VALIDATION MASTER PLAN

Pharmaceutical Guidanace July 30, 2018 QA & QC, Quality Assurance Comments
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VALIDATION MASTER PLAN

CONTENTS
SR. NO. CONTENTS PAGE NO.

1 APPROVAL

2 INTRODUCTION

3 VALIDATION POLICY

4 OBJECTIVE

5 SCOPE

6 VALIDATION RESPONSIBILITIES

6.1 Validation Team Constitution

7 FACILITY DESCRIPTIONS AND DESIGN

7.1 General Description and Design Concept

7.2 Description of Products

7.3 Description of Process

7.4 Description of Equipments

8 VALIDATION PROGRAM AND SUPPORTING SYSTEMS

8.1 Fundamentals of Validation Program

8.2 Supporting systems for validation program

9 VALIDATION CONCEPT AND TYPES

10 ACCEPTANCE CRITERIA

11 RISK MANAGEMENT STRATEGY

12 STANDARD OPERATING PROCEDURES

13 CHANGES AND MODIFICATIONS

13.1 Changes and modification to the validation systems

13.2 Changes and modification to the validated systems

14 VALIDATION SCHEDULE

15 ANNEXURE

16 GLOSSARY
 APPROVAL
The Validation Master Plan has been initiated, checked, approved and authorized for
implementation by the undersigned.

INITIATED BY

DESIGNATION NAME SIGNATURE DATE

Quality Assurance
Executive [Validation]
CHECKED BY

DESIGNATION NAME SIGNATURE DATE

Quality Control Head

Production Head

Engineering Head

IT Department Head
APPROVED BY

DESIGNATION NAME SIGNATURE DATE

Quality Assurance Head

General Manager
AUTHORIZED BY

DESIGNATION NAME SIGNATURE DATE

Vice President
2.0 INTRODUCTION
 Pharmaceutical Formulation plant having tablet , capsule,liquid manufacturing
facility, which is situated ________________________ India.
  The facility was designed in the year ____________________ to meet the
national, International,
regulatory and cGMP requirements.

 The manufacturing facility is supported by Engineering, Ware house, Quality

control and Quality Assurance department. All these departments are covered
under the relevant validation activities.
 The Validation Master plan is a dynamic document which provides complete over-
view of validation program.
 It describes the overall objective, intention approach for establishing performance
adequacy of equipment, utilities, processes and systems.
2.6 It identifies the scope of validation, applicable validation protocols-reports,
procedures and frequency of validations.

3.0 VALIDATION POLICY

3.1 The organisation is committed to the concept of validation and all Processes
facilities, equipment’s, Machines, Instruments, Control Systems, Utilities, and analytical
methods are put through appropriate qualification and validation cycles before being
accepted for use. Performance Qualification shall be carried out for all critical
equipment’s used for manufacturing, Engineering and Quality control.

3.2 All systems are subject to ongoing validation to evaluate the impact of changes in
process, systems, environment, equipment directly or indirectly on the product.

 Three Validation studies are carried out as per protocol prepared by nominated
team members from various departments.
3.4 For certain equipments/ Instruments, on case –by –case basis the manufacturers
qualification documents shall also be taken as inputs for qualification activities. This
includes pre delivery inspection and FAT.

4.0 OBJECTIVE
 Validation Master Plan is a document, which describes our company’s intentions
and the methods which are related with validation of the equipments,
instruments, systems, utilities, facilities, materials, analytical methods and
processes.
 Validation program is designed to demonstrate that the facility for the production
up to final stage of production of different dosage forms is capable of meeting
the process parameters in a repeatable and controllable manner.
  Validation Master Plan ensure that validation activities are carried out as per
respective protocols and after completion will determine whether the equipment,
system, process and methods,
o Meets the specifications of its design.
o Suitable for its intended applications.
o Confirm to the basic cGMP design criteria.
o Will satisfy the regulatory requirements.
o Meets safety requirements as applicable.
o Is capable of consistently producing a product that is fit for use.
4.4 The critical utilities, equipment & process validation program are established
in accordance with the methods and procedures maintained by the product requirements
which are based on the currently available product information and the Current Good
Manufacturing practices, guidelines and other regulations.

