Utility System

Qualification
for
The
Pharmaceutical
Industry
INTRODUCTION

❖Each Pharmaceutical (but also in Cosmetics, Food, Chemical…) industry’s

the manufacturing process uses several support Utility system like Water ,

Compressed Air , Nitrogen Gas , Pure Steam etc.

❖ The Utility System are have different functions and generated and

distributed with centralized installations in the industries.

❖These systems are not necessarily designed and customized for users of a

single production facility, but often serve an entire factory or part of it.
❖Pharmaceutical equipment manufacturing is a highly regulated industry.

❖In pharmaceuticals, critical utilities like water and HVAC (Heating, Ventilation
and Air Conditioning) systems form the backbone of the manufacturing
process.

❖The primary use of a utility system is to help pharmaceutical companies check

the quality and safety of their products and to ensure they comply with the
GMP.

❖To pass inspection, utilities must pass a string of qualitative and quantitative
specifications. Different utility systems have different quality and standard
criteria, designed on the basis of inputs from relevant departments and
organizations as well as manufacturing and engineering provisions.

❖Utility system qualification is designed to ensure that utilities in use conform

to health and safety regulations, as well as pharmaceutical manufacturing
standards and cGMP guidelines.
PHARMACEUTICAL UTILITY SYSTEMS

The most common systems of this type are:

•Process waters (different types)

•Cooling and/or heating fluids (Steam, Water)

•Air conditioning (HVAC systems)

•Compressed Air, Nitrogen

•Burning Gas

•Process Gas (CO2, O2, etc)

•Drinking and Sanitary water

•Fire-Fighting Water

•Vacuum

•Electric power
PHARMACEUTICAL UTILITY SYSTEMS

A Good Working of these systems Ensures Efficiency of Production.

For example,

The sudden lack of steam might impair a heating phase (e.g. during a synthesis

reaction) or a sterilization cycle, with the risk of compromising an entire batch of

production.

The lack of vacuum might block a filtering or drying process, causing damage to

the product.

An accurate preventive maintenance program of the systems can limit such

incidents and subsequent blocks of production.

PHARMACEUTICAL UTILITY SYSTEMS
The production support systems used in pharmaceutical industry can be
classified in three categories as follow:

❖Process Systems (Direct Impact System)

❖Process Support systems (Indirect Impact System)

❖Utility Systems (Non-Impact Systems)

PHARMACEUTICAL UTILITY SYSTEMS

Process Systems (direct impact systems)

They are:

•in direct contact with the product;

•in contact with those materials which will later be transformed in

the product or will be in direct contact with it.

For example -------

process water (Water for Injections, Purified or drinking water) are

generally considered as direct process systems.

PHARMACEUTICAL UTILITY SYSTEMS
Process systems (direct impact systems)
They are always considered critical because they are actually or
potentially in direct or indirect contact with the product.

They must be designed and constructed considering the needs of

product quality and to prevent any contamination to the product itself.

Incorrect design and/or construction methods may leave residues on

the inner surface of equipments or pipes that can cause contamination
of the distributed fluid and, consequently, of the product.

For these reasons, it is often important to have a high degree of surface

finishing, or specific methods of construction (e.g. welding), or cleaning
and keeping systems that can provide the necessary level of protection
against contamination.
PHARMACEUTICAL UTILITY SYSTEMS
Process systems (direct impact systems)

From a GMP point of view, support systems that meet the definition of
" process systems ", should be considered as real raw materials.

Due to the fact that process systems can directly, indirectly or potential
affect product quality, the same degree of control of the production
process should be applied to them, and they must be qualified
according to the classic approach of validation.

It is also important to check the qualitative aspects of the material that

comes to points of use (usually consisting of a fluid), since any chemical
or microbiological contaminants impurities would be found in final or
intermediate products, and compromise quality.
PHARMACEUTICAL UTILITY SYSTEMS
Process support systems (indirect impact systems)

They directly support process operations, but have no contact with the product
or with materials that will be transformed into product.

Some examples of support systems for the process: cooling and heating fluids
that exchange heat with process materials through a surface (heat exchange
jacket applied to reactors, tanks, dryers, etc... shell and tube, double pipe, plate
exchangers, etc…)

The solutions used for equipment and/or machine washing (CIP systems -
Cleaning in Place or manual systems for washing) are generally considered
process support systems, except those used for the final rinsing that are
considered as process fluids.
 PHARMACEUTICAL UTILITY SYSTEMS
Process support systems (indirect impact systems)

The process support systems are not generally considered critical.

