VALIDATION MASTER PLAN (Repaired)

VALIDATION MASTER PLAN
Document No. QA/VMP/01 Revision No. 00 Page No. Page 1 of 56
Department Quality Assurance Effective Date
INTRODUCTION OF HPLC :-
High performance liquid chromatography ,or HPLC,is the most common analytical separation tool and is used
Page | in many aspects of drug manufacture research.HPLC is used for:1..The separation of a compound involves its
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physical nteraction with a stationary phase and a mobile phase.
PRINICIPAL :-
HPLC works on the principal of the separation of the material according to their molecular weight and polarity.
When a mixture of compounds is passed through the, it HPLC column, it gets separate into its components before it
exits from the column.
HPLC USED FOR: -

High-performance liquid chromatography or high-pressure liquid chromatography(HPLC) is a chromatography
method that is used to separate a mixture of compound in analytical chemistry and biochemistry so as to identify,
quantify or purify the individual compound of the mixture.
HPLC APPLICATION:-
HPLC is a high performance liquid chromatography.
High pressure liquid chromatography.
High priced liquid chromatography.
It is column chromatography.
It is liquid chromatography.
It is modified from a gas chromatography.it is application for both volatile as well as non volatile compound.
It is having a high resolution and separation capacity.
It is used as qualitative as well as quantitative analysis.
High performance liquid chromatography(HPLC) is a chromatography technique used to separate a mixture of

compound in analytical chemistry and biochemistry with the purpose of identifying, quantifying or purifying the
individual component of the mixture.
Types of HPLC:-
1. Normal Phase HPLC

This method separates analytes on the basis of polarity. NP-HPLC uses polar stationary phase and non-polar mobile
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phase. Therefore, the stationary phase is usually silica and typical mobile phases are hexane, methylene chloride,
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chloroform, diethyl ether, and mixtures of these.
Polar samples are thus retained on the polar surface of the column packing longer than less polar materials.
2. Reverse Phase HPLC

The stationary phase is nonpolar (hydrophobic) in nature, while the mobile phase is a polar liquid, such as mixtures
of water and methanol or acetonitrile. It works on the principle of hydrophobic interactions hence the more
nonpolar the material is, the longer it will be retained.
3. Size-exclusion HPLC
The column is filled with material having precisely controlled pore sizes, and the particles are separated according to
its their molecular size. Larger molecules are rapidly washed through the column; smaller molecules penetrate inside
the porous of the packing particles and elute later.
4. Ion-Exchange HPLC
The stationary phase has an ionically charged surface of opposite charge to the sample ions. This technique is used
almost exclusively with ionic or ionizable samples.
The stronger the charge on the sample, the stronger it will be attracted to the ionic surface and thus, the longer it
will take to elute. The mobile phase is an aqueous buffer, where both pH and ionic strength are used to control e
Instrumentation of HPLC:-
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As shown in the schematic diagram in Figure above, HPLC instrumentation includes a pump, injector, column,
detector and integrator or acquisition and display system. The heart of the system is the column where separation
occurs.
1. Solvent Resorvoir
Mobile phase contents are contained in a glass resorvoir. The mobile phase, or solvent, in HPLC is usually a mixture
of polar and non-polar liquid components whose respective concentrations are varied depending on the composition
of the sample.
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2. Pump
A pump aspirates the mobile phase from the solvent resorvoir and forces it through the system’s column and
Page | detecter. Depending on a number of factors including column dimensions, particle size of the stationary phase, the
6 flow rate and composition of the mobile phase, operating pressures of up to 42000 kPa (about 6000 psi) can be
generated.
3. Sample Injector
The injector can be a single injection or an automated injection system. An injector for an HPLC system should
provide injection of the liquid sample within the range of 0.1-100 mL of volume with high reproducibility and under
high pressure (up to 4000 psi).
4. Columns
Columns are usually made of polished stainless steel, are between 50 and 300 mm long and have an internal
diameter of between 2 and 5 mm. They are commonly filled with a stationary phase with a particle size of 3–10 µm.
Columns with internal diameters of less than 2 mm are often referred to as microbore columns. Ideally the
temperature of the mobile phase and the column should be kept constant during an analysis.
5. Detector
The HPLC detector, located at the end of the column detect the analytes as they elute from the chromatographic
column. Commonly used detectors are UV-spectroscopy, fluorescence, mass-spectrometric and electrochemical
detectors.
6. Data Collection Devices

Signals from the detector may be collected on chart recorders or electronic integrators that vary in complexity and in
their ability to process, store and reprocess chromatographic data. The computer integrates the response of the
detector to each component and places it into a chromatograph that is easy to read and interpret.
QUALITY CONTROL:-
Various definitions exist regarding QC, as it is often referred to, but the ISO 9000 standard’s definition is the most
important for organisations wanting to ensure compliance with the standard’s requirements. The definition
accordingly defines quality control as an integral part of an enterprise’s quality management aimed at achieving the
requirements for quality. The definition may be confusing, even if you have attended an introduction to quality
control training session. We thus take a closer look below.
An effective quality control approach focuses on controls, the setting up and managing of processes according to
specific quality control measures, and measurement of performance. It includes the identification of relevant
documents and records, and also focuses on training to ensure competence in handling, managing and providing
products or services. It furthermore focuses on personnel, motivation, the overall organisational culture and the
integrity of the employees within the organisation.
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Spectrophotometer Principle:-
The spectrophotometer is an instrument which measures an amount of light that a sample absorbs. The
spectrophotometer works by passing a light beam through a sample to measure the light intensity of a sample.
These instruments are used in the process of measuring color and used for monitoring color accuracy throughout
production. They are primarily used by researchers and manufacturers everywhere. The major Spectrophotometer
Applications are limitless as they are used in practically every industrial and commercial field, however it finds its
major applications in liquids, plastics, paper, metals and fabrics. This helps in ensuring that the color chosen remains
consistent from its original conception to the final, finished product.
A spectrophotometer is made up of two instruments: a spectrometer and a photometer. The spectrometer is to

produce light of any wavelength, while the photometer is to measure the intensity of light. The spectrophotometer
is designed in a way that the liquid or a sample is placed between spectrometer and photometer. The photometer
measures the amount of light that passes through the sample and delivers a voltage signal to the display. If the
absorbing of light change, the voltage signal also changes. Spectrophotometers come in a variety of shapes and sizes
and have multipurpose uses to them. The different types of spectrophotometers available are all different from one
another, based on their application and desired functionality. The most popular spectrophotometers are 45 degree,
sphere and multi-angle spectrophotometers. Another closely related concept is , that simply measures the
absorption of light from its source and the intensity of light as well.
Electrical conductivity meter:-

An electrical conductivity meter (EC meter) measures the electrical conductivity in a solution. It has multiple
applications in research and engineering, with common usage in hydroponics, aquaculture, aquaponics,
and freshwater systems to monitor the amount of nutrients, salts or impurities in the water.
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Principle:-
Common laboratory conductivity meters employ a potentiometric method and four electrodes. Often, the electrodes
are cylindrical and arranged concentrically The electrodes are usually made of platinum metal. An alternating
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current is applied to the outer pair of the electrodes. The potential between the inner pair is measured Conductivity
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could in principle be determined using the distance between the electrodes and their surface area using Ohm's
law but generally, for accuracy, a calibration is employed using electrolytes of well-known conductivity.
Industrial conductivity probes often employ an inductive method, which has the advantage that the fluid does not
wet the electrical parts of the sensor. Here, two inductively-coupled coils are used. One is the driving coil producing
a magnetic field and it is supplied with accurately-known voltage. The other forms a secondary coil of a transformer.
The liquid passing through a channel in the sensor forms one turn in the secondary winding of the transformer. The
induced current is the output of the sensor.
Another way is to use 4 –electrode conductivity sensors that are made from corrosion resistant materials. Benefit of
4 –Electrode conductivity sensor compared to inductive sensor is scaling compensation and ability to measure low
(below 100 µS/cm) conductivities (a feature especially important when measuring near 100% hydrofluoric acid).
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Temperature dependence:-
The conductivity of a solution is highly dependent, therefore it is important to either use a temperature
compensated instrument, or calibrate the instrument at the same temperature as the solution being measured.
Unlike metals, the conductivity of common electrolytes typically increases with increasing temperature.
VALID CALIBRATION:-
Caibrated temperature:-room temp.-23,24,25
PRINCIPAL OF CALIBRATION PH METER:-