4.6 Validation Master Plan helps :

4.6.1 The management to know and access what the validation programme involves and
understand its necessity.

4.6.2 The validation team members to understand their tasks and responsibilities.

4.6.3 To understand the company’s approach towards validation and the set up
of organising validation related activities.

5.0 SCOPE
5.1 The scope of this document is to describe the systems and methodology used
to execute the various phases of the validation program .

5.2 It applies to all critical equipments, instruments, procedures, utilities, facilities

and other quality supporting systems used for manufacturing, processing, testing,
labelling and packaging which may affect the quality of product directly or indirectly.

5.3 Validation Master Plan applies methodology of validation program of following,

1. Facilities
2. Equipments / Instruments / System [ Qualification]
3. Utilities (e.g. HVAC, Water system, Pure steam and Compressed Air.)
 4. Control systems (e.g. computer hardware and soft ware)
5. Manufacturing processes
6. Cleaning processes
7. Analytical methods
8. Environmental (Physical & Microbiological)
9. Personnel ( e.g. Analysts, checkers on inspection or packing line).
10. Revalidation or Re-qualification.
6.0 VALIDATION RESPONSIBILITIES
6.1 Validation Team Constitution
6.1.1 The over all validation process is co-ordinated by a team, which is a working group
comprising of qualified personnel as required for the specific validation activities.

6.1.2 The validation team is made up of representatives from the following areas:

 Quality assurance (Validation)

 Production

 Engineering

 Quality control
6.1.3 Validation team is responsible for :

 Preparation of Validation Master Plan.

 Determining the equipments, instruments, systems, facilities and utilities to be
validated.
 Preparation of validation and Qualification protocols.
 Execution of the validation and Qualification protocols.
 Determining the suitability of the established protocol to qualify a system.
 Approving all validation protocols and report for each validation from respective
functional department heads.
 Reviewing each protocols and reports content to assure compliance with current
regulations and guidelines.
 Verifying the adequacy of the tests used for the verification of the system as
established by the validation protocols.
 Determine the extent of revalidation necessity in case of changes in a validated
system.
 Document control.
6.1.4 Other personnel will be utilised, as necessary, by the members of the
validation team to assist the assessment of the special equipment, system, utilities where
their area of expertise will facilitate the development & execution and assure the quality
of the validation efforts.

6.1.5 Individual responsibilities of different departments as follows:

1. Production: It is responsible for,

 Describing the production process in collaboration with Quality assurance.

 Preparation of the batch records in collaboration with Quality assurance.

 Transferring the processes to the production facility, in collaboration with Quality
assurance.
 Providing all current and approved standard operating procedures to be used as
part of manufacturing process.
 Providing personnel and materials as required for the execution of validation
protocols, equipment trials and process trials.
 Training of all manufacturing personnel in technical, validation and GMP aspects.
 Sampling and execution of process controls.
 Preparing reports on any deviation from occurs during process.
 Participating in preparation of draft validation protocols.
 Executing DQ, IQ, OQ & PQ with validation team members as per validation
protocols.
 Tracking for validation requirements.
 Operating & maintaining plant, facilities, equipment, support systems and the
specific manufacturing processes within its design limits.
2. Engineering: It is responsible for,
1. Building and room drawings

2. Calculations
3. Instrument list
4. Maintenance requirements
5. Spare part list
6. Calibration requirements and procedures
7. Equipment design, installation and system construction procedures.
8. Operational recommendations
  Co-ordination of calibration activities for all critical instruments as defined by the
validation team
 Participating in preparation of draft validation protocols.
 Executing DQ, IQ and OQ tasks and assisting in the execution of
 Preparing and maintaining calibration records for all critical instruments.
 Executingthe installation and maintenance of production facilities and
laboratories.
 Trainingof all engineering personnel in technical, validation and GMP/ GEP
aspects.
NOTE: Critical instruments are those which have direct impact on the product quality,
i.e. Instruments which measure, monitor, or control manufacturing,processing and testing
parameters.
3. Quality Control: It is responsible for,
 Participating in preparation of draft validation protocols.

