“VALIDATION AND QUALIFICATION OF HEATING, VENTILATION, AIR

CONDITIONING SYSTEM & PHARMACEUTICAL EQUIPMENTS”

DISSERTATION PROTOCOL

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

BYPATEL DHRUMIL DILIPKUMAR

B.PHARM,

UNDER THE GUIDANCE OF,DR. SURESH D.

HEAD OF DEPARTMENT,

DEPARTMENT OF QUALITY ASSURANCESHREE DEVI COLLEGE OF PHARMACY

MANGALORE-574 142(2011-2013).

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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. NAME OF THE CANDIDATE

AND ADDRESS (IN BLOCK

LETTERS)

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

MASTER OF PHARMACY IN

QUALITY ASSURANCE

4. DATE OF ADMISSION OF

COURSE JULY-2011

5. TITLE OF TOPIC:-

“ VALIDATION AND QUALIFICATION OF HEATING, VENTILATION, AIR

CONDITIONING SYSTEM & PHARMACEUTICAL EQUIPMENTS”

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6.

6.1

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.”

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Types of validation

Validation can be divided into four types

1 Prospective validation,

2 Rétrospective validation

3 Concurrent validation

4 Revalidation

5 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

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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

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Blower

Motor

RAFC

VCD

SAFC

Access door panelfor Filter

Fire Damper

Cooling coilAccess Door Panel for

Fan section

Supply Air Filter 3

Pre filter 10+5µ

Droplet Eliminator

Ampoule filling Room LIine -1

Category 0.3 µ

SAF (1 filter 3)

RAR (1 filter 5)Leakag

e

Fresh Air through 10

Exhaust Air through 10(During Fumigation)

: Chilled water outlet: Chilled water inlet VCD : Vacuum Control Damper

RAFC : Return Air Flange ConnectionSAFC : Supply Air Flange ConnectionSAF : Supply Air FilterRAR : Return Air

Riser

KEY

AHU - 9

Return Air AHU Air

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.

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.

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(B) Installation qualification (IQ)

The performance of tests to ensure that the installations ( such as machines,

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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6.2

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. End-

product 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 8

terms of mechanical strength, hygroscopicity and compatibility with a wide

range of drugs. Specifically, the new HPMC capsule demonstrated improved

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 9

laboratory robotics and propose guidelines for performing the various steps

required for qualification (i.e., installation, operational, and performance

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,paddleheight–vessel type interaction,and paddle

height–level of deaeration interaction.We also found that the other

variablesexamined—temperature,shaft wobble,vessel centering,vessel tilt,and

base plate levelness—were not statistically significant within the ranges

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6.3

7.0

explored in this study. Acceptance ranges for several assembly variables may

need to be more stringentor more precisely defined in order to decrease inter-

and intralaboratory variability (reproducibility and repeatability) in dissolution

testing.(7)

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

EQUIPMENTS:

HVAC SYSTEM VALIDATION

Anemometer for Air velocity

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7.1

Aerosol generator machine

Validation assembly

Air particulate counter

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)

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

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7.2

www.rxlist.com

www.eurasiajournals.com

www.ajrconline.org

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 environment and photo-catalytic oxidation: state of

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.

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].

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7.3

7.4

Airflow velocity.

Air changes per Hour (ACPH).

Non-viable particle count.

Smoke pattern.

QUALIFICATION OF EQUIPMENTS

On the basis of operation & performance qualification various equipment describes

above.

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 -

Has ethical clearance been obtained from your institution in case of 7.3?

- NOT APPLICABLE-

14

8.

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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9. 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

12. 12.1 Remarks of Principal:17

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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