A pH meter provides a value as to how acidic or alkaline a liquid is. The basic principle of the pH meter is to measure
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the concentration of hydrogen

ions. Acids dissolve in water forming positively charged hydrogen ions (H+).
PH METER:-
A pH meter is a scientific instrument that measures the hydrogen-ion activity in water-based solutions, indicating
its acidity or alkalinity
Hot air ovens:-

Hot air ovens are electrical devices which use dry heat to sterilize. They were originally developed by Pasteur.
Generally, they can be operated from 50 to 300 °C, using a thermostat to control the temperature.
Hot air ovens DIAGRAM:-

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Hot air oven principle:-

Working Principle of HOT AIR OVEN. Sterilizing by dry heat is accomplished by conduction. The heat is absorbed by
the outside surface of the item, then passes towards the centre of the item, layer by layer. The entire item will
eventually reach the temperature required for sterilization to take place. GLASS VAR DRY(60%)
Microscopy:-
Microscopy is the technical field of using microscopes to view objects and areas of objects that cannot be seen with
the naked eye (objects that are not within the resolution range of the normal
ISOPROPYL ALCOHOL STERILE:-

Texwipe's sterile and non-sterile 70% Isopropanol (IPA) contains 70% USP-grade Isopropanol (Isopropyl Alcohol) and
30% USP-grade purified water. The solution is submicron filtered, filled into cleaned containers and double-bagged.
HOT AIR OVEN:-

Hot air ovens are electrical devices which use dry heat to sterilize. They were originally developed by Pasteur.
Generally, they can be operated from 50 to 300 °C, using a thermostat to control the temperature.
Biological oxygen demand:-

Biochemical Oxygen Demand (BOD, also calledBiological Oxygen Demand) is the amount of
dissolved oxygen needed (i.e. demanded) by aerobicbiological organisms to break down organic material present in
a given water sample at certain temperature over a specific time period.
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Biological oxygen demand principle:-
Principle BOD is expressed as weight of oxygenconsumed per unit volume of water during 5 days at 20°C ; BOD is
related to the amount of biodegradable organic matter in water sample ; during oxidative degradation of organic
matter, aerobic micro-organisms which perform it, consume oxygen present in water as dissolved
Baterial incubator:-
Incubator is a device used to grow and maintain microbiological cultures or cell cultures. The incubator maintains
optimal temperature, humidity and other conditions such as the CO (CO2) and oxygen content of the atmosphere
inside. Incubators are essential for a lot of experimental work in cell biology, microbiology and molecular biology and
are used to culture both bacterial as well as eukaryotic cells
Incubator working principle:-

Incubator usually works on the principle known as thermo-electricity. There is a thermostat present inside
the incubator which helps in maintaining the constant temperature. Mainly there are two variations in incubators:
.
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Water injection for sterlization :-

Sterile Water for Injection, USP, is sterile, nonpyrogenic, distilled water in a single dose container for intravenous
administration after addition of a suitable solute. It may also be used as a dispensing container for diluent use. No
antimicrobial or other substance has been added. The pH is 5.5 (5.0 to 7.0).
DIAGRAM FOR WATER GENERATION SYSTEMSCHEMATIC:-

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Authorization and declaration Statement
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The Validation Master Plan is made with and objective to provide all schedule and criteria for the validation of
facility, process equipments, and utility equipments and to describe the firm’s policy on different aspects.
It is designed to facilitate the various regulatory agents to have standard inspection and reporting systems.
Regulatory requirements have been kept in mind while preparing the Validation Master Plan.
The following certifies the validity of the furnished hereunder and hereby approves the Validation Master Plan for its
implementation and execution purpose.
Authorized By:
HEAD-OPERATIONS HEAD QUALITY ASSURANCE AND QUALITY CONTROL

TABLE OF CONTENT
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1.0 INTRODUCTION………………………………………………………….…….…….…….…….……. 03
HPLC CHROMATOGEAPHY
&PRINCIPAL…………………………………………………………..04
2.0 OBJECTIVE OF VALIDATION MASTER PLAN……………………………………………………... 04
3.0 SCOPE OF VALIDATION MASTER PLAN ………………………………………………………….. 04
4.0 VALIDATION 05
APPROACH………………………zzzzzzzzzzzzzzzzzzzzzzzzzzz…………………………………….
…….…….…..
5.0 VALIDATION TEAM…………………………………………………………….…….…….…….…... 05
6.0 VALIDATION METHODOLOGY…………………………………………………………….……..… 08
7.0 UTILITY STREAMS (CRITICAL)………………………………………………………….…….….… 16
8.0 REVALIDATION CRITERIA…………………………………………………………….…….….….... 25
9.0 VALIDATION PROTOCOL…………………………………………………………….…….…….….. 27
10.0 DOCUMENTATION…………………………………………………………….…….…….…….……. 28
11.0 CHANGE CONTROL………………………………………………………….…….…….…….……... 29
12.0 CALIBRATION PROGRAM…………………………………………………………….…….…….…. 30
13.0 PREVENTIVE MAINTENANCE PROGRAM…………………………………………………………. 32
14.0 SUPPORT PROGRAMS………………………………………………………….…….…….…….…… 33

15.0 REFERENCES…………………………………………………………….…….…….…….…….……. 33
16.0 GLOSSARY OF TERMS…………………………………………………………….…….…….……... 34
17.0 APPENDIX…………………………………………………………….…….…….…….…….…….…. 36
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INTRODUCTION
The Company resides in the heart of Pharma Hub Baddi, Himachal Pradesh 40 km away from international
airport of Chandigarh. It has its Administrative office at Panchkula City 10 km away from Beautiful City
Chandigarh.
The various day to day operations are handled by a team of qualified, trained and skilled professionals. The
management philosophy resolves around entrepreneurship, innovations and team spirit with emphasis on the
relationship building with the employees as business associates.
The company carries out manufacturing, packaging setting and marketing of parental products at Baddi site.
All activities related to this plant are carried out in dedicated areas.
The company involved in the manufacturing of sterile dry powder Injections. Besides manufacturing, the
company has In-House testing facility for chemical, instrumental and microbiological.
OBJECTIVE OF VALIDATION MASTER PLAN
The Validation master plan (VMP) is to establish an over-arching validation plan and to provide overall
validation philosophy and approach to be followed for validation activities as per the best understanding of
current Good Manufacturing Practice (CGMP) guidelines and regulatory requirements.
SCOPE OF VALIDATION MASTER PLAN
Scope of VMP includes all relevant aspects relating to the manufacturing of sterile drug products in the
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dedicated production facilities at Prosperity 6 Pharmaceutics, Baddi. The principles of Validation, the
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organization of Qualification, Validation, Design and nomenclature of the documentation and equipment are
also described. VMP covers the dedicated manufacturing facilities used for manufacturing of dry powder
injectables facility for storing the starting materials and finished products, services, Quality Control, Quality
Assurance and all related utility services.
The Validation Master Plan covers the following:

