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A Risk Assessment Approach: Qualification of a HVAC System in Aseptic

Processing Area Using Building Management System

Article in The Quality Assurance Journal · November 2011

DOI: 10.1002/qaj.485

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 Journal Code Article ID Dispatch: 11.09.11 CE:
Q A J 4 8 5 No. of Pages: 9 ME:

1 62
2 63
3 64
4
5
A Risk Assessment Approach: 65
66
6
7 Qualification of HVAC System in 67
68
8 69
9
10
Aseptic Processing Area Using Building 70
71
11
12 Management System 72
73
13 74
14 75
15 Anil K. Shukla1,*, Ashutosh Katole2, Nilesh Jain1, C. Karthikeyan1, Farhad Mehta1 and 76
16 Piyush Trivedi1 77
17 78
1
18 School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, Madhya 79
19 Pradesh, India 80
2
20 Q1 Ranbaxy Laboratories Limited, Industrial Area 3, Dewas, Madhya Pradesh, India 81
21 82
22 83
23 84
24 Abstract 85
25 86
26 87
27 88
In the pharmaceutical industry qualification of HVAC systems is done by using a risk based
28 89
29
Q2 approach. FMEA concept was used for risk assessment in HVAC system to determine 90
30 scope and extent of qualification and validation in this present work. The level of risk was 91
31 assessed, based on the impact and severity on the aseptic practice in sterile 92
32 Q3 manufacturing because the HVAC system is the “direct impact” system in the aseptic 93
33 practice expected to have a direct impact on product quality and regulatory compliance. 94
34 On completion of the risk assessment, existing controls, measures and recommended 95
35 Q4 action were identified required for the better cGMP and upgradation of the system. 96
36 After completion of the risk assessment the recommended actions were extended and 97
37 verified against the qualification stages of the HVAC system. Finally, the HVAC system 98
38 Q5 was subjected to PQ study. All of the tests were performed and a report was generated. 99
39 100
On evaluation of the data collected during PQ, it was found that the HVAC system met all
40 101
41
the specified design criteria and complied with the entire cGMP requirement. Hence the 102
42 system stands validated for PQ. Copyright © 2011 John Wiley & Sons, Ltd. 103
43 104
44 Q6 Key Words: HVAC; UAF; PQ; ICH; FMEA 105
45 106
46 107
Introduction for quality management of pharmaceutical
47 108
48 Quality risk management is an important part of manufacturing. The ICH Q9 guideline, quality 109
49 science based decision making which is essential risk management and other literature provide 110
50 guidance on the principal of quality risk manage- 111
51 *Correspondence to: Anil Shukla, School of Pharmaceu- ment. The FMEA model can be used to facilitate 112
52 ticalSciences,RajivGandhiProudyogikiVishwavidyalaya, risk assessment for any system in the aseptic 113
53 Bhopal,MadhyaPradesh,India.E-mail:aksqargpv@gmail. 114
com
processing area of sterile products. It provides a
54 115
55 116
56 117
57 118
58 Qual Assur J (2011) 119
59 Copyright © 2011 John Wiley & Sons, Ltd. DOI: 10.1002/qaj 120
60 121
61 122
 2 A. K. Shukla et al.

