validation of hvac

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Prepared By:

Vinay Prajapati.M. Pharm Sem-IIRoll no:13Department of Quality Assurance

Guided By:

Mr. Jignesh Shah

S.J.Thakkar Pharmacy College, Rajkot.

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CONTENTS

Introduction AHU HVAC Qualification Validation parameter

INTRODUCTION

To understand:

The need and reason for pharmaceutical air handling systems.

The technical requirements for air handling systems.

Different types of air handling systems.

Qualification and Validation requirements

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WHAT IS CLEAN ROOM?

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A room in which the concentration of airborne particle is controlled and which is constructed and used in a manner to minimize the introduction, generation and retention of particles inside the room and in which other relevant parameters.

e.g.. Temperature, humidity and pressure, are controlled as necessary. (ISO 14644-1)

WHY CLEAN ROOM NECESSARY?

It controls 3 types of contamination transferAir borne contaminationDirect contamination by personnel, equipment etc.

Contamination from fluids like cleaning fluids, solutions etc.

As airborne particulate are reduced, chances of particles entry in the process reduced.

Protects product, personnel & environment.Avoid rejection thereby heavy losses in terms of money & time 5

HOW IT IS ACCOMPLISHED?

A clean room is continuously flushed with highly filtered air that is forced in through HEPA filters.

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TYPES OF CLEAN ROOMS

Horizontal Clean Room – Horizontal Laminar flow

(HEPA filters in a wall force clean air from one side of the room to other.)

Vertical Clean Room – Vertical Laminar flow

(HEPA filters on the ceiling push clean air down to the floor.)

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FOUR BASIC PRINCIPLES OF CLEAN ROOM

Not To Bring Any Dust

Not To Accumulate Any Dust

Not To Generate Any Dust

To Remove Any Dust Quickly

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INTRODUCTION

Air handling systems,

Play a major role in the quality of pharmaceuticals.

Must be designed properly, by professionals.

Must be treated as a critical system.

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INTRODUCTION

The manufacturing environment is critical for product quality.

Environment consists of, Light Temperature Humidity Air movement Microbial contamination Particulate contamination

Uncontrolled environment can lead to product degradation product contamination loss of product and profit 10

INTRODUCTION

HVAC consists of,

1. Air conditioner2. AHUs 3. Dehumidifier / Heater4. Filters (Pre & HEPA)5. Dust Extractors 6. Ducting (For delivery of controlled air)7. Supply Fans8. Smoke Detector9. Dampers10.Humidity / Temperature / Pressure

sensors11.Bag Filters12.Heating / Cooling Coils

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US FDA

21 CFR part 211(Requirement for building & Facilities)

Under 211.42 (c)Operation shall be performed within the specifically

defined areas and such other controls, necessary to prevent contamination or mix ups.

Temperature and Humidity controlled.An air supply filtered through HEPA filter under

positive pressure.A system of monitoring environmental conditions.

Under 211.46 (C) Air filtration system, including pre-filters and

particulate matter air filtration shall be used when appropriate on air supplies to production areas. 12

EU GUIDELINES(PREMISES & EQUIPMENT)

Under 3.12, Production areas shall be effectively

ventilated with air control facilities including temperature & where necessary humidity and filtration.

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SCHEDULE – MPART – 1 (GMP FOR PREMISES AND MATERIALS)

Under point 8.21,The licensee shall prevent mix-ups and

cross contamination of Drug Materials and Drug Products (from environment dust) by proper air handling system.

Part 1A (GMP for Sterile preparation)Section 3 – Details of HVAC systemSection 4 – Parameterrs for Validation and Frequency of Monitoring 14

INTRODUCTION

HVAC (AHU) is

HEART

of Pharmaceutical Industries

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INTRODUCTION

HVAC

Area - 1

Area - 2

Area - 3

Area - 4

Impure Air

IMPURE

AIR

Impure Air

Pure Air

90%

10% Return Air

Exhaust16

CONTAMINATION

What are contaminants ?

Contaminants are1. Products or substances other than the

product being manufactured. 2. Foreign products.3. Particulate matter.4. Micro-organisms.5. Endotoxins (degraded micro-organisms).

