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VALIDATION AND QUALIFICATION OF HEATING, VENTILATION, AIR CONDITIONING SYSTEM & PHARMACEUTICAL EQUIPMENTS

DISSERTATION PROTOCOL SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA.

BY PATEL DHRUMIL DILIPKUMAR B.PHARM, UNDER THE GUIDANCE OF, DR. SURESH D. HEAD OF DEPARTMENT,

DEPARTMENT OF QUALITY ASSURANCE SHREE DEVI COLLEGE OF PHARMACY MANGALORE-574 142 (2011-2013).

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA. ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION PATEL DHRUMIL DILIPKUMAR. HOUSE NO-:856, THIRD STREET, NARANPURA VILLAGE, NARANPURA, AHMEDABAD -: 380013 GUJARAT. 2. NAME OF THE INSTITUTION SHREE DEVI COLLEGE OF PHARMACY, AIRPORT ROAD, KENJAR VILLAGE, MALAVOOR PANCHAYAT, MANGALORE-574 142, KARNATAKA. 3. COURSE OF STUDY AND SUBJECT 4. DATE OF ADMISSION OF COURSE JULY-2011 MASTER OF PHARMACY IN QUALITY ASSURANCE

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NAME OF THE CANDIDATE AND ADDRESS (IN BLOCK LETTERS)

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TITLE OF TOPIC: VALIDATION AND QUALIFICATION OF HEATING, VENTILATION, AIR CONDITIONING SYSTEM & PHARMACEUTICAL EQUIPMENTS

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BRIEF RESUME OF THE INTENDED WORK: NEED FOR THE STUDY: WHAT IS VALIDATION? Definition Food and Drug Administration of United State defines the validation as Validation is defined as a documented program that provides a high degree of assurance that a specific process, method or system will consistently produce a result meeting its predetermined acceptance criteria. Definition The Commission of European communities defines validation as Action of proving, in accordance with the principles of Good manufacturing Practice, that any procedure, process, equipment, material, activity or system actually leads to the expected results.

Definition The World health organization (WHO) define the validation in the same way but elaborates considerably on the concept Validation studies are essential part of Good manufacturing practice and should be conducted in according with predefined protocols. A written report summarizing results and conclusions should be recorded, prepared and stored. Processes and procedures should be established based upon the validation study and undergo periodic revalidation to ensure that they remain capable of achieve the intended results. Particular attention should be accorded to the validation of processing, testing and cleaning procedures. Critical processes should be validated, prospectively or retrospectively. When any new master formula or method of preparation is adopted, steps should be taken to demonstrate its stability for routine processing. The defined process , using the materials and equipment specified, should be shown to yield a product consistently of the required quality. Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process, should be validated. 3

Types of validation Validation can be divided into four types 1 2 3 4 5 Prospective validation, Rtrospective validation Concurrent validation Revalidation Computerized validation

(1) Prospective Validation In prospective validation, an experimental plan called the Validation Protocol is executed (following completion of the qualification of the qualification trials) before the process is put into commercial use. (2) Retrospective Validation The retrospective validation option is chosen for established products whose manufacturing processes are considered stable (e.g. long History State of control operation) and when, on the basis of economic considerations alone and validation experimentation cannot be justified (3) Concurrent Validation In-process monitoring of critical processing steps and end product, the testing of current production can provide documented evidence to show that the manufacturing process is in state of control. (4) Revalidation Conditions requiring revalidation study and documentation are Change in a critical component ( usually refers to raw materials ) Change or replacement in a critical piece of modular (capital ) equipment Change in a facility and /or plant (usually location or site ) Significant (usually order of magnitude ) increase or decrease in batch size . Sequential batches that fail to meet product and process specifications (5) Computer Validation Documented evidence which provides a high degree of assurances that a computerized system analyses, controls and records data correctly and that data processing complies with predetermined specifications