 Trainingof all Quality control personnel in technical, validation and GMP/ GLP
aspects.
 Testing of validation sample as per validation protocols and specifications.
 Preparing
laboratory reports by collecting data and verified summaries of findings
and conclusions.
 Ensuring that the laboratory systems, instruments, devices and equipment to be
used in the course of validation studies have been qualified, validated and
calibrated.
4. Quality Assurance: It is responsible for,
 Co-ordinating and organising the validation team.

 Co-ordinating the preparation of the validation protocols for each Area, system,
Facility, Utility, equipment, Instrument.
 Co-ordinatingthe process validation by monitoring, sampling, testing and
challenging the specific manufacturing processes.
 Co-ordinatingall change control approvals. Organising the changes required to
approved protocols resulting from specification changes or changes in operating
parameters.
 Training of personnel involved in validation activities.
 Collecting and organising the validation data.
 Tracking of all validation requirements based on the review of guidelines or
literatures.
  Preparing the final validation summaries and certification statements.
7.0 FACILITY DESCRIPTIONS AND DESIGN
7.1 General Description and Design Concept of facility as follows:-
7.1.1 Pharmaceutical plant have provide manufacturing facility for different dosage
forms as tablets,Liquid & capsule.

 The plant is functionally divided into different blocks viz. Change Rooms,
Administration, Quality Assurance, Quality Control, Production, Service Floor,
Warehouse, Utility, Engineering Workshop, Canteen and the Gate House.
Quality Control Laboratory is contagious to production operations, whereas
there exists an In-Process Quality Control Laboratory inside the production area.
 The production area has infrastructure to manufacture tablets,liquid & capsule.
 The Production and supporting areas have been made in a cluster module with
covered interconnecting corridors and feasibility for modular expansion. The
building is made of Reinforced Cement Concrete (RCC), and designed such,
that no beams or columns are visible in the manufacturing and testing areas. The
walls of the plant are constructed of brick and plastered to provide a hard
smooth finish, with minimised recesses. The Production, Quality Assurance, and
the interconnecting corridors have quota stone and only warehouse have
hygienic Epoxy flooring.
 The return air risers of the HVAC system are concealed within the wall to avoid
recesses. The terminal filters and lighting fixture are recess type, ceiling
mounted. All the services to the manufacturing area are provided from the first
floor, (designated as the Service Floor) through Galvanised iron.
 Sanitary type drains have been provided in the production and testing areas.
Further, concealed drainage line has supplied to effluent treatment plant. All
drainage is treated to bring down the COD and BOD to predetermined levels.
This treated water is then used for gardening.
 The Ware house is dust resistant and controlled environment.
 The Power Supply system features the facility to control voltage fluctuations and
an automatic changeover system from the state power supply to stand by power
generation system in case of power failure.
7.1.9 The building is surrounded on all sides by a fire hydrant loop, maintained at high
pressure.
7.2 Description of Products: As per attached Annexure (Make and attached Product
list here)
 7.3 Description of Process flow:As per attached Annexure (Make and attached list
here)
7.4 List of equipments: As per attached Annexure (Make and attached list here)
8.0 VALIDATION PROGRAM AND SUPPORTING SYSTEMS
8.1 Fundamentals of Validation Program:-
8.1.1 The validation program shall be divided into five phases as follows,

 Phase I – Preparation and Approval of the Validation Master Plan.

 Phase II – Preparation and Approval of the Validation Protocols.
 Phase III – Execution of Validation protocols, tests laid down in Validation
Protocols and data collection.
 Phase IV – Preparation of Validation Report, Compilation of data collected during
Validation, review, recommendations and Approval of Validation Report.
Document shall be kept under custody of the Quality Assurance.
 Phase V – Ongoing evaluation, review, Change Control, Deviations and
Revalidation.
8.1.2 The Validation Master Plan (VMP) shall be prepared by the Validation Executive.

