Professional Documents
Culture Documents
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:
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
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
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
Medium
High
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
Risk no.
High
Impact
(severity)
Description of
identied risk
(unwanted
events)
High
If any mismatch observed
between user and supplier
specication.
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
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)
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
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
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
4
A. K. Shukla et al.
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.
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).
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).
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.
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.
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)
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
13
12
14
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
Low
The UAF unit is installed.
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.
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.
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
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
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.
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.
Supplementary
Guidelines
on
Good
Q15
References
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
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
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
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