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A Risk Assessment Approach: Qualication of a 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

Abstract
In the pharmaceutical industry qualication of HVAC systems is done by using a risk based approach. Failure mode effect analysis (FMEA) concepts were used for risk assessment of a HVAC system to determine the scope and extent of qualication and validation in this present work. The HVAC is the direct impact system in the aseptic practice which directly affects the product quality and regulatory compliance. The level of risk associated with the HVAC system was assessed based on the impact and severity of the probable risk in aseptic practice in sterile manufacturing. On completion of the risk assessment, control and measures developed and recommended actions for unacceptable risk were identied for improved cGMP compliance and qualication of the system upgrades. 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 a performance qualication (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 Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, Madhya Pradesh, India. E-mail: aksqargpv@gmail.com

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

Copyright 2011 John Wiley & Sons, Ltd.

Qual Assur J 2011; 14, 4049 DOI: 10.1002/qaj.485

Qualication of HVAC System in Aseptic Processing Area Table 1. Risk ranking system
Qualitative ranking High Medium Low Risk factor Severity Impact of unwanted event is severe Impact of unwanted event is moderate Impact of unwanted event is low Occurrence Occurrence is often Occurrence is periodic Occurrence is seldom Detection The process failure will almost certainly escape detection Control may detect the existence of a process failure The process failure is obvious and readily detected

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provides a tool to assess and evaluate different activities and conditions. Risk ranking system in FMEA model is given in Table 1. Risk in sterile product manufacturing and aseptic processing is relatively high when compared to other pharmaceutical process, making risk assessment particularly important [110]. The European Union GMP requirements place specic obligations on manufacturers of medicinal products to implement risk based qualication, validation and change control programs. In pharmaceutical manufacturing, validation is an important part of QA and is a requirement of cGMP and other guidelines [11,1416]. In the air handling system, special attention must be made to keep the environment clean and prevent product contamination. From a technical perspective, the role of the HVAC system is paramount in achieving and maintaining an acceptable manufacturing environment.

represented the risk priority ranking system as per the FMEA model. After completion of the risk assessment, the recommended action of unacceptable risk extended to qualication stages of HVAC system to have a high level of assurance and if the test result are not acceptable, carry out corrective action that may include modication in the existing controls and the system.

Performance Qualication for HVAC and Unidirectional Air Flow (UAF) System Air Velocity and Air Changes
Velocity at the inlet air grills was measured at 5 points in a plane parallel to lter face plane and at a distance of about 6 inches (~ 150mm) from the lter/opening face. The velocity was measured for at least 10 seconds from each point. It is performed by thermal anemometer and vane type anemometer and calculated by formula where, D is no. of air changes, B is air supply volume (CFM), R is volume of the room (ft3), 60 is factor (for air change per hour) [1820]. P D B 60 R

Experimental Risk assessment (FMEA model)


Evaluate the overall risk of the qualication and validation steps by combining individual risk values. For the most of the direct impact system, the severity will always be high. The risk priority ranking (RPR) then becomes a combination of an occurrence and detection. If the level of risk is not acceptable, a recommendation must be made to modify the qualication and validation steps to reduce the risk to an acceptable level or enhance the method of detection to reduce the risk to an acceptable level [10,12,13,24,39]. Preference should be given to reducing the occurrence rather than increasing the level of detection. Table 2
Copyright 2011 John Wiley & Sons, Ltd.

Differential Pressure Test


Measure and record the pressure difference between the room to be tested and any surrounding ancillary environment [1820,32,34].

HEPA Filter Leakage Test


Position the aerosol generator to introduce an aerosol challenge upstream of the HEPA lter to a
Qual Assur J 2011; 14, 4049 DOI: 10.1002/qaj

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A. K. Shukla et al.

Table 2. Determination of RPR


Risk related to probability of detection Occurrence High Low 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. 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. This is not likely to occur and if it does occur it will be detected. This is a Low Risk. Medium This is likely to occur and the detection is not certain. It is a High Risk. High This is likely to occur and the detection is not certain. It is a High Risk.

Medium

This could occur and it could be detected. Depending on our confidence in the detection, its risk would be Medium or High Risk. 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.

This may occur and it will not be detected The Risk is High.