Facility qualification
Utility qualification
Equipment qualification
Process Validation
Cleaning Validation
Analytical method validation
Computer Validation
VALIDATION APPROACH:-
Prosperity 6 Pharmaceutics has designed and constructed the sterile injectables manufacturing facility to meet
various CGMP guidelines. The facility consists of new equipments. This Validation program is designed to
demonstrate that the quality features built in the facility, critical utility services and process which ensure that
they are fully functional, remain in place and confirm to the established specifications and relevant regulatory
requirements.
The Master Validation Plan provides the framework of the procedures to be followed in qualifying these
systems. The detailed procedures for each activity and tests to be performed will be provided in individual
validation protocols. Designated personnel and external parties will carry out all validation activities wherever
appropriate.
Installation, Operational and performance qualification shall be performed before handing over to the
concerned department for regular use. Supplier qualification protocols shall be applicable wherever required.
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For quality control equipments/instruments, User Requirement Specifications, Data sheet (Functional
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Specification) will be prepared. The supplier & Prosperity 6 Pharmaceutics personnel shall perform
Installation, Operational and Performance qualification jointly.
VALIDATION TEAM:-
Validation is a team effort that generally requires the involvement and close interaction of Quality Assurance,
Production, Packaging, and Maintenance departments with other appropriate departments support such as
Product Development and Quality Control. The Validation team should include representatives from the
above mentioned departments to provide the necessary expertise and guidance.
The documentation of the validation process is carried out in the form of protocols that must be developed by
the qualification/validation teams. The review team must approve these protocols.
The validation team comprises of key personnel, both internal and external consultants (based on the
requirement) to coordinate the overall validation program. It will evaluate the progress of the tasks, review the
collected data and prepare the final validation report. This team also determines the extent of revalidation to
be undertaken if a system has been modified of changed.
5.1 Organogram for Validation:
VALIDATION CORE TEAM LEADER - HEAD-QA
VALIDATION CORE TEAM MEMBERS

HEAD-PROD. INCHARGE-QC HEAD-ENGG. IN CHARGE.-QA

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VALIDATION TASK FORCE TEAM
EXEC.-PROD. EXEC.-QC EXEC. - ENGG. EXEC.-QA
 Head-Quality Assurance is responsible for all the planning and coordinating of validation activities and act as
Validation Core team leader.
 Head and incharge of other technical departments are included in the validation Core Team.
 The Executive of the concerned technical department is responsible for execution of the validation as per the
set protocol and is included in the Validation task force team of the following disciplines are as below:
5.2 Validation Task Force:
Equipment Qualification Studies : AM – Maintenance

Executive - Production
Executive - QA
Process Validation : Executive – QA

AM - QC
Cleaning Validation : Executive – QA

AM - QC
HVAC and Utility Validation : AM – Maintenance

Executive - QA
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Water Validation : Executive – QA
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AM - Maintenance
AM - QC
5.3 Organization and Responsibilities:
Validation is a team effort. The validation process requires the involvement and close interaction of Quality
Control, Engineering and Production departments in consultation with other appropriate appropriating
supporting groups.
Quality Assurance:-
Quality Assurance department will coordinate the entire validation process by scheduling meetings and
discussion with the validation team, preparing the validation protocols, monitoring the validation process,
compiling and analyzing validation data and test results, and preparing the final report. All documentation
associated with the validation should be reviewed by quality assurance for completeness and compliance with
cGMP requirements.
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24 Quality Control:-
The QC laboratories should be prepared to provide the necessary support for sampling, testing and reporting
the test results. Supporting groups in Quality control should also perform the necessary monitoring during the
validation process.
Engineering
The Engineering department should define the necessary equipment specifications, limitations, capacity and
maintenance requirements and must provide training on the proper operation and maintenance of the
equipment. In most cases, engineering need to assist the equipment installation and operation qualification and
provide technical support to ensure proper and efficient functioning during the validation process.
Production
Production personnel should perform the validation steps whenever possible for training and personnel
qualification. The department should prepare the necessary SOPs for the new process or equipment and assist
in the collection of validation of validation data.
VALIDATION METHODOLOGY
Validation is carried out according to written protocols for each category of validation namely facility, design
and construction qualification, environmental validation, utilities and services validation, equipment
qualification, process validation.
The document shall be in the prescribed format and shall be authorized before being taken up for validation.
The IQ and OQ documents shall be acceptable from the supplier of that particular machine.
The protocol shall have:

Each page bears a header of
 Title.
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 Department.
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 Protocol number.
 Revision number.
 Effective Date.
 Page number.
The document body should consists of:

Objective: This is to set the aim that the validation document needs to achieve.
Scope: This defines the area to be covered by the document.
Responsibility: Names and designations of the persons responsible for ensuring the document is put into
place and achieve the outcome.
Procedure: The actual steps to be followed in order to accomplish the goal.
The protocol shall be prepared by the validation task force team member from QA. The protocol shall be
checked and approved by the validation core team members and finally authorized by validation core team
leader. After execution, validation team member from QA shall prepare summary and conclusion at the end of
the validation protocol. Executed protocol shall be reviewed by validation core team members and finally
authorized by validation core team leader.
6.1 INSTALLATION QUALIFICATION (IQ)
Installation qualification is associated with the installation of the system/equipment. Its function is to verify
static attributes through defined procedures and supporting documentation that all critical aspects of the
system have been installed in accordance with the approved Design Qualification and manufacturer’s
recommendations.
The following tests shall be covered in installation Qualification. In each of the following tests the documents/
Parameters / systems describe in the appropriate test data sheet shall be verified as per the procedure outlined
therein.
Identification and verification of documents – is to identify & verify the availability of documents
associated with the equipment / system.
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Identification & verification of supporting utilities – is to identify & verify that all the utilities required for
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installation & operation of the equipment / system have been provided as per specifications in P&ID / manual.
Verification of major components & accessories is to verify the major components & accessories of the
equipment / system are present & that no physical damage has occurred to the same. The purpose of this test is
to verify that major component / accessory is as per the specifications.
Verification of material of construction – is to verify the ‘material of construction’ of major components &
accessories present in the Equipment / system is as per the specifications.
Verification of equipment installation – is to verify that equipment / system (including sub-components &
accessories) is properly installed as per the manufacturer’s specifications / system requirements.
Verification of equipment as per the drawing – is to verify that the piping & electrical wiring has been done
as per the wiring diagrams and that the equipment / system has been installed as per the drawing provided in
the installation manual.
Identification & verification of Instruments – is to identify & verify all the safety & interlock features
present with the Equipment / system.
Identification of standard operation procedures – is to verify the relevant SOPs for the equipment.
6.2 OPERATIONAL QUALIFICATION (OQ)

Operational qualification function is to verify the equipment operation with functional testing throughout all
anticipated operating ranges. The operational tests will be designed to demonstrate the equipment’s ability to
operate in accordance with approved functional specifications.
The following tests shall be covered in operational qualification. In each of the following test the parameters /
functional keys described in the appropriate test data sheet shall be verified as per the procedure outlined
therein.
Calibration of Process control instruments – is to verify the calibration status of the process control
instruments that are required for the effective operation of the equipment.
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Verification of functional keys – is to identify the presence of all the functional keys in the equipment & that
they perform the intended action when activated / operated.
Verification of standard operating procedures – is to verify all the relevant SOP’s for their accuracy.
Verification of sequential operation of the equipment [simulation cycles] – is to demonstrate that the
equipment / system is capable of achieving the desired results reproducibility when operated as per the set
parameters.
Verification of effect of power failure on the equipment – is to ensure that the system reverts to fail-safe
condition in the event of power failure, and that it returns to the specified state when power is restored and can
be restarted.
6.3 PERFORMANCE QUALIFICATION (PQ)
The function of performance qualification is to verify through testing whenever the system / equipment can
operate the process as specified in the User Requirement Specification under normal and boundary conditions.
This PQ protocol generally includes the following:

 Describe the specific tests to be conducted and rationale for testing.
 Test procedure includes sampling plan and acceptance criteria.
 A list of all test instruments used in execution of the PQ with calibration status.
 Test data sheets to document all testing and test results.
6.4 PROCESS VALIDATION

Process validation is established documented evidence, which provides a high degree of assurance that a
specific process will consistently produce a product meeting its pre determined specifications and quality
attributes.
There are three basic types of process validation.
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6.4.1 Prospective Validation
Establishing documented evidence prior to process implementation that a system does what it is proposed to
do based on preplanned protocols.
Prospective Validation must be conducted for new products or modification and for relocating equipment and
machinery in the manufacturing process that might affect product quality attributes. Most common steps in
prospective validation area
 Installation Qualification
 Operational Qualification
 Calibration
 Approval of validation protocol
 Protocol execution
 Analysis of results in basic report
 Approval of basic report conclusions.
Validation Concept is usually employed when initial validation data is not available or sufficient and when in
process of finished product testing is not adequate to ensure reproducibility or high degree of confidence for
product quality attributes.
6.4.2 Concurrent Validation
Concurrent validation is used for establishing documented evidence that a process does what it purports to do
based on the information generated during actual implementation of the process. It serves as a backup to
prospective validation.
During the concurrent validation, three batches of a particular product shall be produces, intermittent samples
are withdrawn for testing and also the resulting product shall be tested with respect to finished product
specifications. The validation report shall be submitted by the validation team. The report shall be retained in
the documentation cell of the Quality Assurance. Based on the results, the changes in the Master Batch
Formula shall be recommended by the Quality Assurance department.
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The concurrent validation shall be followed in our plant in following situations.
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a) When a step of a process is modified.
b) A new raw material is introduced.
6.4.3 Retrospective Validation
The retrospective validation is used for facilities, processes and process control controls in operation use that
have not undergone a formally documented validation process. Validation of these facilities, processes and
process controls is possible using historical data to provide the necessary documentary evidence that the
process is doing what it is believed to do.
The initial validation which is not properly documented and whose historical data is to provide necessary
guidance for the documentary evidence is termed as retrospective validation. The steps involved in this type of
validation require preparation of a protocol reporting the results of data review, leading to a conclusion and
recommendation.
This validation exercise is only acceptable for well-established processes and will be inappropriate where
there have been recent changes in the composition of the product, operating procedures of equipment. The
source of data for this validation include batch document, process control chart, maintenance log books,
records of personnel changes, process capability studies, finished product data including trend charts and
storage stability results.
6.4.4 Re-validation
Revalidation provides the evidence that changes in a process and / or the process environment introduced
either intentionally or unintentionally do not adversely affect process characteristics and product quality.
There are two basic categories of revalidation.
Revalidation in cases of known change including transfer of process from one site to another. Documentation
requirements will be the same as for the initial validation of the process and in many cases similar process
validation protocols can be employed. The definition of what constitutes a change to a process or process
environment needs to be agreed.
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6.5 Cleaning Validation
Cleaning validation is establishing the documented evidence, which provides high degree of assurance that
cleaning procedure will consistently remove the residues of product below established limits so that is does
not affect the quality and safety of the second product, manufactured using the same equipments. Cleaning
validation shall be performed on 1st three validation batches of any product being introduced first time for
manufacturing in the area under consideration.
The type of products manufactured in the facility shall be considered for making a clean down validation
matrix to arrive at the acceptable standards for drug products manufacturing operations. The method shell
ensure that any carry – over of product residue does not exceed the following criteria:
6.5.1 Not more than 0.001 dose of any product will appear in the maximum daily dose of another product. There are
three contributing division factors of 10 in the number 0.001. the first is that pharmaceutical are often
considered to be non active at 0.1 (10%) of their normally prescribed dosages. The second is a safety factor
and the third normally prescribed dosages. The second is a safety factor and the third is to ensure the
robustness of the cleaning validation.
6.5.2 No quality of residue should be visible in the equipment after cleaning procedures are performed. A number of
products meet the first two criteria at levels at which there still could be visible residues left on the equipment
after cleaning. Spiking studies have demonstrated that the active ingredients in most products are visible at
approximately 100 mg per 10 x 10 cm (100 cm2) swab area.
The method calculations account for each product’s potency, batch size, and maximum dosing. They also
account for the equipment surface area in common between each product and all the other products made in a
given facility. The limits are set for each product with respect to another product taking into consideration
common surface area of all the equipments used in manufacturing of these two products. Thus in subsequent
processing can result in accumulation if residues from the previous the previous product.
In a multi product facility, there could be situations where a chain such as this could contain many
overlapping links, and by the time the product reaches the final step in processing the residues would be in
large multiples of the originally intended limit. The method takes this situation into account to preserve the
original intended limits.
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Selection of worst-case product:
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The Worst- Case product will be selected from the group of product manufactured/intend to manufacture in
the facility considering the following any one or in combination of the below said parameters.
 The solubility of the active in the cleaning solvent
 The potency or toxicity of the active
Selection of sampling technique

Swab sampling technique and /or rinse sampling technique whichever is most suitable / accurate will be
adopted for sampling. Most difficult to clean (hard to clean) location of each equipment (s) will be selected for
sampling.
Validation procedure:
Sample shall be subjected for estimation of residue using HPLC and TOC and campare both the method to
ensure both results are correlating and these results are within the acceptance limits no period. (TOC will be
used for regular monitoring of cleaning procedure period to be placed.) Cleaning agent if they are using for
cleaning shall be estimated by relevant method and ensure these results are within the acceptance limits. Swab
samples shall also be subjected for microbiological count, yeast and mould and pathogen and ensure these
results are within the acceptance limits.
Cleaning Procedure:
The cleaning procedure shall be written in clear and specific terms which eliminate the potential for
misinterpretation and therefore inconsistent compliance. The cleaning procedures shall be based on
mechanical, chemical and / or microbiological principles rather than human behavior. Initially, the cleaning
procedures shall be written for all the equipment based on the wash water analysis. After the cleaning
validation studies, the standard operating procedure for cleaning shall be modified based on the result of the
study.
Page | 6.6 PROCESS SIMULATION TESTING

32 The process simulation test shall act as an element in the evaluation of sterile product manufacturing process.
This includes simulation of entire aseptic formulation and filling process, which substitutes a microbiological
growth medium for a sterile product.
The Purpose of a process simulation test shall be to :
 Demonstrate the capability of the aseptic process to produce sterile drugs products.
 Qualify or certify aseptic processing personnel.
 Comply with Current Good Manufacturing Practice requirements.
The Manufacturing line shall be revalidated in case of the following cases as below:
For new line / Critical change to the manufacturing line:

It Shall require three consecutive satisfactory media fills per shift before the process is deemed acceptable for
routine manufacturing process.
Routine Manufacturing with no change :
It shall require one satisfactory media fills per shift for each process line in every six months in a year.
For minor change:
It shall require one satisfactory media fills after the change before the process is deemed acceptable for routine
manufacturing process.
Written down protocol shall be executed for the process simulation
UTILITY SYSTEM (Critical)
The critical utility system that must operate at certain level to maintain the required quality level of the final
product shall be validated.
Installation qualification and operational qualification will be carried out as described in above mentioned.
Critical utility systems are