In these systems, in general, the qualitative aspects of the fluid have no

relevance. Instead the physical features available at point of use (temperature,
pressure, flow, etc..), and availability for the needs of process in contemporary
condition of use with other points of use have more relevance.

From a GMP point of view, system availability to users has relevance, while the
qualification of plant and functional aspects of the system follow the Good
Engineering Practices (GEP), which are based mainly on the proper design and a
comprehensive "commissioning" of the system (drawings "as built", tracking
changes, testing, SOPs, etc.).
PHARMACEUTICAL UTILITY SYSTEMS
Utility systems (non-impact systems)
They are not in contact with the product or material that will then be
transformed into product;

• They are not customized systems to specific users but distributed with
general networks serving all the users of the factory;

They deal with side effects of an industrial production

such as waste disposal.
Examples of service systems are the systems of drinking water, sanitary
water, electricity.
PHARMACEUTICAL UTILITY SYSTEMS
Utility systems (non-impact systems)

Typically, such systems did not impact on the product quality and, therefore,
are never considered critical.
In this case also, the qualification of the plant and operating systems follows
the good engineering practices (GEP).
Electricity can instead have a critical role (e.g., Loss of data or interruption of
production processes).
In these cases the supply to its customers critical points is ensured by
appropriate systems (automatic back-up generators, un-interruptible power
systems), that are able to overcome possible discontinuity of supply from the
distribution network.
References

EU GMP volume 4
Annex 15 - “Qualification and Validation”

ISPE Baseline Engineering Guides

Vol. 5 -“Qualification and Validation”(2001)

PIC/S
PI 006/2 - “Recommendations on VMP, IQ and OQ, non sterile process validation,
cleaning validation”(2004)

FDA
“General Principles of Process Validation”(1987)
 What is the Systems Design & Validation
Approach for Utility System
Qualification and Validation of the manufacturing and process systems,

facility and equipment is intended as the documented verification that they,

as installed, comply with the approved design, operate within the approved

functional specification and are consistently able to perform the scopes they

has been intended for.

 PURIFIED WATER
SYSTEM
&
DISTRIBUTION
SYSTEM VALIDATION
 References
USP
<1231> - “Water for Pharmaceutical Purposes ”

FDA
“Guide to Inspections of High Purity Water Systems”
(1993)

ISPE Baseline Engineering Guides

Vol. 4 & APPENDIX -“Water and Steam Systems”(2001)

ISPE Best Practice Guides

“Commissioning and Qualification of Pharmaceutical
Water and Steam
Systems”
 User
Requirements
Specifications
URS

For Purified Water System

HOW TO CREATING A URS FOR A PURIFIED
WATER SYSTEM
❖A User Requirement Specification (URS) is issued by the user to define the
system requirements. Issuing a URS serves many purposes.

For example it:

➢Specifies the system’s parameters, regulations, and standards

➢Establishes the base for pricing the new system

➢Establishes the base for design, manufacturing, and validation

➢Specifies deliveries

Try to keep the system requirements as high level as possible.

Avoid adding unnecessary detail or increasing the requirements, which can
increase the cost.
❖URS Content

➢The requirements of a purified water treatment system are specified in the

various regulations and standards, so don’t spend time repeating this
information in the URS.

➢To optimize your URS, focus on the parameters for the system and the
regulations and standards that will be applicable. Including contradicting
requirements can lead to confusion, so develop clear concise requirements
that are unambiguous.

➢It is not the amount of pages that decide the quality of your URS but how
specific and easy to read and understand it is for the different groups involved
in design, manufacturing, and validation.
❖Process Requirements

Process requirement should include:

➢How much water is needed

➢The required capacity of the system

➢How much water user point requires

➢What user points need to able to use water at the same time

➢Usage priorities if several user points need water at the same time (worst
case scenario)

➢The water quality of the system (whether it should fulfill the USP or the Ph.
Eur. monograph for PW. both, or any other pharmacopeia).

➢Materials that come into contact with WPU should be appropriate and its
Includes: pipework , valves and fittings , seals , diaphragms and Instruments
❖User Prerequisites

Include the following:

➢Maximum available utilities if there are limitations (incoming water,

compressed air, black steam, electrical load, drain capacities, etc.) so
engineering will design it properly.