HVAC SYSTEM VALIDATION The HVAC System is designed to serve the laboratory suite of the biotechnology plant including cell culture rooms, aseptic rooms, preparation rooms, and air locks. The laboratory rooms are designed for Class 10,000 and the air locks for Class 100,000. Corridors are controlled but unclassified areas. Clean benches in the Class 10,000 laboratory rooms are designed for Class 100. The outside air, combined with the return air, is treated by AHU and supplied to the laboratory area. A part of the air exiting from the laboratory rooms is directly exhausted into the atmosphere by an exhaust fan, while the remaining air is re-circulated to the AHU as return air by a return fan. The air entering into the AHU is filtered by pre-filters and medium filters and then air conditioned for humidity and temperature control, and is supplied to the laboratory area by a supply fan at desired pressure. The supply air is terminal filtered by HEPA filers at the entrance to the cleanrooms. The system is designed to satisfy all cGMP requirements. Three Functions of HVAC Heating is significant in maintaining adequate room temperature especially during colder weather conditions. There are two classifications of heating: local and central. The latter is more commonly used because it is more economical. Furnace or boiler, heat pump, and radiator make up the heating system2. Ventilation, on the other hand, is associated with air movement. There are many types of ventilation, but they all function similarly. Ventilation is necessary to allow carbon dioxide to go out and oxygen to get in, making sure that people are inhaling fresh air. Stagnant air causes the spreading of sickness, usually airborne, and allergies. But it is also essential to maintain an efficient ventilation system, especially in the attics. Insufficient ventilation usually promotes the growth of bacteria and fungi such as molds because of high humidity. It will also decrease the effectiveness of rafter and roof sheathing insulation because of water vapor condensation.

The air-conditioning system controls the heat as well as ventilation. They often come in different sizes. Most air conditioners have large air ducts, so it is better to check out the building first to see if they can be installed. Or else, you can use the split system or remote coils. It is necessary, though, that air ducts are properly cleaned. Pathogens thrive in dirty air ducts. Return-air grills are also vulnerable to chemical, microbiological, and radiological elements. Thus, HVAC return-air grill height should be that it is not accessible but visible for any observation.
AHU 9

VC D

Access door panel for Filter

Droplet Eliminator

Blowe r

Supply Air Filter 3

Fire Damper

RAF C

Cooling coil Pre filter 10+5 Moto r

Access Door Panel for Fan section

SAF C AHU Air

Fresh Air through 10 Exhaust Air through 10 (During Fumigation) K : Chilled water E inlet : Chilled water Y RAR outlet : Return Air Riser

Return Air RAR (1 filter 5)

Leakag e VCD : Vacuum Control Damper RAFC : Return Air Flange Connection SAFC : Supply Air Flange Connection SAF : Supply Air Filter

SAF (1 filter 3)

Ampoule filling Room LIine 1 Category 0.3

Flow diagram of the air handling unit system WHAT IS QUALIFICATION System and equipment should be appropriately designed, located and installed, operated and maintained to suit their intended purpose. Types of Qualification

(A) Design qualification (DQ) Documented evidences that the premises, supporting systems, utilities, equipment and process have been designed in accordance with the requirements of GMP. (B) Installation qualification (IQ) The performance of tests to ensure that the installations ( such as machines, 6

measuring devices, utilities and manufacturing areas) used in a manufacturing process are appropriately selected and correctly installed and operate in accordance with established specifications (C) Operational qualification (OQ) Documented verification that the system or subsystem performs as intended overall anticipated operating ranges. (D) Performance qualification (PQ) Documented verification that the equipments or system operates consistently and gives reproducibility within defined specifications and parameters for prolonged periods. (in the context of systems, the term process validation may also be used.)