8.1.3 The document shall be checked by the heads of all Functional area.

The document shall be approved by the Quality Assurance Manager and General
Manager. The document shall be Authorised by Vice President .

8.1.4 There shall be separate Protocols for DQ, IQ, OQ, PQ (where ever applicable),
Environment Control, Analytical method validation, Facility, Utility, Process Validation,
and Cleaning Validation etc. All the protocols shall be numbered as per SOP for the
numbering of protocols and reports.

8.1.5 The Protocols shall consist of the Objective, scope, responsibilities,procedures for
conducting the tests for Validation. The results observed during the validation studies,
summary, conclusion and final approval shall include in the reports.

 Validation Executive and Concerned department Executive shall initiate

the Validation Protocols. Concerned HOD and HOD’s of the Production, Engineering
shall approve. Quality Assurance Manager & General Manager shall finally authorize the
validation protocols.
8.1.7 The Approved Master copies of protocol shall be kept in the custody of the Quality
Assurance Manager. During execution of validation protocol, validation report shall be
prepared as per protocol and attached the collected data of the same to the reports.

8.1.8 Summary & conclusion Report and Approval

 After the execution of the protocols, a validation task report shall be reviewed,
summarise, concluded and recommendations made by the team carrying out the
validation activity and approved by the involved team members.
8.2 Supporting systems for validation program:
8.2.1 Protocol and documentation system:

The system shall designed to assure that all validation documentation shall prepare
accordingly validation policies establish by a validation team, which shall responsible for
the co-ordinating the validation program and approving all validation activities.

8.2.2 Documentation control system:

This system shall design to manage all documents generated during the validation
process, including that from the change control program. The system will include a
numbering system to identify each protocol and an index to list of all approved protocols.
It assures that all documentation shall properly stored and controlled so as to maintain its
integrity.

 Protocol execution system:

This system shall assure that all requirements outlined in the approved validation protocol
are met and thus system shall considered to valid. To comply with these requirements this
system shall establishes the procedures to be followed for co-ordination of the validation
tasks through the validation team. This system shall also provides assurance that the
information collected is timely, correct and is properly reviewed and shall approved by
the validation team members.
8.2.4 Change control system:The SOP for Change Control

9.0 VALIDATION CONCEPT AND TYPES

9.1 Definition:
9.1.1 ‘The collection and evaluation of data, beginning at the process development stage
and continuing through the production phase, which ensures that the facility, equipment,
manufacturing process, control systems, utilities including personnel and materials are
capable of achieving the intended results on a consistent and continuing basis and thus is
capable of consistently producing a product that meets the established products
specification’.

9.1.2 Validation is an documented evidence which can confirm predetermined critical

parameters.
9.2 Validation Types:

1. Facility validation:
 Room no. and location
 Purpose of area for use
 Dimension of area:
Height (Meter), Length (Meter), Width(Meter), Area (M2 / Ft2) Volume (M3/Ft3 ).
 Area Details:
 Walls:
Wall to floor, wall to false ceiling, Wall to return air riser, Wall to door frame.
 Ceiling: Type, Finish, Painting Shade & Jointing.
 Door:
Type, Dimension (W X H meter), No of doors, Location, Painting, No and type of door
closer, No and type of handle, Size of glass view panel, Door interlocking.

 Windows:
 Type & No of windows, Dimensions (W x H meter), Jointing.
 Drainage:
Type of trap, No and location, Material of construction.
 Electrical work:
Wiring type, no. of light fittings and type arrangement for emergency light. No. of
telephone points, no. of computer points, no. of Power sockets, no. of single phase
sockets & type, no. of three phase sockets & type, no. of lighting switch box & type
Illumination level in Lux.
 Building management system:
Indication box, Size, Location Indication, pressure Indication, temperature Indication,
humidity and Door status.
 Other facilities:
Fly killer, Air curtain, PVC strip door, SS corner angle, SS fenders, Fan Safety, Pass
box.
1. Analytical Method validation:
This type of validation shall be done at Analytical Research Development department.