1 Table 1. Risk ranking system Q7

62
2 63
3 Qualitative Risk factor 64
4 ranking 65
Severity Occurrence Detection
5 66
6 High Impact of unwanted event is Occurrence is The process failure will almost certainly 67
7 severe often escape detection 68
8 Medium Impact of unwanted event is Occurrence is Control may detect the existence of a 69
9 moderate periodic process failure 70
Low Impact of unwanted event is Occurrence is The process failure is obvious and
10 71
low seldom readily detected
11 72
12 73
13 74
14 tool to assess and evaluate different activities and extended to qualification stages of HVAC system 75
15 76
conditions. Risk in sterile product manufacturing to have a high level of assurance and if the test
16 77
17 and aseptic processing is relatively high when result are not acceptable, carry out corrective 78
18 compared to other pharmaceutical process, action that may include modification in the 79
19 making risk assessment particularly important. existing controls and the system. Table 2 T2 Q11 80
20 The European Union GMP requirements 81
21 place specific obligations on manufacturers of 82
22
Performance Qualification for HVAC 83
medicinal products to implement risk based and UAF System Q12
23 84
24 qualification, validation and change control 85
25 programs. In pharmaceutical manufacturing, Air Velocity and Air Changes 86
26 validation is an important part of QA and is a 87
27 requirement of cGMP and other guidelines. 88
28 Velocity at the inlet air grills was measured at 5 points in a 89
In the air handling system, special attention plane parallel to filter face plane and at a distance of
29 90
must be made to keep the environment clean and
30 about 6 inches (~ 150mm) from the filter/opening face. 91
31 prevent product contamination. From a techni- The velocity was measuredforat least 10 seconds from 92
32 cal perspective, the role of the HVAC system is 93
each point. It is performed by thermal anemometer
33 paramount in achieving and maintaining an 94
34 and vane type anemometer and calculated by 95
Q8 T1 acceptable manufacturing environment. Table 1
35 formula where, D is no. of air changes, B is air 96
36 supply volume (CFM), R is volume of the room 97
37 3 98
Experimental (ft ), 60 is factor (for air change per hour).
38 99
39 P 100
Risk assessment (FMEA model) B  60
40 D¼ 101
41 R 102
Evaluate the overall risk of the qualification and
42 103
validation steps by combining individual risk Differential Pressure Test
43 104
44 values. For the most of the direct impact system, 105
Measure and record the pressure difference
45 Q9 the severity will always be high. The RPR then 106
between the room to be tested and any
46 becomes a combination of an occurrence and 107
47 surrounding ancillary environment. 108
detection. If the level of risk is not acceptable, a
48 109
recommendation must be made to modify the
49 HEPA Filter Leakage Test 110
50 qualification and validation step to reduce the risk 111
51 to an acceptable level or enhance the method of Position the aerosol generator to introduce an 112
52 detection to reduce the risk to an acceptable level. aerosol challenge upstream of the HEPA filter to a 113
53 Preference should be given to reducing the concentration of 20-100mg/m³ (20–100 mg/lit.) of 114
54 air by opening appropriate number of nozzles. 115
occurrence rather than increasing the level of
55 116
detection. After completion of the risk assessment, Measure upstream concentration of aerosol by
56 117
57 the recommended action of unacceptable risk using upstream port. Adjust the photometer’s gain 118
58 119
59 120
60 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assur J (2011) 121
DOI: 10.1002/qaj
61 122
 Q10 Qualification of HVAC System in Aseptic Processing Area 3

