addressed in the
PQ.

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61

Table 3. (Continued)

Qualication of HVAC System in Aseptic Processing Area


5

Qual Assur J (2011)


DOI: 10.1002/qaj

62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122

Copyright 2011 John Wiley & Sons, Ltd.


High
Air cleanliness in clean
rooms may affect the
contamination sensitive
activities.

13

12

14

Final filtration of supply air


in the room through
terminal mounted HEPA
filter.
High
Airborne particle
concentration may affect
the specification of air
cleanliness in clean rooms.

Medium
Environmental monitoring
devices are in place (FMS).

No
High
High
If there is no check done to
verify the integrity of filters
and air velocity.

No
High
High
If there is no check done to
verify the integrity of filters.

Low
Final filtration of supply air
in the room through
terminal mounted HEPA
filter (H-13) efficiency
99.97% down to 0.3 micron
particles.

Recovery/ decontamination
rate test should be checked
through DOP test in
classified area and recovery
report addressed in the PQ.

High
Comply Grade A environment

The area under the unit should


comply with class A.

Low
The UAF unit is installed.

Unidirectional air flow should be


checked through WFI fogger
ensure that air flow should have a
sweeping action over and away
from the product under dynamic
condition and report addressed in
the PQ.
No
High
High
If the turbulence found in the air
flow pattern.
Airborne particle count
should be checked through
particle counter to
Determine the cleanliness
level as per ISO standards.

High
Temperature may
lead to product
instability,
personnel
discomfort and
microbial growth.
15

No
High
High
Excursion of temp.
beyond the set limit
due to different
operation.
Low
Temperature
sensors are located
in each room and
common return air
duct.

Temperature
should be checked
through calibrated
instrument and
report addressed in
the PQ.

16

High
Relative humidity
may affect the
moisture sensitive
activity.

No
High
High
Excursion of RH
beyond the set
limit due to CIP/
SIP operation.
Low
RH sensors are
provided for
common return
air duct.
Dehumidifier is in
place.

RH should be
checked through
calibrated
hygrometer and
report addressed
in the PQ.

17

High
Microbial contamination
leads to loss of sterility.

Medium
Alert and action limits
are determined by
trends analysis.

No
High
High
Critical for Grade A
environment.

Viable count should be


monitored through
settle plate, air
sampling, swab
sampling and report
addressed in the PQ.

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61

Table 3. (Continued)

6
A. K. Shukla et al.

Qual Assur J (2011)


DOI: 10.1002/qaj

62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122

Qualication of HVAC System in Aseptic Processing Area


1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61

62
63
S. No
Test performed
Acceptance criteria
Results
64
65
1
Air velocity and CFM
20% of the avg. face velocity
4106 CFM
66
2
No. of air changes per hour
NLT 40
66.31
67
3
Differential pressure test
NLT 05 Pa
8 to 10 Pa
68
4
HEPA filter leakage test
less than 0.01%
Max. 0.0004%
69
Min. 0.0002%
5
Air flow visualization (non-unidirectional flow)
from +ve to ve pressurized zone. Meets the
70
acceptance
71
criteria for flow
72
pattern
73
6
Airborne particle count
condition
Class area
0.5 mm 5 mm
74
at rest condition
With in class B
191
6
75
at operational condition With in class B
500
15
76
7
Recovery/decontamination rate test
Within 10 min
4 min.
77
8
Environmental conditions -Temperature
22  3 C
Max. 23 C
78
9
Environmental conditions - Relative humidity
NMT 20%
Max. 14
79
10
Viable count monitoring
Sampling
Class area
TBC
TFC
active air sampling
With in class B
9
<1
80
settle plate method
With in class B
4
<1
81
82
83
84
85
86
87
Table 5. Performance Qualication of UAF System
88
89
S. No
Test performed
Acceptance criteria
Results
90
1
Air velocity
9020 FPM at 6 inch. From filter
Complies
91
face
92
2
Differential pressure test
NLT 10mm of WC
14 to 16mm of
93
WC
94
3
HEPA filter integrity test
Less than 0.01% of upstream conc.
Max. 0.002 %
95
4
Air flow visualization (unidirectional flow)
Flow should be unidirectional
Meeting the
96
acceptance
97
criteria under
dynamic
98
condition
99
5
Airborne particle count
condition
Class area
0.5 mm 5 mm
100
at rest condition
With in class A
0
0
101
at operational
With in class A
247
0
102
condition
103
6
Viable count
Sampling
Class area
TBC
TFC
104
monitoring
active air sampling
With in class A
<1
<1
105
swab sampling method With in class A
<1
<1
106
107
108
109
110
Viable Count Monitoring - Settle Plate
the oor and also at work level for better exposure.
111
and Air Sampling
For air sampling, 1m3 of air from specied
112
Settled plates should be of 90mm diameter and
locations should be sampled using Soybean Casein
113
0
should be exposed for duration of 4 hours. Plates
Digest Agar. Incubate settle plate at 20 - 25 C for
114
should be exposed at a height above 1 meter from
T3 T4 T5115
Q14
TFC and at 30 - 350C for TBC. Table 35
116
117
118
119
120
Copyright 2011 John Wiley & Sons, Ltd.
Qual Assur J (2011)
121
DOI: 10.1002/qaj
122

