Key Words: HVAC; UAF; PQ; ICH; FMEA. Q6 ... The ICH Q9 guideline, quality ... Performance Qualification for HVAC and. Q12. UAF System. Air Velocity and Air ...
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Article ID Dispatch: 11.09.11 4 8 5 No. of Pages: 9
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A Risk Assessment Approach: Qualification 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
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In the pharmaceutical industry qualification 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 qualification 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 identified required for the better cGMP and upgradation of the system. After completion of the risk assessment the recommended actions were extended and verified against the qualification 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 specified 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
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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 qualification 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 modification 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 specific obligations on manufacturers of Performance Qualification for HVAC 83 medicinal products to implement risk based Q12 and UAF System 84 qualification, 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 filter face plane and at a distance of 90 must be made to keep the environment clean and 91 about 6 inches (~ 150mm) from the filter/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) D¼ 101 R 102 Evaluate the overall risk of the qualification 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 qualification 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 filter to a 113 detection to reduce the risk to an acceptable level. 114 concentration of 20-100mg/m³ (20–100 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 photometer’s 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
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Qualification of HVAC System in Aseptic Processing Area
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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 deflection on 100% range. Scan the downstream side of the HEPA filter. The photometer probe should be about 1 inch from the surface and at a transverse rate not more than 10ft/minute with a sample flow rate of 1cft/min 10%.
Air Flow Visualization (Non-unidirectional flow) 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 airflow direction. Record the airflow 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 ¼ √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. Artificially generate DOP/PAO aerosol in the classified area and check the count (1000 times more than classified 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 specified 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
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Copyright © 2011 John Wiley & Sons, Ltd.
Risk no.
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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 identified risk (unwanted events)
High If any mismatch observed between user and supplier specification.
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.
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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.
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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.
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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.
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Table 3. Risk assessment for HVAC system
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High Air velocity and air changes may affect the cleanliness class, heat load and recovery from contamination.
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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.
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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.
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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.
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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.
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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.
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Table 3. (Continued)
Qualification of HVAC System in Aseptic Processing Area 5
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Copyright © 2011 John Wiley & Sons, Ltd. High Air cleanliness in clean rooms may affect the contamination sensitive activities.
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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.
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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.
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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.
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Table 3. (Continued)
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Qualification 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
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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