➢A water analysis report of the incoming water so engineering can design and
size pre-treatment of the system for optimal operation. Attach water analysis
reports from different seasons of the year so the changes in water quality can
be considered

➢Room layout with measurements for where the system will be located

➢Interface points for each utility and the PW treatment system

❖Mechanical Requirements

Include the following:

➢Pipe standard, if applicable (for instance, DIN or ASME)

➢Use of sanitary components and valves on the product-wetted side (no

threaded connections on the product wetted side)

➢Use of sanitary connections such as tri-clamp connections on the product-

wetted side

➢Welding requirements according to current ASME BPE standard or European

equivalent standards

➢Air break to floor drains to prevent back flow back up to the system

➢Dead-leg specifications according to ASME BPE or 3di (calculated as

maximum length of the branch equal to 3 x the inner diameter of the branch)
➢Slope of purified water distribution piping (often 0.5%)

➢Drain-ability of the distribution piping, which must be sloped to low points

where it’s possible to drain the water with a valve. Many times the distribution
pump will represent a low point and would also need to be drainable and
supplied with a valve to accommodate that.

You should not need to specify drain-ability and slope requirements for the PW
treatment system itself. Since you will never steam sterilize it you will not have
to worry about any condensation in the lines. If the system won’t be used for a
longer time or “stored”, it would be filled with preservation chemicals and not
emptied. Note also that several components in this process are not drainable
(for instance, RO vessels and CEDI modules). Many times pre-treatment
vessels have both an inlet and outlet on the top.
❖Electrical Requirements

Applicable European Directives, NEMA Standards, and/or UL Standards are

required depending on where the system will be installed.

❖Automation/Software Requirements

The system must be provided with design documents specifying how it will
operate and the components and structure of the automation:

•Functional Specification

•Hardware Design Specification

•Software Design Specification

The program must be logically structured and must be provided with clear
comments and free of dead code.
Tests typically include:

➢A software review before implementation in the water system

➢Electrical inspections and tests of all inputs and outputs

➢Software testing according to the Functional Specification

➢The back-up of the software must be provided.

❖FDA Part 11 Compliance

FDA 21 CFR Part 11 requires that a water system’s software have an audit trail
capability, data storage, individual passwords, and so on. Note that a PLC
which is commonly used in water treatment systems will not have the feature
of tracking changes, store them in a log and refer to the specific user who
implemented the change and show at which time it happened.

For FDA Part 11 compliance there is special software available.

❖Quality Assurance

The following need to be specified:

➢Quality control activities

➢Design review

➢Required manufacturing inspections

➢Validation requirements

➢Responsibilities and supervision of contractors

❖Safety Requirements

➢If the system is going to be installed in the European Union it must comply

with the Machinery Directive. Operator safety should be considered, especially

for hot distribution systems and during hot water sanitizations. Requirements

regarding insulation, automatically interlocked points of use (POU),

sanitizations scheduled to times when production is not working, and warning

signs/lamps can mitigate burning risks.

➢Site or Company Specific Requirements

❖Site- or company-specific requirements might include:

➢Preferred instruments list

➢Preferred components list

➢Equipment signs specification

➢Site specific tag numbering system

➢Special work procedures for contractors working on the site

➢Ergonomic requirements on design (for instance, height specifications for

sample ports)

➢Suppliers normally have a “standard” design that fulfils most regulations. Site-

specific requirements, in general, increase the cost of the system as custom

requirements affect the standard and imply change.

FACTORS TO CONSIDER IN URS FOR PURIFIED WATER :
❖ feed-water quality (and variation over seasons) and water-
quality

❖ specification;

❖ quantity of water required;

❖ sequence of purification stages and energy consumption;

extent of pre-treatment needed;

❖ performance optimization;

❖ appropriately located sampling points;

❖ appropriate instrumentation to measure parameters such as

flow, pressure, temperature, conductivity, pH and total organic
carbon.
 The purification processes (pre treatments and final
purification) must produce water of the required quality

&

The storage system and the distribution of the water for

pharmaceutical use must not alter the quality of the water in
the points of use.
 DESIGN SPECIFICATIONS

✓ Building drawings of the main equipment

✓ Selection of the equipment and standard instruments

✓ Piping dimensioning

✓ Building piping sketches (welds position, sloops)

✓ P&I scheme for building

✓ Implementation and customization of the software

✓ Etc…
 Design Specifications

European GMP – ANNEX 15

“The first element of the validation of new facilities, systems or equipment could

be design qualification (DQ)”

“The compliance of the design with GMP should be demonstrated and

documented”
The Commissioning Phase

Commissioning activities
•Verification of the system conformity upon the specs and the purchase order
•Supplier documentation collection, control and adequacy verification
•FAT and SAT non conformities resolution verification
•As-Built drawings (P&ID, electrical schemes, isometric sketches, etc...) on field
verification
•Verification of the system components upon the cGMP requirements
•Initial calibration of the critical instrumentation
•Operators’ training
•Operational tests of the components (engines, sensors, controllers)
•Functional test of all the operative range of the system (reliability and stability of the
system functions)
•Set-ups, PID control algorithms, thresholds, etc. Optimization
•Design documentation updating, changes documenting
•Alarms and interlocks tests
•Control system I/O test
•Operational sequences test
•Etc….
 The importance of the “as built” drawings

In the review of a validation report, or in the validation of a high purity water system,
there are several aspects that should be considered.
Documentation should include a description of the system along with a print.