Cross-contamination is a particular case of contamination 17

CONTAMINATION

Cross-Contamination From where does Cross-

Contamination originate?

1. Poorly designed air handling systems and dust extraction systems

2. Poorly operated and maintained air handling systems and dust extraction systems

3. Inadequate procedures for personnel and equipment

4. Insufficiently cleaned equipment

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CONTAMINATION

Cross-contamination can be minimized by:

1. Personnel procedures2. Adequate premises3. Use of closed production systems4. Adequate, validated cleaning

procedures5. Appropriate levels of protection of

product6. Correct air pressure cascade 19

AIR FLOW PATTERNS

Prefilter

AHU

Main filter

Uni-directional TurbulentTurbulent

1 2 3

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Workbench (vertical) Cabin/ booth Ceiling

AIR FLOW PATTERNS

HVAC QUALIFICATION

To ensure that equipment is designed as per requirement, installed properly.

Action of proving that any equipment works correctly and leads to the expected results.

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HVAC QUALIFICATION

QU

LIFI

CA

TIO

N

VALIDATION 23

• This document should contain

Validation policyOrganizational structure of validation

activitiesSummary of facilities, systems,

equipment and processes to be validated

Documentation format to be used for protocols and reports

Planning and schedulingChange controlReferences to documents

THE VALIDATION MASTER PLAN

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USER REQUIREMENT SPECIFICATION

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Capacity of HVAC depends on,

1.Room Volume.2.No. of Air Changes Required.3.Production / Consumption Data4.Seasonal fluctuation.5.Air Classification of Rooms.6.Future Development.

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Parameters to be defined in Levels of Protection :

Air cleanliness requirements 1. filters type and position, 2. air changes, 3. air flow patterns, 4. pressure differentials, 5. contamination levels by particulate matter &

micro-organisms.

• User Requirement Specification should be approved by Production, Engineering and QA Heads. 27

Based on the URS supplier designs the equipment-First step in the qualification of new HVAC systems.

It documents the design of the system and will include :

1. Functional Specification.2. Technical / Performance specification for equipment.3. Detailed Air Flow Schematics.4. Detailed layout drawing of the system.

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DESIGN QUALIFICATION

DESIGN QUALIFICATION

Compliance with GMPs and other regulatory requirements.

Ensures that design,1. meets the user requirements.2. details facility airflow and pressure

cascade philosophy.3. takes into account process and personnel

flow (cross-contamination issues)4. Details materials of construction.5. Details safety requirements.6. Full details of the intended construction

prior to implementation.7. Details all equipment that must be

ordered.

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INSTALLATION QUALIFICATION

System Description Equipment Delivery Utilities / Facility / Environment Assembly & Installation

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IQ Should include,

Instrumentation checked against current engineering drawings and specifications

Verification of materials of construction Installation of equipment and with

piping Calibration of measuring instruments

requirements Collection and collation of supplier

operating and working instructions and maintenance requirements

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Practical aspect of IQ (Cont….)

Calibration of measuring instruments. Calibration of additionally used instruments. Initial cleaning records. Basic commissioning checks. Maintenance requirements. IQ process checks that the correct components

are installed in the correct location. Materials of construction Spare parts Change controls

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IQ Document should contain,

Instrument name, model, I.D. No., Personnel responsible for activities and Date.

A fully verified installation that complies with the documented design. (all deviations will have been recorded and assessed.)

All equipment documentation and maintenance requirements would be documented.

Completed calibration of measuring instruments.

Verification of Materials of construction.

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OPERATION QUALIFICATION

ISPE definition : The purpose of OQ is to establish, through documented testing, that all critical components are capable of operating within established limits and tolerances.

The purpose of OQ is to verify and document that an HVAC system provides acceptable operational control under “at-rest” conditions. 34


Operation Qualification Checks,

Ability to provide air of sufficient quality and quantity to ensure achievement of specified clean room conditions.

Ability to maintain temperature, relative humidity and pressure set points.

Ability to maintain any critical parameters stated in the DQ consistently.

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Includes the tests that have been developed from knowledge of processes, systems and equipment.

Tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as ‘worst case’ conditions.

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IQ reports must be completed and signed off.OQ protocols to be written and approved prior to

completion. Measurement reports are required to

demonstrate achievement of critical parameters as detailed in DQ.