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REVIEW OF LITERATURE : (1) Shah M, et al., suggested that the process validation is an essential process in pharmaceutical industry The purpose of this work is to present an introduction and general overview on process validation of pharmaceutical manufacturing process especially tablet manufacturing process with special reference to the requirements stipulated by the US Food and Drug Administration (FDA). Quality is always an imperative prerequisite when we consider any product. Therefore, drugs must be manufactured to the highest quality levels. Endproduct testing by itself does not guarantee the quality of the product. Quality assurance techniques must be used to build the quality into the product at every step and not just tested for at the end. In pharmaceutical industry, Process Validation performs this task to build the quality into the product because according to ISO 9000:2000, it had proven to be an important tool for quality management of pharmaceuticals.(1) (2) Goldschmidt N, et al., suggested that first steps for sustainable bio/pharma HVAC systems are usually equipped with an array of filters designed

primarily to clean outdoor air. In typical outdoor air it's estimated that are more than 90% of particles and are less than 1.0 micron in size, low-efficiency filters do a good job at removing large particles, but miss the larger number of these small particles(2) (3) Ku M, et al., suggested that performance qualification of a new hypromellose capsule Part I is comparative evaluation of physical, mechanical and processability quality attributes of Vcaps Plus, Quali-V and gelatin capsules This Part I paper describes the qualification of a new high performance hypromellose (hydroxypropyl methylcellulose, HPMC) capsule shell which contains no gelling agent and is dissolution friendly. The development history and the test results for a series of quality attributes including scanning electron microscopy, hygroscopicity, machineability, weight variation, powder leakage, mechanical strength, stability, cross-linking, animal and human

pharmacokinetic results are reported. Comparisons to gelatin and HPMC capsule `containing carrageenan showed the new HPMC capsule is superior in terms of mechanical strength, hygroscopicity and compatibility with a wide range of drugs. Specifically, the new HPMC capsule demonstrated improved 8

weight variation, machineability and powder leakage than the HPMC capsule containing carrageenan. And the new capsule demonstrated a broader applicability than gelatin capsule for new drug development due to its inertness and compatibility for a wide range of excipients including those used for liquid fill formulations. In the second phase of qualification, disintegration and dissolution properties of the new HPMC were evaluated and reported in a Part II paper for 10 new clinical compounds with a variety of formulations optimized based on the biopharmaceutical classification system of solubility and permeability. Based on the superior performance, the new HPMC capsule is satisfactorily qualified and has since been used successfully for nearly 20 investigational new drug (IND) compounds. (3) (4) Shukla A, et al., suggested that in the pharmaceutical industry qualification 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 qualification 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 identified for improved cGMP compliance and qualification of the system upgrades. 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 a performance qualification (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. (4) (5) Caillet C, et al., suggested that Qualification of robotic laboratory equipment Robotic laboratory equipment malfunctions may affect the performance of integrated laboratory instruments. Thus, the qualification of robotics is necessary to ensure adequate performance of complete integrated systems. In this JALA Tutorial, we adapt the methods used in production processes to laboratory robotics and propose guidelines for performing the various steps required for qualification (i.e., installation, operational, and performance 9

qualification), while emphasizing specific aspects of laboratory robotics. We think that the application of such guidelines will help in standardizing the acceptance of robotic equipment, facilitate their operation and performance evaluation, and improve traceability with quality assurance documentation.(5) (6) Sigvardson K, et al., suggested that the qualification of laboratory equipment The main goal in qualifying laboratory equipment is to ensure the validity of data.The current equipment qualification programs and procedures used within the pharmaceutical industry are based on regulatory requirements, voluntary standards, vendor practices, and industry practices. The result is considerable variation in the way pharmaceutical companies approach the qualification of laboratory equipment and the way they interpret the often vague requirements The authors summarize the conclusions of the pharma Workshop on Acceptable Analytical Practices for the topic Qualification of Laboratory Equipment.(6) (7) Eaton J, et al., suggested that the perturbation study of dissolution apparatus variables which is a design of experiment approach The specifications and acceptable ranges for nine critical dissolution apparatus variables were examined during a perturbation study of USP dissolution Apparatus 2 using USP Prednisone Reference Standard (RS) Tablets. A Design of Experiment(1) approach was used to screen the nine variables to determine the contribution of each, alone and in combination,to mean percent dissolved and standard deviation results.We observed a wide range of dissolution results,including several values that fell outside of current acceptance limits,even though the variables were kept within currently acceptable ranges .When we analyzed mean percent dissolved results, we found three variables that were statistically significant: level of deaeration, vessel type,and rotation speed. When we examined standard deviation results, We found that five variable sor combinations of variables were statistically significant:vessel type, level of deaeration,paddle height,paddleheightvessel type interaction,and paddle heightlevel of deaeration interaction.We also found that the other variablesexaminedtemperature,shaft wobble,vessel centering,vessel tilt,and base plate levelnesswere not statistically significant within the ranges explored in this study. Acceptance ranges for several assembly variables may need to be more stringentor more precisely defined in order to decrease inter10