The drawing needs to show all equipment in the system from the water feed to points

of use. It should also show all sampling points and their designations.
If a system has no print, it is usually considered an objectionable condition. The
thinking is if there is no print, then how can the system be validated?

How can a quality control manager or microbiologist know where to sample? In those

facilities observed without updated prints, serious problems were identified in these

systems.

The print should be compared to the actual system annually to insure its accuracy,

to detect unreported changes and confirm reported changes to the system.

Rif.: FDA Guide to Inspections of High Purity Water Systems (1993)

2) DESIGN QUALIFICATION:

•ONCETHE URS IS APPROVED AND GRADE/TYPE OF WATER IS BEING

DECIDED, NECESSARY WATER TREATMENT SYSTEM MUST BE DESIGNED
SO THAT IT GENERATES THEDESIRED QUALITY OF WATER ( E.G. PURIFIED
WATER, WFIETC.)

•THE FIRST STEP IS TO QUALIFY ALL THE COMPONENTS OF A WATER

GENERATION AND DISTRIBUTION SYSTEM.

•EQUIPMENT (COMPONENTS OF WATER SYSTEM) SELECTION IS BASED

ON URS.
STORAGE TANKS / STORAGE VESSELS :

•BASED UPON THE REQUIREMENT, CAPACITY OF STORAGE TANKS SHALL

BE PROCURED.

Storage vessels should be appropriate for their intended use .

•STORAGE TANKS ARE PREFERABLY MADE OF SS316L, HOWEVER HDPE

TANKS ARE ALSO USED WHERE STORAGE AT AMBIENT TEMPERATURE IS
SUFFICIENT.

•STORAGE TANKS SHOULD BE PROVIDED WITH VENT FILTERS (1.0 MICRON)

TO PREVENT MICROBIAL CONTAMINATION.
STORAGE TANKS / STORAGE VESSELS :
STORAGE TANKS / STORAGE VESSELS :
As a minimum, the following should be considered:

• the design and shape

• the provision for drainage of water from the vessel, when required

• construction materials

• capacity, including buffer capacity, between the steady state, water

generation rate and the potentially variable simultaneous demand from user
points, short-term reserve capacity in the event of failure of the water-
treatment system or the inability to produce water (e.g. due to a
regeneration cycle);

• prevention of stagnant water in the vessel (e.g. the headspace where

water droplets can accumulate) and the need for the use of a spray-ball or
distributor devices to wet the inner surfaces of the vessel
STORAGE TANKS / STORAGE VESSELS :

As a minimum, the following should be considered: Conti……

• limitation and design of nozzles within the storage vessels;

• the fitting of bacteria-retentive, hydrophobic vent filters which are tested

for their integrity at appropriate intervals;

• the fitting of sanitary design bursting discs provided with external rupture
indicators to ensure that loss of system integrity is detected;

• the design and sanitization, as required, of level indicators;

• the design and location of valves, sampling points and monitoring devices
and sensors; and
STORAGE TANKS / STORAGE VESSELS :

As a minimum, the following should be considered: Conti……

• the need for heat exchangers or jacketed vessels. Where these are used,
double tube sheet or double plate heat exchangers should be used, ideally
with the utility pressure less than the system pressure to minimize the risk of
contamination.
PIPINGS:
•PIPING'S ARE MADE OF SS316L EVEN SOMETIMES SS304L BASED UPON
THEAREA OF USAGE AND TYPE OF WATER.