1. Vendor Qualification :
 Vendor Qualification shall be carried out for all vendors of Raw and Packing
Materials, to ensure that the components of the product, consistently meet
predetermined specifications.
 Vendor evaluation shall be done on the basis of questionnaire, pre-shipment
samples, machine trials and/or a vendor audit .
 The supplied materials shall be checked / analysed with respect to in- house
specifications.
1. Control system validation:
 Computer software and hardware Validation.
 The objective of the computer system validation is to demonstrate that the
computer system performs (Create, modify, archive, and retrieve) as it is
supposed to.
 This shall be based on following:
 Specification for hardware and software depending on intended use.
 Computer and manual modes of data validation giving similar results.
 Accessibility, durability and accuracy of stored data.
 Levels of authority for data entry and change.
 Accuracy and reliability of data entered.
 Security system to ensure any alteration or pilferage of data.
v Qualification (DQ/ IQ/ OQ/ PQ) of Computer Hardware and
software:
 To control the equipment/ instrument/ system, computer hardware and software
systems used as a part of equipment or instrument or system must be validated.
Design qualification, Installation qualification and operational qualification shall
be executed prior to performance qualification of associated equipment/
instrument/ system.
 To expedite the process of validation, the computer system validation shall be
done as a part of equipment/ instrument/ system validation.
 Thefollowing are the contents for computer hardware and software validation:
1. Detail description of control system
 Control panel

 Power supplies
 Temperature sensor (Wherever applicable)
 Humidity sensors (Wherever applicable)
 Smoke detectors (Wherever applicable)
 CPU

 Location

 Manufacturer

 Model

 Processor

 Capacity

 Disk type
 Floppy disk drive
 Hard disk drive
 Ports

o Monitor
 Manufacturer

 Model

 Type

 Size

 Software

 Operating system version

 Application program version
 Password control
 Input devices
 RAM

 CDROM

2. Computer Hardware
 Manufacturer

 Model No.
 Serial No.
 CPU board Model No.
 CPU board Serial No.
 Communication processor
 Printers

 Screens

 Floppy disk drives

 Hard disk drives
 Computer operating environment:-
 Temperature

 Humidity

 Electromagnetic field
 Calibration
– List of all calibrated instruments for the computer control systems
and make this list as a part of validation document.
 Electrical– Verification of the control system and/ or control wiring has been
installed as per manufacturer’s drawing and specifications and confirm correct
identification of wires or air control lines in the control panel and the control
panel / computer system are properly grounded.
3. Computer Software
 Software

 Verification that software prevents unintentional access.

 Verify back up procedures.
 Verification of restart of software procedures after system failure.
 Verification of software change control procedures.
 Verificationwhether the controller operates as a stand alone device or as part of a
distributed system. If the controller operates as part of a distributed system,
verify that the program is written to prevent unauthorised access between the
system.
 Verification that the following phases of software life cycle have taken place ,
o Requirements
o Design phase
o Installation and check out phase
o Operation and maintenance phase
o Performance phase
 Verification that supplier has provide the following
o Logic flow diagram
o Operating manual
o Software description
o Where does memory reside ( RAM, Tape Disk)
4. Controlled devices:
 Verification that the controlled devices for the system as per approved drawings,
specifications and authorised change orders.
 Verification that all the controlled devices have been installed and tagged as per ,
o Manufacturer
o Model
o Location
o Description
o Function
o Calibration date
o ID number
 Verificationthat all the wiring done as per specifications. Execution of point to
point verification between the control panel. Confirm the correct identification
of wires and / or air control lines.
 Evaluate the controlled functions for their potential effect on the quality strength,
purity and safety of the final product.
1. Equipment validation (Qualification):
2. Design Qualification
 3. Installation Qualification
4. Operational Qualification
5. Performance Qualification
1. Design Qualification (DQ)
The following sections are to be included in design qualification:

 User requirement specification (U.R.S.)