1 Table 2. Determination of RPR 62

2 63
3 Risk related to probability of detection 64
4 Low Medium High
65
5 66
6 Occurrence High This is likely to occur, but when This is likely to occur and the This is likely to occur and 67
7 it does, it will be detected. If detection is not certain. It is a the detection is not certain. 68
8 we are certain it will be High Risk. It is a High Risk. 69
9 detected, it is Low Risk, but if 70
we are not certain then it
10 71
should be a Medium Risk.
11 72
Medium This could occur but if it did, it This could occur and it could This may occur and it will
12 would be detected. be detected. Depending on not be detected The Risk is 73
13 Depending on the frequency our confidence in the High. 74
14 of occurrence and the detection, its risk would be 75
15 confidence in the detection, it Medium or High Risk. 76
16 is a Low or a Medium Risk. 77
17 Low This is not likely to occur and The cause is not likely to occur The cause is not likely to 78
18 if it does occur it will be and if it did, it may be detected. occur but if it did occur, it 79
19 detected. This is a Low Risk. Depending on the frequency of probably would not be 80
occurrence and the confidence detected. The Risk is
20 81
in detection method, it would Medium.
21 be a Low or Medium Risk.
82
22 83
23 84
24 85
25 / span control for a full-scale deflection on 100% Volume of sample (for grade B at operation 86
26 range. Scan the downstream side of the HEPA and other grades at both conditions) -1 ft3 87
27 88
28
filter. The photometer probe should be about 1 89
29 inch from the surface and at a transverse rate not 90
30 more than 10ft/minute with a sample flow rate of Recovery/decontamination rate test 91
31 1cft/min  10%. Take the particle count in the area before aerosol 92
32 generation at rest condition. The sampling rate 93
33 should be 1 CFM. Artificially generate DOP/PAO 94
34 Air Flow Visualization (Non-unidirectional aerosol in the classified area and check the count 95
35 flow) (1000 times more than classified area “at rest”).
96
36 97
37 Q13 Generate the tracer particles by WFI fogger. Record the particle count and time. Stop the 98
38 Position the tracer at the appropriate place, aerosol generator. The time at which the aerosol 99
39 generator is stopped should be the starting time 100
such as at the downstream of supply air and the
40 for establishing the recovery rate. Start the 101
41 return air risers as well as at the doors opening 102
42 and check for the indication of the airflow particle counting at the specified location at a 103
43 direction. Record the airflow pattern using sampling rate of 1 CFM. Establish the time 104
44 photography/videography. required for attaining the “at rest” condition. 105
45 106
46 107
47 Airborne Particle Count 108
Environmental Conditions -
48 109
49 Derive the number of sampling point locations Temperature and Relative Humidity 110
50 by using the equation where, NL is the minimum 111
51 number of sampling locations and √A is Area of It was performed by digital hygrometers and 112
52 the room in square meter. Sling hygrometer and performed the test for 5 113
53 consecutive days for category A1 AHUs and for 114
54 NL ¼ √A 115
3 consecutive days for AHUs of other catego-
55 116
56 Volume of sample (for grade A at rest and ries. Readings should be for minimum 16 117
57 operation,gradeBatrest)-1m3 equivalentto35.3ft3 hours/day at 2 hour interval. 118
58 119
59 120
60 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assur J (2011) 121
DOI: 10.1002/qaj
61 122
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4

Table 3. Risk assessment for HVAC system

Recommended User and supplier specifications and Duct leakage should be Schematic, P&ID, GA Identify and verify the SOP DP switches are provided across
action drawings are evaluated for their checked through smoke drawings should be during OQ. HEPA filter for monitoring the
compliance to the intended use and test and reports verified in IQ. chocking of the filter and
cGMP during DQ. addressed in the IQ. feedback given to DDC which
generates an alarm.
Risk accepted? No No No No No
(yes/no)
Risk priority High Medium High High High
rank

Copyright © 2011 John Wiley & Sons, Ltd.

Risk related to High High High High High
Probability of If any mismatch observed If there is no check If drawings are not If the operating and If the sensors are fail to
detection between user and supplier done to verify the duct available. maintenance person are not generate alarms.
specification. leakage. trained with respect to the
related SOP.
Likelihood of Low Low Low Medium Low
occurrence URS and vendor DQ are in place. Sheets are lock forming Vendor installed Instrument is runing as per Differential pressure
(probability quality. component as per approved SOP with control monitoring switches are
and frequency) approved drawing. parameter. placed across the filter.
lock. Insulation Pre filter are in place.
thermocole.
Cladding- aluminum.
Impact High Medium High High High
(severity)
Description of New equipment facility or system Air/energy losses may Installation of Inappropriate operation of Chocking of the filter
identified risk or any “major change in the occur during air component at AHU may lead to non- affected the differential
(unwanted existing equipment” may affect distribution through inappropriate places compliance with respect to pressure level and may lead
events) the product requirement safety ducts. leading to performance requirement to contamination in area at
feature and environment. Contamination due to inadequate and frequent maintenance. higher cleanliness class.
air leakage when AHU performance of
is shutdown. (negative AHU.
pressure may lead to
contamination)
Risk no. 1 2 3 4 5

(Continues)
A. K. Shukla et al.