•GLASS OR POLYCARBONATE IS UTILIZED WHEN TRANSPARENCY IS

REQUIRED, PVC FOR AMBIENT TEMPERATURE OPERATIONS

•IT IS ALSO IMPORTANT TO REMOVE THE “DEAD LEGS” TO PREVENT

CONTAMINATION AT SUCH SPACES AND WELD ALL THE JOINTS PROPERLY.
VALVES:

•GATE, BALL, BUTTERFLY AND DIAPHRAGM ARE THE TYPE OF VALVES

UTILIZED IN THE WATER SYSTEMS

•FOR PREPARING WATER FOR INJECTION AND PURIFIED WATER

DIAPHRAGM VALVE IS USED BECAUSE OF IT’S COMPLETE CONTAINMENT FOR
IN PROCESS MATERIALS AND IT IS EASY TO CLEAN

•PLUNGER VALVES ARE USED WHEN COMPLETE CONTAINMENT IS NOT

REQUIRED AND THEY OFFER BETTER INSTALLATION AND OPERATIONAL
QUALITIES THAN DIAPHRAGM VALVES.
VALVES:
VALVES:
PUMPS:

•THE DESIGN OF THE PUMPS SHOULD BE SANITARY THAT PREVENTS ANY

TYPE OF CONTAMINATION.

•CENTRIFUGAL, ROTARY LOBE, PERISTALTIC AND DIAPHRAGM PUMPS ARE

COMMONLY USED EASILY CLEANABLE PUMPS USED IN PHARMACEUTICAL
INDUSTRY.
HEAT EXCHANGERS:

•THESE ARE DESIGNED TO PREVENT DISTILLATE CONTAMINATION FROM

FEED WATER.
•TWO COMMON TYPES OF HEAT EXCHANGERS ARE: DOUBLE TUBE SHEET
AND CONCENTRIC TUBE DESIGN. OTHER THAN THESE DESIGNS THE
PRESSURE DIFFERENTIAL SHOULD BE MAINTAINED ANDMONITORED IN
SUCH A WAY THAT HIGHER PRESSURE IS CONSTANTLY MAINTAINED ON
THE DISTILLATE SIDE.
PRESSURE GAUGES:

•DIAPHRAGM STYLE, PRESSURE GAUGES ARE USED COMMONLY AND WHEN

THEY ARE INSTALLED INPIPING, THE DIAMETER SHOULD BE LESS THAN 6D.
FILTERS:

•WATER FILTERS ARE FITTED AT DIFFERENT LOCATIONS THROUGH OUT THE

WATER SYSTEM LOOP LINE AND EACH ONE OF THEM HAS SPECIFIC
FUNCTIONS. COMMON USES INCLUDE REMOVAL OF UNDISSOLVED SOLIDS
AND BACTERIAL CONTAMINANTS FROM FEED WATER.

•TYPES OF FILTERS: HYDROPHOBIC FILTERS (1 MICRON), CARBON AND

RESIN BEDS FILTER (10-15 MICRON), MEMBRANE FILTER (0.2 MICRON). THEY
SHOULD BE ARRANGED IN PROPER ORDER SO AS THE WATER SYSTEM
WORKS EFFICIENTLY.
DEIONIZERS:

•REMOVES DISSOLVED SOLIDS FROM THE FEED WATER. SINGLE BED

RESINS (CATIONIC OR ANIONIC) OR MIXED BED RESINS (CATIONIC AND
ANIONIC) ARE USED TO REMOVED EXCESS IONS THAT MAY IMPOSE
PROBLEMS IN THE DOWNSTREAM OF THE WATER SYSTEM.
DISTILLATION UNIT: (if for Water for Injection )

•USED TO REMOVE SOLIDS THAT ARE NOT REMOVED BY DEIONIZERS OR RO

UNITS. THESE UNITS PROVIDE MICROBIAL PURIFICATION THROUGH
THERMAL VAPORIZATION, MIST ELIMINATION AND CONDENSING.

•AREAS OF CONCERN FOR THESE SYSTEMS INCLUDE CARRY-OVER

IMPURITIES, EVAPORATOR FLOODING, STAGNANT WATER, PUMP AND
COMPRESSOR DESIGN AND CONDUCTIVITY VARIATIONS DURING START-UP
AND OPERATION
 Installation Qualification

The Below Mentioned points are to be verified during the Installation

Qualification
❖Compliance with installation and startup procedures.
❖Supplier Manuals.
❖Review of all Components Certifications
❖Drawings « as built»: P&ID – electric schemes – isometric sketch– etc….
❖Tagging of all the system components, of the instruments and of the support
utilities.
❖Availability of the samples point
❖Identification of the critical instrument and the formalization of a periodic
calibration control program.
❖Standard Operating Procedures (SOP) for the use of the system, for its
cleaning, its maintenance, the calibration of the critical instruments, etc., (at least
in draft).
❖List of the critical spare parts.
❖Significant characteristics of the system, and of its significant components with
the recording of the principal data (manufacturer, type, model, serial )
 Installation Qualification
Tests to be performed during system installation
✓Tracks and Slopes

Isometric sketch for the slope verification

 Installation Qualification
Tests to be performed during system installation

✓Materials in contact with water

✓Welds / Orbital Welding

 Installation Qualification
Tests to be performed during system installation

✓Passivation

✓Boroscopic Inspections
 Installation Qualification
The below mentioned documentation / reports are collected during
The Installation Qualification ------

❖ Building sketches as-built

❖ Certifications of the materials that come in contact with water

❖ “Welding book”, welding procedures, welding samples, identification of

the used orbital weldings.