 Heating Ventilation and Air Conditioning (HVAC)

 Water System
 Compressed Air System
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 Nitrogen Gas System
33
7.1 HEATING, VENTILATION AND AIR CONDITIONING (HVAC)
7.1.1 Description of Ventilation Systems
Ventilation systems are equipped with centralized HVAC System. Dedicated AHUs have been designed to
each critical area in order to avoid cross contamination. All processing areas are provided with HVAC
System.
7.1.1.1 Air Handling Units

Air handling units of desired CFM is equipped with 10µ, 5µ, and 1µ followed by 0.3µ superfine filters. 90%
return air is collected from rooms and 10 % fresh air is added to the system. The air temperature is controlled
with the help of chilled water coil. Wherever humidity requirement are there, de-humidifiers are installed to
control the humidity.
7.1.1.2 Ventilation And Exhaust System

HVAC System is designed to maintain an environment of 23±20 C and not more than 30% of RH incase of
powder handling area.
In all the return air ducts 20 µ air filter are provided to avoid powder contamination. Dehumidifiers along with
the AHU are provided at all critical location of Cephalosporin and Carbapenem manufacturing.
HVAC is designed in such a way that each critical process area is provided with an independent AHU. The
AHU’s are provided with 10µ, 5µ, and 1µ followed by 0.3µ (terminal HEPA) Superfine filters in the
processing area and process corridors.
7.1.2 Performance qualification of HVAC

Once the installation and operation have been completed, the performance qualification shall be carried out to
verify that the system does consistently as per the requisite specification when operated under the
operationally established standard operating conditions.

Performance qualification shall describe all essential test plans and acceptances criteria as described below.
TEST OBJECTIVE FREQUENCY

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34 Air velocity and air change test To ensure the air system is balanced
and capable of delivering sufficient
Every six months
air volume to maintain a cross
section velocity under absolute filter.
Filter integrity test To verify the integrity of the HEPA
Every six month
filter and Seals.
Recovery test To verify that the control system can
maintain the components of the air

Everyone Years
handling unit within the specified
range after powder failure.
Temperature and relative humidity To verify the ability of the system to
control temperature and humidity Daily
during operating conditions.
Air flow pattern test To verify the parallelism of the air

Every one year
flow throughout the work area.
Pressure differential To verify the air volumes delivered
to the controlled area is able to
maintain the pressure differential Daily
gradients between the adjacent
environments as specified.
Non viable particle count test (at rest To determine that the complete as
Every one year
condition & working condition) built operational facility meets the
air cleanliness requirements
specified in the process functional
requirements
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35
7.2 WATER SYSTEM
7.2.1 Brief Description of Water System :

The source of water is from the Municipal Corporation supply, which is stored at Terrace in Syntax storage
tank. From the overhead storage tank, water is chlorinated and passes through the multi grade sand bed filter
for the removal of suspended solid and further to be activated carbon bed to be free from colour. The water is
then passed through 10 micron and 5 micron filter. Water is subjected to Sodium Meta Bisulphite dosing to
remove chlorine followed by Anti-Scalant dosing (as applicable). The water is then passed to Reverse
Osmosis (RO) Plant. The product water is stored in Storage tank and after it will passes through Mix bed.
After that it will stored in SS tank and directly passes to Ultra filtration Product water is collected in 1.5 KL
Storage jacketed tank of SS 316L.
All the purified water storage tank and loop lines are kept under continuous recirculation at a velocity of
above 1.5 m / sec. A slope of 1:100 is maintained for the water circulation System loop line.
All water quality is monitored through on line conductivity meter provided in the return loop line for each
storage tanks.
Water purification system Includes Ultra Filtration system so as to produces high purity water qualifying Ph,
Eur, specification of purified water & WFI Generation system (Multicolumn distillation) so as to produces
Water for Injection qualifying Ph, Eur, specification of Water for injection.
Water distribution system Include storage of HPW and WFI in SS 316L Storage tank and distribution of
water circulating continuously through SS 316 L Pipe line at different user points with diaphragm valves.
ULTRA FILTRATION SYSTEM
The water from final RO storage tank enters the Ultra filtration system and flow into the UF Module. The
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water flows tangentially across the U.F. Membrane surface over the entire length of the cartridge. The
36
membrane retains particles, Bacteria and other organic molecules greater than 6,000 Nominal molecules
weight limit (NMWL), the retained material is called as the ‘Retentive or Reject.’ The reject exits at the
bottom of the module. Fluid that passes through the membrane is called the ‘Permeate’ or ‘Filtrate’. System
has facility of Sanitization in suitable frequency. Sanitization is possible chemically or by pure steam.
WATER FOR INJECTION GENERATION SYSTEM
The water from the highly purified water loop line enters the multi column (containing 4 vertical columns) of
WFI Generation System. Feed Water enters the inner tubes of the column and falls freely from the other end,
during this process the outer side of the tubes is heated with the Boiler steam in first column & with generated
pure steam in subsequent columns. Heating of the feed water with steam results in generation of pure steam
in the column of the WFI Generation Plant. The pure steam, which is generated, is passed through a pipeline
into the Condenser where it is condensed and collected as water for injection from the Distillation system
outlet and is collected in to Water For Injection Storage Tank.
WATER DISTRIBUTION SYSTEM (Schematic diagram of water system is

attached)
The purified water generated in the existing Primary reverse osmosis plant containing two qualified RO
system is pretreated through filtration including sand filtration and Activated Carbon filtration and dosing of
SMBS, Sodium Hypochlorite and Osmodose is supplied through a supply line and is collected in the primary
RO water storage tank (SS 316)
The water generated in the Ultra Filtration system having the capacity of 1000 L/ hour is the Highly purified
water, and is connected to centrifugal Pump. Pump is placed in Highly purified water distribution loop line.
The distribution loop is connected through solenoid inlet valves to point of use at all the four section described
in the drawing.
The water generated in the Multicolumn distillation plant having the capacity of 300 liters/ hours is the water
for injection, and is collected in water for injection storage tank having the capacity of 1000 liters. The water
is maintained at not less than 80 0C and continuously reticulated from user point to WFI Storage tank.
The steam generated in the Pure Steam Generator having the capacity of 300 kg/ hours is the pure steam,and
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is directly connected for input distribution of pure steam to various user points.
37
All the user points are kept in continuous circulation at a velocity of 1.5 to 2.0 meter per second. There is a
provision to drain the water in loop if the conductivity of the same increase and fresh water is supplied into
the loops.
The material of construction of the pipes used for raw water supply is galvanized Iron. Highly Purified water
and Water For Injection supplied through pipeline to production areas are made up of SS 316L. The storage
tank is equipped with level transmitter and vent filter for purification of air.
7.2.2 General Aspects of Validation Program:
The basis validation strategy is to maintain the system under normal operating Conditions during which
frequent and extensive sampling and testing are performed in order to assess the water system.
Validation program is made in view to cover the following.
 Engineering design.
 Operating procedure and key control parameters.
 Maintenance procedure.
Engineering Design:
Here verification of the design parameters of the water system is performed. Installation Qualification (IQ)
protocols ensures all the requirements to verify the installation of the components of the water system as per
the requirement. Operational Qualification (OQ) protocol specifies and ensures the functioning of different
components as per the manufacturer manual. Detail of IQ and OQ programme are not within the scope of this
protocol and are described under Equipment Qualification studies Separately.
Operating procedure and key control parameters:
Validation program includes the verification of the procedures used to operate the system and to keep it in a
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state of control. Examples of these procedures includes startup and flushing prior to daily use, daily
38
monitoring of the key control parameters, cleaning, storage and sanitization of pipeline and storage tank etc.
These procedure shall be drafted prior to the validation study and the personnel operating the system shall be
trained to these procedures. Other key parameters and their operating ranges shall be finalized after the
validation program.
Maintenance Procedure:
Maintenance procedure shall ensure consistent delivery of the desired quantity and quality of water. These
procedures may include sanitization, filter sanitization and change, UV light monitoring and replacement etc.
All the preventive maintenance procedure must be in writing and consistently followed.
7.2.2 Validation test program:

Performance Qualification of Water System shall be carried out in three phase (Ref. US FDA Guide for
inspection of high purity water system 1994.)
7.2.2.1 Phase – I Validation Study :
Once the water purification and distribution system has been verified, having installed and operated, the initial
phase of water system validation shall be undertaken. In this periods worst case Simulation condition should
be arised just before the sampling which normally occurs during routine manufacturing conditions.
A tentative frequency of sanitization of not more than two weeks shall be set before the Phase I study and
Confirmed after the Phase II Study. If there is any failure with respect to bioburden in between two weeks, the
Phase I Study has to be re-initiated with increase in the frequently of sanitization. At the end of this Phase
draft SOP for Operation, cleaning, sanitization and Sampling method of Water System shall be Confirmed.
7.2.2.2 Phase – II Validation Study :

This Study is to demonstrate that the system shall consistently produce the desire quality of water when
operated in conformance with the SOPs. The Sampling Shall be done from all the sampling points for a
periods of two weeks. In this Phase worst case conditions need not be simulated.
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7.2.2.3 Phase –III Validation Study:
39
The third phase of validation is designed to demonstrate that when the water system is operated in accordance
with the SOPs over a long period of time (One Year) with all seasonal variations, it shall consistently
produces water of desired quality attributes. During this periods sampling shall be done as per the routine
sampling plan which includes all water treatments point,, minimum of one point of use and minimum of one
outlet of storage tank in rotation completing in a week.
7.2.3 Acceptance Criteria:
While framing acceptance criteria the design parameters of the major components of the water system is kept
in mind. Whenever possible USP / BP limits have been incorporated as acceptance limits. For raw water in
house limits are established. Lower and upper quality control limits have been calculated from the statistical
evaluation of the validation data. Routine monitoring of water system will be performed after the validation.
Routine monitoring palns shall be reviewed from time to time if required so as to assess the system.
7.2.4 Validation Documentation:
It includes the following:

 Sampling and testing plan.
 Tabulation of test result.
 Control chart for all critical parameters.
 Statically assessment.
 Including upper and lower limit.
 Executive Summary Report.
 Conclusion and recommendation.
7.3 Compressed Air

7.3.1 Description :
Plant has oil free compressed with a total capacity of 106 CFM. Air compressor is having an in-let air filter of
5 micron (99.9% of efficiency). The non-lubricated Air Compressor draws air from atmosphere into the
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cylinder through air cleaner during the downward strock of the piston by means of an electrical motor. The air
40
is compressed on the upward strock as the two valves remains closed and air is compressed to high pressure.
At the end of the compression stroke the delivery valve opens and air is delivered to a storage tank through a
cooler and dryer. Non-return valves ensure the movements of the air in the correct direction.
Oil separator elements will remove the oil/oil mixer from the receiving air and water separator will remove the
moisture from air. A safety valve present will safe guard the high-pressure circuit. Compressed air is further
filtered through 1 micron filter and is received in MS air receiver. The air is further filtered through 0.2
micron terminal filter and is circulated to different user point through SS 316 L pipeline. All the user point
lines are made out of SS 316 L.
The compressed air is maintained at high pressure in the line to the points of use. Consequently there is
possibility of liquid being carried over in to the plant air line. To remove condensed water affecting the
operation of the pneumatic devices.
All pressure gauges in the compressed air line will be calibrated as per the calibration program, the filter will
be monitored at defined intervals and will be replaced after the lifetime.
Validation of compressed air system includes the following :
 Moisture contents.
 Oil content.
 Non viable particles count (Infromative).
 Viable particles count (Informative).
 Dew Point.
Accordingly a protocol is designed for the validation of compressed air sustem. The validation is performed
annually.
7.4 Nitrogen Line
The Nitrogen is filtered through 0.2 micron and is circulated to different user point through SS 316 L pipeline.
All the point lines are made out of PU.
Validation of nitrogen gas system includes

 Moisture content.
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 Oil content.
41
 Non viable particles count (Informative).
 Viable particles count (Informative).
 Potency.
Accordingly a protocol is designed for the validation of nitrogen gas system. The validation is performed is
performed annually.
7.4.1 Equipment Description
Suitable codification system is used for identification of equipments. Details like equipment name, make,
capacity and identification code are made as a general document and archived in Quality Assurance.
Standard operating procedures are available for operation, cleaning and calibration as applicable for the above
instruments. A list of systems / equipments to be validated is enclosed. The plan shall be executed depending
upon the availability of the equipment.
7.4.1.1 Revalidation Frequency
The revalidation and recalibration shall be performed as per the frequency mentioned on the master validation
monitor. This master revalidation / recalibration schedule is attached and shall be executed on monthly basis.
The list of activities shall be compiled by Quality Assurance department.
7.5 Quality Control Laboratory Validation
Quality control laboratory serves as one of the most critical functional department in facility. Hence a
Comprehensive validation program will be initially performed for procedures and equipment used for all
products as well as for any new analytical methods. Revalidation will be performed for the changes made to a
existing validation method. All Quality Control instruments will be calibrated as per the respective SOPs at
periodic intervals.
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42
All analytical test methods (in-house) will be validated. Analytical methods from USP / NF / BP will be
verified for its suitability.
All critical instruments like HPLC will be qualified prior to use. Performance Qualifications will be done
annually in such cases.
Laboratory equipment such as incubator, laminar airflow chambers, sterilizers, etc will be qualified. Process
of sterilization (in case of Microbiology) will be validated against a predefined validation protocol.
For calibration / validation an external agency service may be used, and implement annual maintenance
contract in all such cases.
REVALIDATION CRITERIA
 The transfer of a product from one plant to another.

 Changes to the product, the plant, the manufacturing process, the cleaning process, or other changes
that could affect product quality Viz.
 Changes in the plant.
 Changes in production composition.
 Changes in manufacturing process.
 Changes in the Packaging material.
 Changes to computer system.
 Changes, which may affect the quality and efficiency of product.
 The necessity of periodic checking of the validation results.
Periodic revalidation must be done to ensure that no unintentional changes were made and to prove that the
results of the previous validation procedures are still valid.
The need for periodic re-validation of non-sterile processes is considered to be a lower priority that for sterile
processes and in case of standard processes on conventional equipment, a data review similar to what would
be required for retrospective validation may provide an adequate assurance that the process continues under
control. In addition, the following points should be considered.
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43
 The occurrence of any changes in the master formula, methods or sources of material.
 Equipment calibration carried out according to the established program.
 Preventive maintenance carried out according to the program.
 Standard operating procedures up to date and being followed.
 Cleaning and hygiene program still appropriate.
 Unplanned changes or maintenance to equipment of instruments.
The revalidation process is essential to maintain the validated status of the plant, equipment,
Manufacturing process and computer system validation. It should be as important as calibration and
maintenance.
1.1 Revalidation policy
Reason for revalidation and categories needing a revalidation are described under 6.4.4 of this document. The
regulatory revalidation schedule the site has developed a planned revalidation schedule for different
applications. The following table illustrates the same.
Immediately after the commission and installation at site for each equipment. PQ is
performed after the process validation or is clubbed along with the process
validation.
Equipment Qualification
Initially once.
(IQ/OQ/PQ)
OQ and PQ is repeated in-case of any major change / modification to the
equipment.
Revalidation for equipments will be carried out every one year.
Prospectively for the first three commercial batches (or till such a number to get
consistency in validation test results).
Process Validation
After Successful consecutive batches for new line and thereafter on successful
batch for six months.
Utility Validation Annually
Compressed air and Nitrogen