Low

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

concentration of 20-100mg/m (20100 mg/lit.) of air by opening appropriate number of nozzles. Measure upstream concentration of aerosol by using upstream port. Adjust the photometers gain / 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% [1820,32,34].

NL A Volume of sample (for grade A at rest and operation,gradeBatrest)-1m3 equivalentto35.3ft3 Volume of sample (for grade B at operation and other grades at both conditions) -1 ft3 [1720,27,28].

Recovery/decontamination rate test


Take the particle count in the area before aerosol generation under resting conditions. 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 [1820,34].

Air Flow Visualization (Non-unidirectional ow)


Generate the tracer particles by water for injection (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 [1820,32,34].

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.
Copyright 2011 John Wiley & Sons, Ltd.

Environmental Conditions Temperature and Relative Humidity


Digital hygrometers and a Sling hygrometer were used to perform the test for 5 consecutive days for category A1 AHUs and for 3 consecutive days for AHUs of other categories. Readings
Qual Assur J 2011; 14, 4049 DOI: 10.1002/qaj

Qualication of HVAC System in Aseptic Processing Area Table 3. Risk assessment for HVAC system
Description of identied risk (unwanted events) New equipment facility or system or any major change in the existing equipment may affect the product requirement safety feature and environment. 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) 3 Installation of component at inappropriate places leading to inadequate performance of AHU. Inappropriate operation of AHU may lead to noncompliance with respect to performance requirement and frequent maintenance. Blocking of the filter affected the differential pressure level and may lead to contamination High Likelihood of occurrence (probability and frequency) Low URS and vendor DQ are in place. Risk related to Probability of detection High If any mismatch observed between user and supplier specication. Risk priority rank High Risk accepted? (yes/no) No

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Risk no. 1

Impact (severity) High

Recommended action User and supplier specifications and drawings are evaluated for their compliance to the intended use and cGMP during DQ.

Medium

Low Sheets are lock forming quality. lock. Insulation thermocole. Claddingaluminum.

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

Medium

No

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

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.

High

Medium Instrument is running as per approved SOP with control parameter.

High If the operating and maintenance person are not trained with respect to the related SOP.

High

No

Identify and verify the SOP during OQ.

High

Low Differential pressure monitoring switches are placed across the lter.

High If the sensors fail to generate alarms.

High

No

DP switches are provided across HEPA filter for monitoring the blocking of the filter and feedback given

Copyright 2011 John Wiley & Sons, Ltd.

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Table 3. Continued
Description of identied risk (unwanted events) in area at higher cleanliness class. 6 Uncalibrated instrument affected the monitoring and controlling the desired product environment condition. Failure of Audio/ visual indication of alarms may not alert the personnel and will continue to operate in noncomplying conditions. High Likelihood of occurrence (probability and frequency) Pre lters are in place. Risk related to Probability of detection Risk priority rank Risk accepted? (yes/no)

Risk no.

Impact (severity)

Recommended action to DDC which generates an alarm.

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

High If the instruments are not calibrated as per frequency.

High

No

Instrument/ component should be calibrated (temp., RH, DP) and report addressed in the OQ.

High

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

High If the alarms are not generated during the excursion in temperature/ RH/DP beyond the set limit.

High

No

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

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

High

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

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

High

No

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. 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. The integrity should be checked through DOP test and report addressed

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

High

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

High If differential pressure value less than alarm limit and greater than specied time between similar and non similar classes.

High

No

10

The validation status with respect to the filter integrity may be affected.

High

Low Change in the HEPA lter at regular

High If there is no check done to verify the

High

No

Copyright 2011 John Wiley & Sons, Ltd.

Qual Assur J 2011; 14, 4049 DOI: 10.1002/qaj

Qualication of HVAC System in Aseptic Processing Area Table 3. Continued


Description of identied risk (unwanted events) Likelihood of occurrence (probability and frequency) intervals and as required. 11 Air flow pattern may affect the effective cleanliness of the area. High Low Rooms are designed from positively to negatively pressurized zone. Dampers maintain the desired differential pressure in the room. 12 Comply with Grade A environment High Low The UAF unit is installed. The area under the unit should comply with class A. Risk related to Probability of detection integrity of lter. High If differential pressure value less than alarm limit and greater than specied time between similar and non similar classes. High No Risk priority rank Risk accepted? (yes/no)

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Risk no.

Impact (severity)

Recommended action in the PQ.