Eg: * All relevant SOPs should be in place * Temperature measurement report

* Humidity measurement report* Differential pressure measurement report* Air flow direction measurement report * Room particle count measurement report* All drawings etc. – done in ‘as-built’ status* All maintenance/ cleaning instructions available* All O & M staff to be trained to use and maintain the

system. * Sign off. (Compliance Certificate by Engineering Dept & QA)

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PERFORMANCE QUALIFICATION

The purpose of PQ is to verify and document that an HVAC system provides acceptable control under ‘ Full Operational ‘ conditions.

PQ should follow successful completion of IQ and OQ.

PQ verifies that over time, the critical parameters, as defined in the DQ are being achieved.

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PERFORMANCE QUALIFICATION

PQ Should include,Tests, using production materials, qualified

substitutes or simulated product, that have been developed from knowledge of the process and facilities, systems or equipment.

Test to include a condition or set of conditions encompassing upper and lower operating limits.

PQ is used to demonstrate consistent achievement of critical parameters over time. ( under manufacturing conditions)

PQ is ongoing.39

QUALIFICATIONCOMPLETE DOCUMENTATION

Verification of design documentation, including Description of installation and functions Specification of the requirements

Instructions for performance controlOperating proceduresMaintenance instructionsMaintenance recordsTraining of personnel (program and records)Environmental records Discussion on actions if OOS valuesWalking around the plant Finally certification (Sign Off) by Engineering,

User (Production) and QA Heads. 40

VALIDATION

Document act of proving that any procedure, process, system / equipment ACTUALLY leads to expected results.

To ensure that system provides continuously required environmental conditions.

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VALIDATION PARAMETERS

1. Air flow measurement2. Room air changes per hour.3. Filter Integrity Testing (HEPA Leak test)4. Pressure Differentials5. Particulate count measurement6. Recovery test7. Temperature and Relative Humidity 8. Air Flow Pattern9. Microbial Count

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A. PHYSICAL TESTS A1. NON-VIABLE PARTICLE COUNTS

•Equipment•Optical Particle Counter (Discrete Particle Counter)•Air sample is drawn into the instrument & passed through light scattering device. The signal that this generates is electronically processed to display particle counts at different size ranges.

•Sample Volume•1 cubic ft

•Sample Time•1 Min

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Sample Location (ISO 14644) No. of sampling location = NLT Sq. Rt.A

Where A = Area of entrance plan in Sq.Meter

No. of location rounded to nearest higher integer

Minimum location 3 Evenly distributed within the area under

test and at a position related to the working activity (typically at bench height 1m from the floor and NMT 1 Ft from work station.).


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FrequencySch M - 6 MonthlyGMP compliance – Quarterly

Acceptance Criteria

AT REST IN OPERATION

Grade Maximum number of permitted particles per cubic metre equal to or

above

0.5 5.0 0.5 5.0

A 3520 29 3500 29

B 35,200 293 3,52,000 2930

C 3,52,000 2,930 35,20,000 29,300

D 35,20,000 29,300 Not defined Not defined


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A2. PRESSURE DIFFERENTIALS

Introduction Correct degree of overpressure can be

maintained relative to the adjacent areas of lower classification to ensure that air moves from clean areas to less clean areas.

Equipment Electronic manometer (portable and easy to

use), Incline manometer

Sample Location Between adjacent areas connected either by

a door or grille. Frequency of sampling Continuously by gauges / manometer &

recorded daily.


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–Acceptance Criteria> 10 Pa between classified area &

adjacent area of lower classification> 15 Pa between classified area &

unclassified area

–ActionHEPA filter blockageIncrease fan speedIncrease air flow to specific area by

altering dampers


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A3. AIRFLOW VELOCITY

Equipment :- Anemometer. Reading should be taken 10cm from the surface

of filter. Record velocity reading from all the four corners

and the Centre of the filter surface. Repeat twice at each location For Grade A laminar flow workstations, the air

flow rates shall be 0.3 meter per second + 20% (for vertical flows) and 0.45 + 20% (for Horizontal flows)

* No value may deviate from the mean by more than + 20 %


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Air velocity exceeding the stated value may cause excessive air movement & affect work zone protection.