DOI: 10.1002/qaj
Qual Assur J (2011)
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Table 3. (Continued)

Instrument/ component All alarms should be
should be calibrated checked, verified and set
(temp., RH, DP) and the parameters related to
report addressed in the safety of product/person/
OQ. environment during OQ.
No No
High High
High High
If the instrument are If the alarms are not
not calibrated as per generated during the
frequency. excursion in temp./RH/DP
beyond the set limit.
The air velocity and ACPH should DP should be checked through The integrity Non unidirectional air
be checked by anemometer to magnehelic gauge to verify the should be flow should be checked
ensure that adequate amount of capability of complete installation checked through through WFI fogger and
air is supplied in the room and to maintain the specified pressure DOP test and report addressed in the
report addressed in the PQ. difference and report addressed in report addressed PQ.
PQ. in the PQ.
No No No No
High High High High
High High High High
If there is no check done to If differential pressure value less If there is no If differential pressure
verify the air velocity air than alarm limit and greater than check done to value less than alarm
changes per hour (ACPH). specified time between similar and verify the limit and greater than
non similar classes. integrity of filter. specified time between

Copyright © 2011 John Wiley & Sons, Ltd.

similar and non similar
classes.
Medium Medium Medium Low Low Low
Instrument/ List of all alarms are Supply and return air volume DP gauge continuous monitor the The change in Rooms are designed from
component are verified and classified in (CFM) of AHU are as per pressure difference between HEPA filter at positively to negatively
identified for critical/ non critical on the requirement of area and different class room (one for each regular interval pressurized zone.
calibration with tag basis of impact on occupancy. room separately). and as required.
no. product quality/purity. The HEPA filter Dampers maintain the
installed by the desired differential
certified pressure in the room.
supplier.
Qualification of HVAC System in Aseptic Processing Area

High High High High High High

Uncalibrated Failure of Audio/ visual Air velocity and air changes Differential pressure is critical for The validation Air flow pattern may
instrument affected indication of alarms may may affect the cleanliness maintaining cleanliness class and status with affect the effective
the monitoring and not alert the personnel and class, heat load and recovery cross contamination. respect to the cleanliness of the area.
controlling the desired will continue to operate in from contamination. filter integrity
product environment non-complying conditions. may be affected.
condition.
6 7 8 9 10 11

(Continues)

DOI: 10.1002/qaj
Qual Assur J (2011)
5

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6

Table 3. (Continued)

Unidirectional air flow should be Airborne particle count Recovery/ decontamination Temperature RH should be Viable count should be
checked through WFI fogger should be checked through rate test should be checked should be checked checked through monitored through
ensure that air flow should have a particle counter to through DOP test in through calibrated calibrated settle plate, air
sweeping action over and away Determine the cleanliness classified area and recovery instrument and hygrometer and sampling, swab
from the product under dynamic level as per ISO standards. report addressed in the PQ. report addressed in report addressed sampling and report
condition and report addressed in the PQ. in the PQ. addressed in the PQ.
the PQ.
No No No No No No
High High High High High High
High High High High High High
If the turbulence found in the air If there is no check done to If there is no check done to Excursion of temp. Excursion of RH Critical for Grade A
flow pattern. verify the integrity of filters. verify the integrity of filters beyond the set limit beyond the set environment.
and air velocity. due to different limit due to CIP/

Copyright © 2011 John Wiley & Sons, Ltd.

operation. SIP operation.
Low Low Medium Low Low Medium
The UAF unit is installed. Final filtration of supply air Environmental monitoring Temperature RH sensors are Alert and action limits
in the room through devices are in place (FMS). sensors are located provided for are determined by
terminal mounted HEPA in each room and common return trends analysis.
filter (H-13) efficiency common return air air duct.
The area under the unit should 99.97% down to 0.3 micron Final filtration of supply air duct. Dehumidifier is in
comply with class A. particles. in the room through place.
terminal mounted HEPA
filter.
High High High High High High
Comply Grade A environment Air cleanliness in clean Airborne particle Temperature may Relative humidity Microbial contamination
rooms may affect the concentration may affect lead to product may affect the leads to loss of sterility.
contamination sensitive the specification of air instability, moisture sensitive
activities. cleanliness in clean rooms. personnel activity.
discomfort and
microbial growth.
12 13 14 15 16 17
A. K. Shukla et al.