❖ Procedure and certificate of passivation

❖ Documentation of the boroscopic inspections

 Operational Qualification

Objective

To guarantee that the system is ---------

adequate to serve different User Points ,

satisfying the needs of the process from the quantity point of view (Flow-
rate, temperature, pressure, etc…)

and from the quality point of view (chemical- physical and microbial
characteristics).
 Operational Qualification
VERIFICATION AND TESTS

❖Approved SOPs must be available (at least in draft: following the results of the
CQ tests it is possible that is evidenced the need to include adequate corrections
applied to the SOPs following the workflow for the approval).

❖Utilities (clean steam, industrial steam, cooling water, compressed air, electric
energy, etc...) must be completely operative and able to maintain the established
supplying specs (temperature, pressure, quantity, electric power, etc.).

❖Critical Instrument for the control of the system and that used for the OQ
tests must be calibrated in compliance to the procedures approved and
referable to the Metrology recognized Institution.

❖Analytical Methods as a support for the tests as in the OQ protocol must be

available and duly qualified.
 OPERATIONAL QUALIFICATION
Verification and Tests
❖Control system verification tests :
• I/O Signals
• Alarms
• Operation sequences
• Interlocks
• Power fail and system re-start up
• Passwords
• Functionality of the operator interface
• Printouts and video images
• Audit trail
• Functioning of the loops/regulation algorithms, etc.
❖Flow rate at the points of use.
❖Water speed in the loop (choosing the worst case, e.g. in the return pipe
under conditions of maximum sampling)
❖Temperature in the distribution loop and at points of use.
❖Sterilization cycle verification and temperature mapping.
 PERFORMANCE QUALIFICATION
Objective

To verify and give documental evidence that the system can supply water to
the user points, in a continuous and reproducible way, under the working
conditions detailed in the operating procedures, at the operation temperature
and respondent to the qualitative specs (chemical – physical and microbial)
already set, maintaining the values of the critical parameters of functioning of
the system within the pre established values.
The tests must include all the cases of variability of the factors that can have a
potential influence on the water quality (i.e. those induced by seasonal cycles)
and/or taking into consideration situations of worst-case for the performance
of challenge tests.
 PERFORMANCE QUALIFICATION
Verifications and Test

❖Systems of critical utilities that have been qualified.

❖SOPs for the operation and the maintenance of the system approved in a final

form.

❖Critical Instruments, for the control of the system and that used for the PQ

test, calibrated in accordance to the procedures approved and referable to a

metrology recognized institution (NAT).

❖Analytical Methods for the tests included in the PQ protocol qualified

❖Test to verify the efficacy of the sanitization system (with the biological

indicators or other challenge systems – optional).

 PERFORMANCE QUALIFICATION
Phase 1

Phase I should cover a period of at least two weeks. The system should be
monitored intensively for its performance. The system should operate
continuously without failure or performance deviation. Normally, water should
not be used for FPP manufacturing during this phase.
The procedures and protocols for Phase I should cover at least the following
activities and testing approaches:

❖chemical and microbiological testing in accordance with a defined plan

❖sample, test and monitoring of the incoming feedwater daily to verify its
quality
❖sample, test and monitoring after each step in the purification process
❖sample, test and monitoring at each point of use and at other defined
sample points
❖develop the appropriate operating ranges
❖develop and finalize the operating, cleaning, sanitizing and maintenance
procedures
❖demonstrate the production and delivery of product water of the required
quality and quantity
 PERFORMANCE QUALIFICATION
Phase 1 Continued ……….

❖use and refine the standard operating procedures (SOPs) for operation,
maintenance sanitization and troubleshooting

❖verify provisional alert levels

❖develop and refine test-failure procedure

 PERFORMANCE QUALIFICATION
Phase 2

Phase 2 should cover at least a further test period of two weeks. The system
should be monitored while deploying all the refined SOPs after the
satisfactory completion of Phase 1.
The sampling program should be generally the same as in Phase 1. The use of
the water for FPP manufacturing purposes during this phase may be
acceptable, provided that both commissioning and Phase 1 data demonstrate
the appropriate water quality and the practice is approved by QA.