gas
HVAC Semi Annually
Page | Water system Initially three phase study and thereafter any major discrepancy.
44 Critical gauges
(Pressure, temperature,
vacuum, etc) and other Periodic re-calibration as per the respective SOPs.
measuring and testing
equipment’s.
Initially for 3 similar product change over.
Cleaning Validation *
For a similar product of different strength, the higher strength will be validated.
Analytical method Revalidation not considered as on date.
validation (Except any changes or modification in the method / Equipment)
Computer system validation Revalidation not considered as on date.
Calibration of critical QC
equipments Semi annually
(HPLC, UV)
* Can be validated at random as per in-house Quality Assurance plan from time to time.
Note: All the above revalidation plans are totally in-house and are not based on any regulatory guide lines. It is
derived based in the regular calibration, preventive maintenance and routine Quality Assurance inspection Plans.
2.0 VALIDATION PROTOCOL
2.1 Definition
Validation protocol in an experimental design, which outlines the validation program. This document outlines
the precise method to obtain and analyze the process parameters associated with the manufacturing of
formulations.
The completed validation protocol should be subjected to a thorough review and approval. The review process
may initiate supportive changes in the experimental design resulting in the protocols revision. Once the
protocol is approved, the validation study may begin.
Contents of Validation Protocol
There are some basic rules for preparing a validation protocol that the protocol should include the necessary
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details and information for performance of the specific tests. The test procedures, operating parameters,
45
specifications and limits must be practical and attainable. The protocol should be concise to facilitate its
review and approval.
Prior to the initiation of any validation program, a validation protocol must be prepared and approved.
Headings in the protocol should include the introduction, responsibility, procedures and acceptance criteria.
Introduction section should explain the purpose of the process or system to be validated and should include
who us to validate and the reason for validation.
Responsibility section should detail the department and / or personnel required for each phase of the study,
including the approval process for both the validation protocol and report. Procedure section should describe
methods including number of samples, locations of sampling and transport of samples to the appropriate
place. Also the experiments that will be conducted shall describe the responsibility of performing test and
methodology.
Testing methodology would be detailed with reference to pertinent SOP and documentation. This section
should also list specific equipment to be used as a part of the validation program and should indicate number
of replicates required for completing the validation.
Acceptance criteria must be established with limits clearly defined and may include recommendation for the
investigation and correction, if there limits exceed. Preliminary studies are helpful to determine realistic limits
prior to the preparation of the validation protocol.
DOCUMENTATION
2.2 General Requirements

For effective use of any documents, they should be designed and prepared with utmost care. Each document
shall:
 Have a clear title.
 Have a protocol identification number.
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 Be approved by authorized persons.
46
 Have the effective date.
2.3 Origin, Execution and Approval

 Validation team / concerned department shall generate validation protocols in a standard formats,
Validation task force leader shall review and validation core comities shall do pre-approval before the
effective date.
 Approved protocols shall be forwarded to execution team for execution as per the schedule.
 Approved team shall execute IQ, OQ & PQ protocols and generate a report.
 Discrepancies (if any) that are found during the execution of a validation study shall be recorded in
discrepancy report and fully evaluate the impact. These discrepancies shall be rectified within
stipulated period and record the same.
 QA respective of execution team shall summarize the data and prepare a final report.
Documentation system provides provision for revision of any document, or part by a change control.
The validation core committee should also approve such revised versions. Revised versions shall
supersede the previous version and the document should clearly indicate this. Superseded document
should made as “Obsolete” and retain only for reference.
In case of additional tests / information to be added to the existing document. A new protocol should be
prepared as addendum to the existing document. Addendum shall ba retained along with the existing protocol.
Format style and content of protocols and reports is to be as per the temple protocol. Each protocol will have a
unique identification number.
All major equipments / systems shall have a formal URS which will be prepared by the user and approved by
authorized person.
Engineering department shall prepare FS based on the URS and forward to the purchase department.
The vendor shall submit a DQ which should be approved by the both vendor and client.
Validation coordinator shall prepare qualification protocols (IQ, OQ and PQ) which shall be approved by the
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validation core committee before execution by the execution team. Upon commissioning of the equipment a
47
report shall be prepared including discrepancies (if any), which shall be assessed and rectified in stipulated
period based on the impact.
Finally validation core committee should approve validation reports.
CHANGE CONTROL
Change control is an important element in quality assurance system. Written procedures should be in place to
describe the actions to be taken if a change is proposed to a product component, process equipment (or site),
method of production or testing or any other color change that may affect product quality or support system
operation or which have an impact on regulatory requirements. All changes are formally documented and
accepted by the validation team. The likely impact of the change control system should ensure that all the
notified or requested changes are satisfactorily investigated, documented and authorized.
This is designed to guarantee the integrity of the validation process. This system applies to the changes in
facility, utility, equipment and procedures (SOPs). The change must be evaluated in terms of its impact on the
related areas.
The system determines the process to be followed each time when a validated system or procedure is changed,
modified or replaced. The system determines the nature of the requalification work to be under taken upon the
type and nature of the change as well as the qualifications of approved to participate in it.
The system determines the routing and approval of all the required documentation and associated data in
addition to controlling the overall process until the system is prequalified. The validation team is responsible
for evaluating and approving any changes. Changes that are likely to require revalidation are:
 Changes of raw material (Physical properties such as density, viscosity, particle size distribution may
affect process or product).

 Change of source or starting material.
 Changes of packing material.
 Changes in the process (Blending times, drying temperature etc).
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 Changes in equipments (Addition of automatic detection systems).
48
 Production area and support system changes (Rearrangement of areas, new water treatment method).
 Transfer of process to another site.
 Unexpected changes (Those observed during self-inspection or during routine analysis of process
trend data).
CALIBRATION PROGRAM
Description
The calibration program will ensure that all critical instruments used are maintained in a calibrated state.
Specific acceptance criteria limits will be established based on system and processing requirements.
Periodic calibration orders generated by the calibration program will contain information such as department,
location accuracy, SOP number etc needed by the calibration technician Instrumentation in this program will
include, but is not limited to, timers monitoring probes (temperature, relative humidity, etc) pressure gauges,
balances etc. Each instrument will be placed in one of three categories, Critical, Non-Critical, and
Convenience. A critical instrument is one whose failure or precision directly affects the quality, purity and/or
integrity of the product. A non-critical instrument does not fall into the critical category, but can be used in
troubleshooting, maintaining, controlling or monitoring a process or test that is potentially hazardous. A
convenience instrument is any instrument that does not fall into the critical or non-critical category.
Instrument calibration are required at intervals based on the critically of the instruments, instrument
capability, and instrument calibration history. An instrument will also be calibrated following the repair of the
instrument, following the repair of the system that the instrument is monitoring/controlling, if the repair could
have affected the instrument accuracy, and /or after installing the instrument into a system. All equipment
used to perform calibration will be calibrated to standards traceable to the National Institute of Standards and
Technology (NIST) or other approved standards and maintains the following:
 Calibration SOPs.
 Instrument numbering system.
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 Instrument Calibration schedules.
49
 Instruments Calibration reports.
Calibration Frequency
 Pressure gauges / vacuum gauges / compound gauges are calibrated every 3 months.
 Temperature gauges / controllers / temperature sensors are calibrated every 6 months.
 Balances are calibrated daily or before use.
 Analytical balances are calibrated as per SOP.
 Quality Control instruments are calibrated as per the SOP.
 Glassware’s are calibrated as per the SOP.
 Critical instruments are calibrated as per the SOP.
2.4 Calibration Documentation
All the above calibrations will be documented in specified formats as per the respective SOP. The calibration
will be performed by user department and verified by the concerned department head. In certain cases an
external agency service will be used. Proper action plan is defined in case of out of calibration results. The
defected gauge will be replaced with fresh calibration unit.
All process and facility instruments are classified as to their calibration status into one of the three following
categories.
 Calibration.
 Preventive maintenance.
 No calibration / No preventive maintenance.
 All instruments providing critical process information necessary to make a quality Determinations are
calibrated with the available standards.
 Engineering department will be responsible for scheduling, tracking and maintenance of standards,
records etc. all standards will be traceable to NIST standards.