DOI: 10.1002/qaj
Qual Assur J (2011)
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 Qualification of HVAC System in Aseptic Processing Area 7

1 Table 4. Performance Qualification of HVAC and UAF System 62

2 63
3 S. No Test performed Acceptance criteria Results 64
4 1 Air velocity and CFM 20% of the avg. face velocity 4106 CFM
65
5 2 No. of air changes per hour NLT 40 66.31 66
6 3 Differential pressure test NLT 05 Pa 8 to 10 Pa 67
7 4 HEPA filter leakage test less than 0.01% Max. 0.0004% 68
8 Min. 0.0002% 69
9 5 Air flow visualization (non-unidirectional flow) from +ve to –ve pressurized zone. Meets the 70
10 acceptance 71
11 criteria for flow 72
12 pattern 73
6 Airborne particle count condition Class area 0.5 mm 5 mm
13 74
at rest condition With in class B 191 6
14 75
at operational condition With in class B 500 15
15 7 Recovery/decontamination rate test Within 10 min 4 min. 76
16 8 Environmental conditions -Temperature 22  3 C Max. 23 C 77
17 9 Environmental conditions - Relative humidity NMT 20% Max. 14 78
18 10 Viable count monitoring Sampling Class area TBC TFC 79
19 active air sampling With in class B 9 <1 80
20 settle plate method With in class B 4 <1 81
21 82
22 83
23 84
24 85
25 86
26 87
27
Table 5. Performance Qualification of UAF System 88
28 S. No Test performed Acceptance criteria Results 89
29 90
30 1 Air velocity 9020 FPM at 6 inch. From filter Complies 91
face
31 92
2 Differential pressure test NLT 10mm of WC 14 to 16mm of
32 WC
93
33 3 HEPA filter integrity test Less than 0.01% of upstream conc. Max. 0.002 % 94
34 4 Air flow visualization (unidirectional flow) Flow should be unidirectional Meeting the 95
35 acceptance 96
36 criteria under 97
37 dynamic 98
38 condition 99
39 5 Airborne particle count condition Class area 0.5 mm 5 mm 100
40 at rest condition With in class A 0 0 101
at operational With in class A 247 0
41 102
condition
42 6 Viable count Sampling Class area TBC TFC
103
43 monitoring active air sampling With in class A <1 <1 104
44 swab sampling method With in class A <1 <1 105
45 106
46 107
47 108
48 109
49 Viable Count Monitoring - Settle Plate the floor and also at work level for better exposure. 110
50 and Air Sampling For air sampling, 1m3 of air from specified 111
51 Settled plates should be of 90mm diameter and 112
locations should be sampled using Soybean Casein
52 0 113
should be exposed for duration of 4 hours. Plates Digest Agar. Incubate settle plate at 20 - 25 C for
53 114
54 should be exposed at a height above 1 meter from TFC and at 30 - 350C for TBC. Table 3–5 T3 T4 T5115
Q14

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60 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assur J (2011) 121
DOI: 10.1002/qaj
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 8 A. K. Shukla et al.

