Risk Assessment of HVAC

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Arti Articl clee ID Disp Dispat atch ch:: 11.0 11.09. 9.11 11 4 8 5 No. of Pages: 9

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A Risk Assessment Approach: Quali�cation 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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Abstract

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In the pharmace pharmaceutic utical al industry industry quali quali�cati cation on of HVAC HVAC syst system emss is done done by usin using g a risk risk base based d approach. FMEA concept concept was used for risk assessme assessment nt in HVAC system system to determin determine e scop scope e and and exte extent nt of qual qualii�cati cation on and and vali valida dati tion on in this this pres presen entt work work.. The The leve levell of risk risk was was asse assess ssed ed,, base based d on the the impa impact ct and and seve severi rity ty on the the asep asepti ticc prac practi tice ce in ster steriile manufacturing because the HVAC system is the “direct impact” system in the aseptic prac practi tice ce expe expect cted ed to have have a dire direct ct impa impact ct on prod produc uctt qual qualit ity y and and regu regula lato tory ry comp compli lian ance ce.. On completion of the risk assessment, existing controls, measures and recommended action were identi�ed required for the better cGMP and upgradation of the system. After completion of the risk assessment the recommended actions were extended and veri�ed against the quali�cation 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 eval evalua uati tion on of the the data data coll collec ecte ted d duri during ng PQ, PQ, it was was foun found d that that the the HVAC HVAC syst system em met met all all the speci speci�ed desi design gn crit criter eria ia and and comp compli lied ed with with the the enti entire re cGMP cGMP requ requir irem emen ent. t. Henc Hence e the the system stands validated for PQ. Copyright © 2011 John Wiley & Sons, Ltd. Key Words: Words: HVAC; UAF; PQ; ICH; FMEA

Introduction Qual Qualit ity y risk risk manag managem emen entt is an impor importa tant nt part part of science based decision making which is essential *Correspo *Corresponden ndence ce to: Anil Anil Shukla, Shukla, School School of Pharmace PharmaceuuticalSciences,RajivGandhiProudyogikiVishwavid ticalSciences,RajivGandhiProudyo gikiVishwavidyalaya, yalaya, Bhopal,MadhyaPradesh,India.E-mail:aksqargpv@gmail. com

Copyright © 2011 John Wiley & Sons, Ltd.

for for qual qualit ity y mana manage gemen mentt of phar pharma mace ceut utic ical al manufacturing. The ICH Q9 guideline, quality risk manageme management nt and other other literatu literature re provide provide guida guidance nce on the the princ princip ipal al of quality quality risk risk manag manageement. The FMEA model can be used to facilitate risk risk asse assess ssmen mentt for for any any syst system em in the the asep aseptic tic processing area of sterile products. It provides a

Qual Assur J (2011) (2011) DOI: 10.1002/qaj 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 quali �cation 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 modi�cation in the 79 making risk assessment particularly important. existing controls and the system. Table 2 T2 Q11 80 81 The European Union GMP requirements 82 place speci�c obligations on manufacturers of Performance Quali�cation for HVAC 83 medicinal products to implement risk based and UAF System Q12 84 quali�cation, 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 atthe inlet air grillswas measuredat5 pointsina 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 velocitywasmeasuredforat 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 quali �cation 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 be high. The RPR then Q9 the severity will always 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 quali�cation 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/m³ (20–100 m g/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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Quali�cation 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.

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.

/ span control for a full-scale de �ection 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 FlowVisualization (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 air �ow direction. Record the air�ow 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.

Volume of sample (for grade B at operation and other grades at both conditions) -1 ft 3

Recovery/decontamination rate test Take the particle count in the area before aerosol generation at rest condition. The sampling rate should be 1 CFM. Arti�cially generate DOP/PAO aerosol in the classi �ed area and check the count (1000 times more than classi �ed 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 speci �ed 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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e n e i v a t i e h l t c t s n e n c s i e f s f s a n o e i n y t i l a a . n s n m i e a s m i e a i t l t i v h c m n r o g i i o o t c H A r c a

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7

62 63 S. No Test performed Acceptance criteria Results 64 65 1 Air velocity and CFM 4106 CFM 20% of the avg. face velocity 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 <1 active air sampling With in class B 9 80 <1 settle plate method With in class B 4 81 82 83 84 85 86 87 Table 5. Performance Quali�cation of UAF System 88 89 S. No Test performed Acceptance criteria Results 90 1 Air velocity 9020 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 <1 <1 monitoring active air sampling With in class A 105 <1 <1 swab sampling method With in class A 106 107 108 109 110 the �oorandalso at work level for better exposure. Viable Count Monitoring - Settle Plate 3 111 For air sampling, 1m of air from speci�ed and Air Sampling 112 Settled plates should be of 90mm diameter and locations should be sampled using Soybean Casein 113 should be exposed for duration of 4 hours. Plates Digest Agar. Incubate settle plate at 20 - 25 0C for 114 should be exposed at a height above 1 meter from TFC and at 30 - 35 0C for TBC. Table 3–5 T3 T4T5115 Q14 116 117 118 119 120 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assur J (2011) 121 DOI: 10.1002/qaj 122

Table 4. Performance Quali�cation 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, 4–6. 4. Nash Robert A, Wachter Alfred H. Quali�cation of water and air handling systems. Pharmaceutical Process Validation, 3rd ed. vol. 129. Marcel Dekker, 22–24. 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, 1–26. 6. Swarbrick J. Encyclopedia of Pharmaceutical Tech-

Failure Mode Effect Analysis (FMEA)

nology, 3rd ed. vol. 1. USA: Informa health care, 127–128. 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, 2–9. 8. Agalloco JP, Carleton FJ. Validation of Aseptic

Conclusion Quali�cation and validation is appearing to be the beginning of a continuous development process in pharmaceutical QA. Risk assessment is an essential tool for quali �cation of HVAC system in aseptic processes. It is not just a tool for cGMP compliance, its offers real bene �ts 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 quali �cation and validation efforts.

Pharmaceutical Process. 2nd ed. New York: Marcel Dekker, Inc., 2–3. 9. WHO.

Supplementary

Guidelines

on

Good

Manufacturing Practices (GMP): Validation, June 2004, 7–15. 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, 6–14. 13. McDermott RE, Mikulak RJ, Beauregard MR. The Basics of FMEA. Portland: Productivity, Inc; 1995, 3–44. 14. Annex 15. EU Guide to Good Manufacturing

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Risk Assessment of HVAC

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