Table 4. Performance Qualication of HVAC and UAF System

8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61

A. K. Shukla et al.

3. FDA. Guidance for Industry. Sterile Drug Products


Produced by Aseptic Processing, Current Good
Manufacturing Practice, Food and Drug Administration. Rockville, MD, 2004, 46.
4. Nash Robert A, Wachter Alfred H. Qualication of
water and air handling systems. Pharmaceutical
Process Validation, 3rd ed. vol. 129. Marcel Dekker,
2224.
5. WHO. Supplementary Training Modules on Good
Manufacturing Practice, Heating Ventilation and
Air Conditioning (HVAC) Part 1 (a). Introduction
and Overview Technical Report Series, no. 937,
2006, 126.
6. Swarbrick J. Encyclopedia of Pharmaceutical Tech-

Failure Mode Effect Analysis (FMEA)

nology, 3rd ed. vol. 1. USA: Informa health care,


127128.
7. Annex 1. EU Guidelines to Good Manufacturing

Results

Practice, Medicinal Products for Human and Veterinary Use. Manufacture of Sterile Medicinal
Products, vol. 4. March 2009, 29.
8. Agalloco JP, Carleton FJ. Validation of Aseptic

Conclusion
Qualication and validation is appearing to be
the beginning of a continuous development
process in pharmaceutical QA. Risk assessment
is an essential tool for qualication of HVAC
system in aseptic processes. It is not just a tool
for cGMP compliance, its offers real benets to
the validation process by identifying risks and
ensuring that critical risks are controlled. By
focusing managing risks to the patient, pharmaceutical manufacturers can ensure that the
right resources are applied at the right place
and at the right time improving patient safety
while eliminating unnecessary qualication and
validation efforts.

Pharmaceutical Process. 2nd ed. New York: Marcel


Dekker, Inc., 23.
9. WHO.

Supplementary

Guidelines

on

Good

Manufacturing Practices (GMP): Validation, June


2004, 715.
10. ICH Q9. Quality Risk Management. Current Step 4
Version, November 2005.
11. Annex 20. EU Guidelines to Good Manufacturing
Practice, Medicinal Products for Human and
Veterinary Use. Quality Risk Management, vol. 4,
March 2008.
12. PDA. Technical Report No. 44: Quality Risk Management for Aseptic Processes. Supplement to the
PDA Journal of Pharmaceutical Science and Technology, vol. 62, 2008, 614.
13. McDermott RE, Mikulak RJ, Beauregard MR. The
Basics of FMEA. Portland: Productivity, Inc; 1995,
344.
14. Annex 15. EU Guide to Good Manufacturing

Q15

References

Practice. Qualication and validation, 2001, 37.


15. ISPE Baseline Guide. Commissioning and Qualica-

1. WHO. Annex 4, Supplementary Guidelines on


Good Manufacturing Practices: Validation, World
Health Organization. Technical Report Series, No.
937, 2006, 116121.
2. Sugarman Samuel C. HVAC Fundamentals. The
Fairmont press, Inc; 2005, 13.

Copyright 2011 John Wiley & Sons, Ltd.

tion, vol. 5, 2001.


16. Potdar AM. Pharmaceutical Quality Assurance, 2nd
ed. Pune: Nirali Prakashan, 2007, 8.6
17. ISO 146441. Cleanrooms and Associated Controlled Environments, Part-1: Classication of Air
Cleanliness, 1999(E), 14.