Air velocity below the limit may be insufficient to maintain critical work zone protection.

Action: Deviation indicates blockage of filter Solution : Alteration of fan speed

HEPA filter replacement


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A4. HEPA FILTER INTEGRITY TEST(DOP Test)

Purpose : To confirm that there is no damage to filter, seals and there is no leakage of particles.

Equipment : 1. Aerosol generator (Using Dioctylphthalate) 2. Photometer Scan at 1 inch from filter surface. Traverse at NMT 10Ft. Min. Cover entire range. Make separate passes at peripheries.

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A5. TEMPERATURE & RELATIVE HUMIDITY

Use a sling psycrometer to measure the dry bulb and wet bulb temperature of the air.

Check the wick of the sling psycrometer, it should be always in wet conditions in order to record correct wet bulb temperature.

Sling the psycrometer in air for about a minute’s time and record the dry bulb and wet bulb temperature.

Check the wet bulb depression i.e. difference between dry bulb and wet bulb temperature.

Refer the psycrometric chart to check the relative humidity corresponding to the dry bulb temperature and wet bulb depression.

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ACCEPTANCE CRITERIA

Temperature : NMT 27 degree centigradeHumidity : NMT 55 %

FREQUENCY :Daily

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A6. AIR CHANGE RATE (ACR) Introduction

Conventional clean rooms operate on the principle that the air supplied to the room is of sufficient quantity to dilute or remove the contamination generated within the room.

Measurement of the air supply volume and determination of the air change rate (ACR) is a measure of the frequency of air turnover in the clean room.

This gives some idea as to how quickly contamination may be removed from the clean room provided there is acceptable mixing of air in the room.

The ACR can be determined by measuring the mean air velocity at the supply HEPAs or grilles and calculating the air change rate based on the mean air supply volume or by using a flow measuring hood which collects all of the air from the supply and gives an air supply volume directly.

•a

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EquipmentAnemometer

Sample locationsAt least four positions are tested across the filter or grille face to obtain the mean supply air velocity.

Frequency of samplingSch M - 6 MonthlyGMP compliance – Quarterly 54


Results and interpretation of results

The ACR (per hour) can be calculated using the following formula: ACR = Air supply volume (m³/s) x 3600/ Room volume (m³)

Air Volume = Sum ( Avg. Velocity x Filter area)

Where there is more than one supply HEPA in a room the air supply volume for each filter should be determined and the volumes summed (to give a total air supply volume) before multiplying by 3600 and dividing by the room volume.

To achieve the level of cleanliness in an aseptic room and a clean support room the ACR should be greater than 20 air changes per hour.

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Requirement : Class B = 60, C & D = 20 ACPHAction

• Change the filter• ACR to be rebalanced

B. MICROBIOLOGICAL TESTS

Solid growth media (e.g. settle and contact plates) Soybean Casein Digest Agar medium can be used for both Bacteria & Fungi tested.

The recommended size of solid media is 90 mm in diameter (for settle plates)

55 mm (surface area 25 cm²) for contact plates.

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• Sampling conditions Sampling in the at rest condition may be

continued at an agreed frequency to monitor baseline contamination levels.

The operational conditions and the activities being performed at the time of testing should be recorded.

• Incubation conditions Incubation of samples, inverted, at 20 - 25C

for at least 5 days is suitable for the growth of mould and fungi.

Incubation of samples, inverted, at 30 - 35C for at least 2 days is suitable for the growth of bacteria.


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Total Viable Count(Guidelines)

Conditions : In operation Grade EU Schedule – M

US Air Sampling (90mm / 4 Hrs) (90mm / 2 Hrs) (90mm

/ 4 Hrs) (1000cc)

A <1 <1 <1 <1

B <10 <5 <3 <7

C <100 <50 <5 <10

D <200 <100 <50 <100

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Recommended Limits for microbiological monitoring of clean

areas

REFERENCES

1. “Validation in pharmaceutical industry” ; edited by P.P. sharma ;first edition 2007 ; 169-192

2. “Pharmaceutical Process Validation”; An international 3rd edition; edited by R. A. Nash and A. H. Wachter; 413-432

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GTU QUESTIONS

• Describe validation parameters of HVAC system

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validation of hvac

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