and intralaboratory variability (reproducibility and repeatability) in dissolution testing.(7) 6.3 OBJECTIVES OF THE STUDY: Review of literature revealed that there is scope for the validation and qualification of heating, ventilation, air conditioning system & pharmaceutical equipments. Hence the goals of the present work are, To do validation of HVAC systems by different method (1)High efficiency particulate air (HEPA) filters integrity [Dioctyl Phthalate (DOP/PAO) test]. (2) Airflow velocity. (3) Air changes per Hour (ACPH). (4) Non-viable particle count. (5) Smoke pattern. To do qualification of different equipments The performance Qualification performed for following equipments are; (1) Dissolution test apparatus (2) Cadmach-cad press IV 55 station (3) Double Cone blender. (4) Strip packing machine (SE-310) (5) Digital Metal Detector The operational Qualification performed for following equipments are; (1) Fluidized bed dryer/ evaporator (model FBE-500) (2) Rotary mixing granulator (model RMG-400 ltrs) To comply with the current GMP regulations To gain confidence on the activities carried out To minimize the risk of failure To strengthen the quality assurance system

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EQUIPMENTS: HVAC SYSTEM VALIDATION Anemometer for Air velocity Aerosol generator machine Validation assembly Air particulate counter 11

EQUIPMENTS FOR QUALIFICATION The performance Qualification performed for following equipments are; (1) Dissolution test apparatus (2) Cadmach-cad press IV 55 station (3) Double Cone blender. (4) Strip packing machine (SE-310) (5) Digital Metal Detector

The operational Qualification performed for following equipments are; (1) Fluidized bed dryer/ evaporator (model FBE-500) (2) Rotary mixing granulator (model RMG-400 ltrs)

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Source of data: Data will be obtained from Science Direct, Pubmed.gov and other internet facilities, literature search and related articles from library of Shree Devi College of Pharmacy, Mangalore, Digital Library of RGUHS, Bangalore, etc.

(A) Journals Asian Journal of Research in Chemistry. International Journal of ChemTech Research. Journal of Young Pharmacists. Indian Journal of Pharmaceutical Science. International Journal of Pharmacy and Pharmaceutical Science. Journal of Pharmacy Research. The Indian Pharmacist. Pharma Times. IDR Drug Compendium. Journal of the air and waste management Journal of Photochemistry anr Photobiology (B) World wide web www.sciencedirect.com www.rxlist.com www.eurasiajournals.com www.ajrconline.org 12

www.jpronline.info www.googlescolar.com www.pharmainfo.net www.ijpsonline.com

(C) Text Books and Pharmacopoeia 1. Iyer S. Text book of guidelines on CGMP and quality of pharmaceutical product, HVAC System 2003 : 1; 137-139. 2. Imtiaz HS. Pharmaceutical Master Validation Plan ,St.Lucie press Function of HVAC 2006: 1; 355-378. 3. Sharma PP. validation in pharmaceutical industry , Validation of HVAC system 2007 : 1; 169-175 . 4. Shah DH. Q .A manual Air handling System 2007 (3) : 55-56. 5. Ang HM, Tade M, Wang S. Environmental International "Volatile organic compounds in the indoor the art".2007: 33; 694-705. 6. Carleton FJ and Agalloco JP.Validation of Pharmaceutical Processes , Sterile products, Second Edition, Marcel Dekker Inc. 1999. 7. Guideline on general principles of Qualification and validation USFDA 8. Hong SU.Principle of process Validation and Qualification Korea Food and Drug Adminstritation July 16,2003 9. Nash R.A. and Berry I.R.,Pharmaceutical Process Validation Second Edition, MARCEL Dekker Inc., 1993. environment and photo-catalytic oxidation: state of