Qual Assur J (2011)


DOI: 10.1002/qaj

62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122

Qualication of HVAC System in Aseptic Processing Area


1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61

18. ISO 146442. Cleanrooms and Associated Controlled Environments, Part-2: Specications for
Testing and Monitoring to Prove Continued Compliance with ISO 146441, 2000(E), 14.
19. ISO 146443. Cleanrooms and Associated Controlled Environments, Part 3: Metrology & Test
Methods, 2005(E), 13.
20. A working group of the Scottish Quality Assurance
Specialist Interest Group. Guideline On Test Methods For Environmental Monitoring For Aseptic
Dispensing Facilities, 2nd ed. February 2004, 36.
21. Health Canada, Process Validation. Aseptic Processes for Pharmaceuticals, Health Products and Food

the Pharmaceutical Sciences, vol. 164. USA: Informa Health Care; 206210.
33. McDowall R. Fundamentals of HVAC Systems, inch
edition. USA: American society of heating, refrigerating and air-conditioning Engineers Inc.; 2006,
26.
34. ISO 146444. Cleanrooms and Associated Controlled Environments-Part 4: Design, Construction
and Startup, 24.
35. WHO. Guide To Good Manufacturing Practice
(GMP) Requirements, Part 2: Validation. Geneva:
World Health Organization; 1997, 2432.
36. PIC/S. Guide to Good Manufacturing Practice for

Branch Inspectorate, Guide, June 2003, 1012.

Medicinal Products. Pharmaceutical Inspection

22. ICH Q10. Pharmaceutical Quality System, Current

Convention, Pharmaceutical Inspection Co-Opera-

Step 4 Version, June 2008.


23. Garvey W. Essentials of validation project management part-I. Pharm Technol 2005: 16.
24. Akers JE, Agalloco JP. The simplied AkersAgalloco method for aseptic processing risk analysis.
Pharm Technol 2006: 18.
25. Lander V. 21 CFR part 11 and risk assessment:
adapting fundamental methodologies to a current
rule. Pharm Technol Eur 2004: 13.

tion Scheme, PE 0095, August 2006, 612.


37. WHO. Annex 6, Good Manufacturing Practices for
Sterile Pharmaceutical Products, World Health
Organization. Technical Report Series, No. 902,
2002.
38. FDA. Pharmaceutical cGMP for The Twenty First
Century: A Risk Based Approach. Food and Drug
Administration, Rockville, MD, September 2004.
39. PDA. Technical Report No. 22: Process Simulation

26. Drakulich A. Risk management: practical applica-

Testing for Aseptically Filled Products. Supplement

tions and value. EPT--The Electronic Newsletter of

to The PDA Journal of Pharmaceutical Science and

Pharmaceutical Technology 2007, 12.


27. Del Valle MA. Keeping clean rooms compliant.
Pharm Technol Eur 2006;18(11):14.
28. Straker M. Clean rooms and air handling systems:

Technology, vol. 50, 1996.


40. Akers J, Agalloco JP. Risk analysis for aseptic
processing: the Akers- Agalloco method. Pharmaceutical Technology 2005, 35.

design for compliance. Pharm Technol Eur 2005:13.

41. ISPE Baseline Guide. Pharmaceutical Engineering

29. Tidswell EC, McGarvey B. Quantitative risk model-

Guides for New and Renovated Facility, 1st ed., vol.

ing in aseptic manufacture. PDA J Pharm Sci


Technol September 2006;60:267269.

3. Sterile Manufacturing Facility, January 1999.


42. FDA. Guidance for Industry, Process Validation:

30. Li J, Poulton G. Dynamic zone modeling for HVAC

General Principles and Practices. Food and

system control. Int J Model Ident Control April

Drug Administration, Rockville, MD, November

2010;9:514.

2008.

31. PIC document PE 0091. Guide to Good Manufacturing Practice for Medicinal Products, September
2003, 27.
32. Dixon AM. Environmental Monitoring for Clean
Rooms and Controlled Environments, Drugs and

Copyright 2011 John Wiley & Sons, Ltd.

43. GAMP 4. Guide for Validation of Automated


Systems, 2003.
44. FDA. Draft Guidance for Industry, Process Validation:
General Principles and Practices. Food and Drug
Administration, Rockville, MD, 2008.

Qual Assur J (2011)


DOI: 10.1002/qaj

62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122