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

High If the turbulence found in the air ow pattern.

High

No

Unidirectional air flow should be checked through WFI fogger; the air flow should have a sweeping action over and away from the product under dynamic condition and report addressed in the PQ. Airborne particle count should be checked through particle counter to Determine the cleanliness level as per ISO standards.

13

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

High

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

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

High

No

14

Airborne particle concentration may affect the specification of air cleanliness in clean rooms.

High

Medium Environmental monitoring devices are in place (FMS). Final ltration of supply air in the room

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

High

No

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

Copyright 2011 John Wiley & Sons, Ltd.

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Table 3. Continued
Description of identied risk (unwanted events) Likelihood of occurrence (probability and frequency) through terminal mounted HEPA lter. 15 Temperature may lead to product instability, personnel discomfort and microbial growth. Relative humidity may affect the moisture sensitive activity. High Low Temperature sensors are located in each room and common return air duct. High Low RH sensors are provided for common return air duct. Dehumidier is in place. High Medium Alert and action limits are determined by trends analysis. High Excursion of temperature beyond the set limit due to different operation. High Excursion of RH beyond the set limit due to CIP/SIP operation. High No High No Temperature should be checked through calibrated instrument and report addressed in the PQ. Risk related to Probability of detection Risk priority rank Risk accepted? (yes/no)

Risk no.

Impact (severity)

Recommended action

16

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

17

Microbial contamination leads to loss of sterility.

High Critical for Grade A environment.

High

No

Viable count should be monitored through settle plate, air sampling, swab sampling and report addressed in the PQ.

Table 4. Performance Qualication of HVAC and UAF System


S. No 1 2 3 4 5 Test performed Air velocity and CFM No. of air changes per hour Differential pressure test HEPA filter leakage test Air flow visualization (non-unidirectional flow) Acceptance criteria 20% of the avg. face velocity NLT 40 NLT 05 Pa less than 0.01% from +ve to ve pressurized zone. Results 4106 CFM 66.31 8 to 10 Pa Max. 0.0004% Min. 0.0002% Meets the acceptance criteria for flow pattern 0.5 mm 5 mm 191 6 500 15 4 min. Max. 23 C Max. 14 TBC TFC 9 <1 4 <1

Airborne particle count

7 8 9 10

condition at rest condition at operational condition Recovery/decontamination rate test Environmental conditions -Temperature Environmental conditions - Relative humidity Viable count monitoring Sampling active air sampling settle plate method

Class area With in class B With in class B Within 10 min 22 3 C NMT 20% Class area With in class B With in class B

Copyright 2011 John Wiley & Sons, Ltd.

Qual Assur J 2011; 14, 4049 DOI: 10.1002/qaj

Qualication of HVAC System in Aseptic Processing Area Table 5. Performance Qualication of UAF System
S. No 1 2 3 4 Air velocity Differential pressure test HEPA filter integrity test Air flow visualization (unidirectional flow) Test performed Acceptance criteria 9020 FPM at 6 inch. From filter face NLT 10mm of WC Less than 0.01% of upstream conc. Flow should be unidirectional Results Complies

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Airborne particle count

Viable count monitoring

condition at rest condition at operational condition Sampling active air sampling swab sampling method

Class area With in class A With in class A Class area With in class A With in class A

14 to 16mm of WC Max. 0.002 % Meeting the acceptance criteria under dynamic condition 0.5 mm 5 mm 0 0 247 0 TBC <1 <1 TFC <1 <1

should be for minimum 16 hours/day at 2 hour interval [1820,27,30,34].

Results
Performance qualication of HVAC system was done using risk assessment approach. Table 3 shows the risk assessment of HVAC system. Tables 4 and 5 represented the performance qualication parameters of HVAC and UAF system, specications and results observed.

Viable Count Monitoring - Settle Plate and Air Sampling


Settled plates should be of 90mm diameter and should be exposed for duration of 4 hours. Plates should be exposed at a height above 1 meter from the oor and also at work level for better exposure. For air sampling, 1m3 of air from specied locations should be sampled using Soybean Casein Digest Agar [7,8,12]. Incubate settle plate at 20 - 250C for TFC and at 30 - 350C for TBC.

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 on 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.

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Qual Assur J 2011; 14, 4049 DOI: 10.1002/qaj