1 3. FDA. Guidance for Industry. Sterile Drug Products

62
2 63
Produced by Aseptic Processing, Current Good
3 64
4 Manufacturing Practice, Food and Drug Adminis- 65
5 tration. Rockville, MD, 2004, 4–6. 66
6 4. Nash Robert A, Wachter Alfred H. Qualification of 67
7 water and air handling systems. Pharmaceutical 68
8 69
Process Validation, 3rd ed. vol. 129. Marcel Dekker,
9 70
10 22–24. 71
11 5. WHO. Supplementary Training Modules on Good 72
12 Manufacturing Practice, Heating Ventilation and 73
13 Air Conditioning (HVAC) Part 1 (a). Introduction 74
14 75
and Overview Technical Report Series, no. 937,
15 76
2006, 1–26.
16 77
17 6. Swarbrick J. Encyclopedia of Pharmaceutical Tech- 78
18 nology, 3rd ed. vol. 1. USA: Informa health care, 79
Failure Mode Effect Analysis (FMEA)
19 127–128. 80
20 7. Annex 1. EU Guidelines to Good Manufacturing 81
21 82
Practice, Medicinal Products for Human and Veter-
22 Results 83
23 inary Use. Manufacture of Sterile Medicinal 84
24 Products, vol. 4. March 2009, 2–9. 85
25 8. Agalloco JP, Carleton FJ. Validation of Aseptic 86
26 Pharmaceutical Process. 2nd ed. New York: Marcel 87
27 Conclusion 88
Dekker, Inc., 2–3.
28 89
9. WHO. Supplementary Guidelines on Good
29 Qualification and validation is appearing to be 90
30 Manufacturing Practices (GMP): Validation, June 91
the beginning of a continuous development
31 2004, 7–15. 92
process in pharmaceutical QA. Risk assessment
32 10. ICH Q9. Quality Risk Management. Current Step 4 93
33
is an essential tool for qualification of HVAC 94
Version, November 2005.
34 system in aseptic processes. It is not just a tool 95
11. Annex 20. EU Guidelines to Good Manufacturing
35 for cGMP compliance, its offers real benefits to 96
Practice, Medicinal Products for Human and
36 the validation process by identifying risks and 97
37 Veterinary Use. Quality Risk Management, vol. 4, 98
ensuring that critical risks are controlled. By
38 March 2008. 99
focusing managing risks to the patient, phar-
39 12. PDA. Technical Report No. 44: Quality Risk Man- 100
40 maceutical manufacturers can ensure that the 101
agement for Aseptic Processes. Supplement to the
41 right resources are applied at the right place 102
PDA Journal of Pharmaceutical Science and Tech-
42 and at the right time improving patient safety 103
43 nology, vol. 62, 2008, 6–14. 104
while eliminating unnecessary qualification and
44 13. McDermott RE, Mikulak RJ, Beauregard MR. The 105
validation efforts.
45 Basics of FMEA. Portland: Productivity, Inc; 1995, 106
46 3–44. 107
47 108
14. Annex 15. EU Guide to Good Manufacturing
48 109
49 Q15 References Practice. Qualification and validation, 2001, 3–7. 110
50 15. ISPE Baseline Guide. Commissioning and Qualifica- 111
51 1. WHO. Annex 4, Supplementary Guidelines on tion, vol. 5, 2001. 112
52 Good Manufacturing Practices: Validation, World 16. Potdar AM. Pharmaceutical Quality Assurance, 2nd 113
53 Health Organization. Technical Report Series, No. ed. Pune: Nirali Prakashan, 2007, 8.6
114
54 115
937, 2006, 116–121. 17. ISO 14644–1. Cleanrooms and Associated Con-
55 116
56 2. Sugarman Samuel C. HVAC Fundamentals. The trolled Environments, Part-1: Classification of Air 117
57 Fairmont press, Inc; 2005, 1–3. Cleanliness, 1999(E), 1–4. 118
58 119
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 Qualification of HVAC System in Aseptic Processing Area 9

1 18. ISO 14644–2. Cleanrooms and Associated Con- the Pharmaceutical Sciences, vol. 164. USA: Infor-
62
2 63
trolled Environments, Part-2: Specifications for ma Health Care; 206–210.
3 64
4 Testing and Monitoring to Prove Continued Com- 33. McDowall R. Fundamentals of HVAC Systems, inch 65
5 pliance with ISO 14644–1, 2000(E), 1–4. edition. USA: American society of heating, refrig- 66
6 19. ISO 14644–3. Cleanrooms and Associated Con- erating and air-conditioning Engineer’s Inc.; 2006, 67
7 trolled Environments, Part 3: Metrology & Test 2–6. 68
8 69
Methods, 2005(E), 1–3. 34. ISO 14644–4. Cleanrooms and Associated Con-
9 70
10 20. A working group of the Scottish Quality Assurance trolled Environments-Part 4: Design, Construction 71
11 Specialist Interest Group. Guideline On Test Meth- and Startup, 2–4. 72
12 ods For Environmental Monitoring For Aseptic 35. WHO. Guide To Good Manufacturing Practice 73
13 Dispensing Facilities, 2nd ed. February 2004, 3–6. (GMP) Requirements, Part 2: Validation. Geneva: 74
14 75
21. Health Canada, Process Validation. Aseptic Process- World Health Organization; 1997, 24–32.
15 76
es for Pharmaceuticals, Health Products and Food 36. PIC/S. Guide to Good Manufacturing Practice for
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