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Method of Collection of Data (Including Sampling Procedures, If Any) HVAC SYSTEM VALIDATION

High efficiency particulate air (HEPA) filters integrity [Dioctyl Phthalate (DOP/PAO) test]. Airflow velocity. Air changes per Hour (ACPH). 13

Non-viable particle count. Smoke pattern. QUALIFICATION OF EQUIPMENTS On the basis of operation & performance qualification various equipment describes above. 7.3 Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly. - NOT APPLICABLE 7.4 Has ethical clearance been obtained from your institution in case of 7.3? - NOT APPLICABLE-

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LIST OF REFERENCES:

1) Shah M. Process Validation : An Essential Process In Pharmaceutical Industry. 2011. 2) Goldschmidt N. First steps for sustainable bio/pharma HVAC.2009 3) Ku M, Li W, Dulin W, Donahue F, Cade D, Benameur H, Hutchison K. Performance qualification of a new hypromellose capsule: Part I. Comparative evaluation of physical, mechanical and processability quality attributes of Vcaps Plus, Quali-V and gelatin capsules. Int J Pharma. 2010; 386:30-1. 4) Shukla A, Katole A., Jain, N., Karthikeyan, C., Mehta, F. and Trivedi, P. Risk Assessment Approach: Qualification of a HVAC System in Aseptic Processing Area Using Building Management System. The Quality Assurance Journal. Article first published online: 2011; 485. 5) Caillet C, Pegon Y, Neel T, Morin D, Baudiment C. Qualification of robotic laboratory equipment. J Asso Lab Auto. 2005;10(1):48-53 6) Sigvardson K, Manalo J, Roller R, Saless F, Wasserman D. Laboratory Equipment Qualification. 2001; 102-108. 7) Eaton J, Deng G, Hauck W, Brown W, Manning R & Wahabs. Pertubation study of dissolution apparatus variables technologies. 2007; 20-6. 8) http://en.wikipedia.org/wiki/HVAC.

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Signature of the candidate

(PATEL DHRUMIL D) 10. Remarks of the Guide: VALIDATION AND QUALIFICATION OF HEATING, VENTILATION, AIR CONDITIONING SYSTEM & PHARMACEUTICAL EQUIPMENTS to be carried out by Mr. Patel Dhrumil D. of M.Pharm has been discussed and worked out under my direction and supervision as an official guide. The project work envisaged is of great importance in the field of analytical research. The work can be carried out in Quality Assurance Laboratory of Shree Devi College Of Pharmacy for which facilities are available. Hence the project is viable and is recommended for clearance and approval. 11. Name & Designation of (in block letters) 11.1 Guide DR. SURESH D. Department of Quality Assurance. Shree Devi College Of Pharmacy, Airport Road, Kenjar Village, Malavoor Panchayat, Mangalore, 574 142 Karnataka. 11.2 Signature 11.3 Head of the department DR. SURESH D. Department of Quality Assurance. Shree Devi College Of Pharmacy, Airport Road, Kenjar Village, Malavoor Panchayat, Mangalore, 574 142 Karnataka. 11.4 Signature

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12.1 Remarks of Principal: The Program and the Research that is undertaken by Mr. Patel Dhrumil D. has the potential implication in the field of Quality Assurance. The work can be carried in the Research Laboratories of Quality Assurance Department at Shree Devi College Of Pharmacy. Hence the project is recommended and requested for clearance and approval. 12.2 Signature

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