The approach should also:

❖demonstrate consistent operation within established ranges; and

❖demonstrate consistent production and delivery of water of the required

quantity and quality when the system is operated in accordance with the
SOPs.
 PERFORMANCE QUALIFICATION
Phase 3

Phase 3 should cover at least a further 12 months after the satisfactory

completion of Phase 2. The sample locations, sampling frequencies and tests
may be reduced to the normal routine pattern based on the established
procedures proven during Phase 1 and Phase 2.
After completion of the qualification and validation programme of Phase 3, a
system review should be undertaken. This may include the trending of
results and the evaluation of system performance capability. The
appropriate action should be taken where identified.

Water can be used during this phase (e.g. for manufacturing and cleaning)
which has the following objectives

• to demonstrate a reliable performance over an extended period of time;

and

• to ensure that seasonal variations are evaluated.

 CONTENT
❖ Introduction

❖ How Compressed Air System(CAS) works?

❖ Test functions and Acceptance criteria

❖ Validation protocol :

✓ Installation Qualification (IQ)

✓ Operational Qualification (OQ)

✓ Performance Qualification (PQ)

68
 Introduction

What is Compressed Air?

❖ Commonly called Industry's Fourth Utility

❖ Air that is condensed and contained at a pressure that is greater

than the atmosphere.

❖ The process takes a given mass of air, which occupies a given

volume of space, and reduces it into a smaller space. In that space,
greater air mass produces greater pressure. The pressure comes
from this air trying to return to its original volume.

❖ It is used in many different manufacturing operations. A typical

compressed air system operating at 100 psig (7 bar) will compress
the air down to 1/8 of its original volume. (figure CA1-1).

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 Compressed air is an important component of pharmaceutical
manufacturing facilities.

 It provides many of the air types necessary for a manufacturing

facility to function, including: breathing air , motive air for machines
, process air , analytical air and Product Direct Impact , or "cGMP" air.

 The application for which the compressed air will be used will dictate
the level of air quality that is appropriate for use.

 There are two main categories of applications: Direct Impact

Systems and Indirect Impact System .

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Direct Impact Systems :

 The systems will have direct contact with the product

 The system will provide an excipient, or produce an ingredient or

solvent

 The system will be used in cleaning or sterilizing

 The system will preserve product status

 The system will produce data which is used to accept or reject the
product

 The system will be a process control system that can affect product
quality and there will be no system for independent verification of
control system performance
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Indirect Impact or No Impact Systems :

 The system will not contact the product or materials that ultimately
become part of the product

 The systems are generally site or building systems and are not
tailored specifically to aseptic manufacturing facilities

 The systems will deal with a side activity of the manufacturing

process (such as waste disposal)

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How the Compressed Air System(CAS) works?

 Each component in a typical system helps to deliver clean, dry,

compressed air that’s free of pressure fluctuations at its point of
use

 If any component is working inefficiently, the system’s

performance suffers and operating costs rise

 Like any high-pressure system, they are prone to leaks or other

failures that can result in lower performance

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Components of the CAS system

 Inlet filter:

Removes particles from the air entering the compressor

 Compressor :

Compresses air to a small volume, increasing the pressure

(Reciprocating compressors are frequently used)

 Motor : Drives the compressor

 Compressor Controller :

Directs the compressor’s output and it may be microprocessor,

electromechanical or pneumatically based

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 Aftercooler :

Compression leaves the air hot and wet. The aftercooler lowers
the temperature of the air leaving the compressor and removes
water that condenses as the air cools

 Separator : Removes liquids from the compressed air

 Receiver : Stores a large reserve of compressed air to maintain a

smooth flow to the plant

 Air line Filter :

Removes solids and liquids from the compressed air stream. Can
be placed throughout the system

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• Dryer :

❖ Helps to eliminate any remaining moisture in the compressed air by

using either a refrigerated condenser or a desiccant

❖ Refrigerated condensers cool the air to condense water vapours

into a liquid that is then drained from the system. Desiccants are
powders or gels that remove water by absorbing it

• Condensate Trap :

Collects and discharges liquid that condenses out of the air stream
Integral part of aftercoolers, dryers and separators

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 Distribution Piping :

Links the components. It distributes the air from a main header to

branch lines and sub headers to drop points connected to
individual tools

 Pressure Regulator :

Controls air pressure and flow at individual points of use

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Test Functions :
1. Perform Installation Qualification

2. Perform general operational controls verification testing

3. Operate system throughout the range of operating design

specifications or range of intended use

4. Verify that the compressed air system is capable of supplying

pressurized compressed air to all use points. Perform an
operational test of the distribution system and pressure
regulators by monitoring the pressure output at the respective
use points