 Pre-and post-calibration of instruments utilized in validation studies are performed to ensure data
accuracy.
 All instruments providing critical process information should be calibrated before performing the
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validation studies.
50
PREVENTIVE MAINTENANCE PROGRAM
2.5 Description
A preventive maintenance program is developed and implemented to maintain production systems in proper
working condition and reduce equipment breakdowns.
The manufacturer’s specifications, past experience, and history of the equipment will be used to establish the
preventive maintenance schedule. Procedures will be developed for issuing work orders, performing the
maintenance work, documenting the work in the proper logbooks and files, frequency of performing
preventive maintenance, reviewing the impact of maintenance on validation state, etc. and maintain the
following documents.
Preventive Maintenance Programs Adapted At Site
 Well established preventive maintenance procedures are defined for each equipment in related SOPs.
 Preventive maintenance program is scheduled weekly, fortnightly, quarterly, half yearly and yearly as
applicable to each equipment.
 Engineering department will be responsible for scheduling, tracking and execution of preventive
maintenance program.
13.3 Preventive Maintenance Documentation

It Includes
 Preventive Maintenance SOPs.
 Annual Preventive maintenance calendar.
 Preventive maintenance Check sheet
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Training programs
Each person engaged in and each person responsible for supervising the manufacture, processing, packing or
holding a drug product shall have education, training and experience or any combination thereof to enable the
individual to perform the assigned functions. The personnel in the validation team, who are involved in the
validation tasks are fulfilling this requirement and are trained in the particular operations that they perform in
accordance with the current good manufacturing practices.
The frequency of training should be at least twice in a year in the areas where personnel are familiar. New
employees are trained should immediately after requirement and before giving the jobs individually.
Effectiveness of the trainer is evaluated and necessary actions are taken to improve the performance. The
concerned records are maintained by the Quality Assurance department.
REFERENCE
2.6 GOOD MANUFACTURING PRACTICES FOR PHARMACEUTUCALS, A plan for Total Quality Control,
Sidney H. Willing / Murray M. Tuckerman / William S. Hitchings IV.
2.7 FOOD AND DRUG ADMINISTRATION, Title 21, Code of federal regulations, parts 210 and 211,m “Good
Manufacturing Practices for finished Pharmaceuticals” Superintendent of documents, U.S Government
Printing Office, Washington, D.C.
2.8 PHARMACEUTICAL DOSAGE FORMS/ PARENTERALS, Liebermann/Lachman, Marcel Dekkar Series.
2.9 A PRACTICAL GUIDE TO VALIDATION DOCUMENTATION, Bennet and company, Clarksville,

Maryland, USA.
2.10 VALIDATION OF PHARMACEUTICAL PROCASS – STERILE PROUCTS, Edited by J. Carleton, James

P. Aglloco. Second Edition, Marcel Dekkar Inc.
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GLOSSARY OF TERMS
Definition of terms relating to qualification and validation are given below.
Calibration:
Demonstrating that a measuring device produces results within specified limits of those produced by a
reference standard device over an appropriate range of measurements. This process results in corrections that
may be applied if maximum accuracy is required.
Certification:
Documented testimony by qualified authorities that a system qualification, calibration, validation or

revalidation has been performed appropriately and that the results are acceptable.
Change Control:
A formal system by which qualified representatives of appropriate disciplines review proposed or actual
changes that might affect the validation status of facilities, systems, equipment or processes. The intent is to
determine the need for action that would ensure and document that the system is maintained in a validated
state.
Cleaning Validation:
Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment,
which is suitable for processing medicinal products.
Concurrent Validation:
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Validation carried out during routine production of products intended for sale.
Design Qualification (DQ)
The documented verification that the proposed design of the facilities, systems and equipment is suitable for
intended purpose.
Installation Qualification (IQ):
The documented verification that the facilities, systems and equipment, as installed or modified, comply with
the approved design and the manufacturer’s recommendations.
Operational Qualification (OQ):
The documented verification that the facilities, systems and equipment, as installed or modified, perform as
intended throughout the anticipated operating ranges.
Performance Qualification (PQ)
The documented verification that the facilities, systems and equipment, as connected together, can perform
effectively and reproducibly, based in the approved process method and product specification.
Process Validation:
The documented evidence that the process, operated within established parameters can perform effectively
and reproducibly to produce a medical product meeting its predetermined specifications and quality attributes.
Prospective Validation:
Validation carried out before routine production of products instead for sale.
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Retrospective Validation:
Validation of a process for a product which has been marketed based upon accumulated manufacturing,
testing and control batch data.
Re-validation:
A repeat of the process validation to provide an assurance that changes in the process/ equipment introduced
in accordance with change control procedures do not adversely affect process characteristics and product
quality.
Risk analysis:
Method to assess and characterize the critical parameters in the functionality of an equipment or process.
System:
A group of equipment with a common purpose.
Worst Case:
A condition or set of conditions encompassing upper and lower processing limits and circumstances, within
standard operating procedures, which pose the greatest chance of product or process failure when compared to
ideal conditions. Such conditions do not necessarily induce product or process failure.
APPENDIX
The validation schedules can be modified / updated without revising the validation master plan
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1 Master Validation Plan.
END OF DOCUMENT
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VALIDATION MASTER PLAN (Repaired)

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Document No. QA/VMP/01 Revision No. 00 Page No. Page 1 of 56

Department Quality Assurance Effective Date

HPLC USED FOR: -

High pressure liquid chromatography.

High priced liquid chromatography.

It is having a high resolution and separation capacity.

It is used as qualitative as well as quantitative analysis.

High performance liquid chromatography(HPLC) is a chromatography technique used to separate a mixture of

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1. Normal Phase HPLC

2. Reverse Phase HPLC

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6. Data Collection Devices

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A spectrophotometer is made up of two instruments: a spectrometer and a photometer. The spectrometer is to

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Electrical conductivity meter:-

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PRINCIPAL OF CALIBRATION PH METER:-

the concentration of hydrogen

Hot air ovens:-

Hot air ovens DIAGRAM:-

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Hot air oven principle:-

ISOPROPYL ALCOHOL STERILE:-

HOT AIR OVEN:-

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Biological oxygen demand:-

Incubator working principle:-

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Water injection for sterlization :-

DIAGRAM FOR WATER GENERATION SYSTEMSCHEMATIC:-

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