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5. Perform a capacity test to verify that the system is capable of
supplying the required gas, pressure, and flow rate at each use
point

6. Verify that in-line filters are integrity tested. Confirm that all
documentation clearly indicates acceptable test results

7. Perform dew point measurement

8. Perform hydrocarbon content measurement

9. Perform viable particulate count, microbiological at critical use

points after sterile filters (refer to Federal Standard 209E)
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10. Identification of oxygen content

11. Record the range of all process or equipment parameters (set

points, flow rates, timing sequences, concentrations, etc.)
verified during Operational and Performance Qualifications
testing

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Acceptance Criteria :

1. The system is installed in accordance with design specifications,

manufacturer recommendations and cGMPs. Instruments are
calibrated, identified, and entered into the calibration program

2. General controls, alarms, and interlocks operate in accordance

with design specifications

3. The system operates in accordance with design specifications

throughout the operating range or range of intended use

4. The compressed air distribution system must consistently deliver

pressurized compressed air to the use points at the design
pressure as specified
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5. All in-line filters are integrity tested and qualify per manufacturer’s
operating specifications

6. Dew point must be <0° or lower

7. Hydrocarbon content must be ≤ 1 ppm

8. Viable particulate must be ≤ 1.0 cfu/10 ft3

9. Nonviable particulate counts must be ≤ 100/ft3 of 0.5μ or larger at

all critical use points

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Method for Dew Point and Oil Content

 As per Air Quality Standards ISO 8573 and Filter Standard ISO 12500 for
compressed air there are nine part to it as follows :

❖ Part 1 - Contaminants and Purity classes

❖ Part 2 - Test methods for aerosol oil content

❖ Part 3 - Test methods for the measurement of humidity

❖ Part 4 - Test methods for solid particle content

❖ Part 5 - Determination of oil vapor and organic solvent content

❖ Part 6 - Test methods for gaseous contaminant content

❖ Part 7 - Test method for viable microbiological contaminant content

❖ Part 8 - Test methods for solid particle content by mass concentration

❖ Part 9 - Test methods for liquid water content

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Validation Protocol :
 It includes :
✓ Installation Qualification
✓ Operational Qualification
✓ Performance Qualification
✓ Final Report

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Installation Qualification (IQ)

 This section establishes documented verification that key

aspects of equipment adhere to approve design intentions and
recommendation of manufacturer have been suitably consider

 In addition to the common requirements outlined in the

"General" section, the following are required for Distribution
systems

 The piping should be supported, labeled, and sloped to drain

completely

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Contd…

 Materials of construction will vary with gas type, and must agree
with specification

 Verify that in-line filters can be integrity tested

 Verify that the systems have been thoroughly cleaned and dried
before operation

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Operational Qualification

 This section Establishes that there is a documented verification

that the installed system functions as a specified and that there is
a sufficient documentary evidence to demonstrate this

 The OQ protocol will outline tests to study capacity and pressure

during estimated minimum and maximum use

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Contd…

 All use points supply the specified pressure prior to any pressure
reducing valves or equipment

 All use point supply the volume of gas as specified

 Each peak load use point as specified by use or equipment

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Performance Qualification

 This section gives documented verification that the

equipment performance in its normal operating environment
is consistently exactly as specified in User Requirement
Specification (URS)

 Testing will include viable and total particulate counts, dew

point, hydrocarbon analysis, and purity analysis

 Each point of use will be tested at least three times over 10

working days. Every use point of the system must be tested
several times over the course of the study.

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Contd…

• Hydrocarbon Monitoring should show less than 0.2 mg/m3 (25

mg/125 liters) detected. (the lower limit of a Dragger tube)

• The highest total particulate count from the five one-minute runs
must meet class 100 or EC Class A criteria

• Viable Monitoring (not needed of integrity tested final filter is in

place) less than 0.03 CFU/ft3 or less than 1 CFU/m3

• Since the gas is field sampled under non-sterile conditions, a few

sporadic, individual, tests may fail. Persistent test failures with
any individual test, or group of tests, will indicate a system
failure

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Contd…

 The dew point of compressed air less than or equal to -10°C, or

less than the lowest temperature to which the system is
exposed

 Identity and Purity (Nitrogen) Not less than 99.0% nitrogen by

volume. Not more than 0.001% Carbon Monoxide. No
appreciable odor

 Identity and Purity (Oxygen) Not less than 99.0% Oxygen by

volume. No appreciable odor

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