 User requirement specification (U.R.S.):
 The following sections are to be included in User Requirement Specification:

1.0 Introduction

2.0 Overview

3.0 Operational Requirements

3.1 Capacity

3.2 Specifications

3.3 Functional Requirements

3.4 Environment

3.5 Maintenance

4.0 Life Cycle

4.1Prefered vender list

4.2Development

4.3Testing

4.4 Delivery

4.5 Support

5.0 Glossary
6.0 References

7.0 Approval

Note: Numbering system as per SOP of User requirement specification

 Functional Requirement specification ( FRS):

o Specification provided by the supplier end is to be attached to the
report.
 Factory acceptance test procedure (F.A.T.):
o Remark of team of selector on F.A.T.

o Approval
2. Installation Qualification (IQ)
 Installation Qualification is documented check that all key aspects of the
installation adhere to appropriate codes, approved design intentions and that
manufacturer’s recommendations are suitably considered.
 To qualify, the specifications of the new equipment received, must match with the
URS . Any exceptions to the original Purchase order or Functional specification
shall be documented and justified. Attribute inspection of the equipment/
Instrument/ System shall be carried out, documented and proper installation
shall be verified.
 All modifications in existing equipments shall be properly documented through a
change control procedure.
 It may not be possible to inspect and verify every feature associated with a piece
of equipment. In such cases, a
certificate of conformance shall be consider, obtained from the equipment manufacturer.

 The following sections are to be included in Protocol of Installation Qualification

protocol:
 Approval

 Objective

 Scope

 Responsibility

 Procedure

 Re-qualification criteria
 Abbreviations
 Reference

3. Operational Qualification (OQ)

1. OQ demonstrates that the equipment/ Instrument/ System can operate
throughout it’s dynamic range of operation, within limits and
tolerances as per specified in the operating manual or instructions.
 Thisdemonstration of equipment’s basic operation shall involve all control
parameters of the equipment.
 OQ shall be carried out for equipment/ Instrument/ System that will be used
routinely in manufacturing, testing or in critical utilities.
 The following sections are to be included in Operational Qualification protocol:
o Approval
o Objective
o Scope
o Responsibility
o Procedure
o Re-qualification criteria
o Abbreviations
o Reference
4. Performance Qualification (PQ)
 Performance qualification is documented verification of performance of
equipment/ Instrument/ System as intended for the process under specified
operating ranges.
 All
critical equipment / Instrument/ System are qualified for performance
verification.
 The study shall involve the challenging of the system to simulated worst case
situations, and establishment of operating variables.
 The following sections are to be included in performance qualification protocol:
o Approval
o Objective
o Scope
o Responsibility
o Procedure
o Acceptance criteria
o Re-qualification criteria
 o Abbreviations
o Reference
NOTE: All equipment, Instrument and system shall have required separate qualification
protocol and report.

1. 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 predetermined specifications and quality characteristics.
 Ifa new product is duplicasy of the existing product then its validation shall be
bracketed with the existing product.
 The purpose of process validation is to demonstrate the reliability and
reproducibility of manufacturing process, within established parameters and to
assure batch uniformity and integrity of drug products. A process validation
program shall establish a documented evidence of three full-scale production
batches.
 The validation protocol shall be a written document that defines and gives the
detail of critical steps of manufacturing process. It shall state, how the validation
program will be conducted and lists acceptance criteria for successful
validation.
The process validation batches shall be taken for packing after completion of 30 days
hold time study for the initial batches manufactured, Provided the product meets the
Finished product / release specification/ upon re analysis.

 There are four types of the process validation.

o Prospective validation
o Concurrent validation
o Retrospective validation
oRevalidation
1. Prospective validation:
 Prospective Validation shall be carried out on the small scale or R & D batches
during development stage.
 These validations were carried out to identify the processing steps, equipment
settings and process timings, which can prove to be critical in overall impact of
product quality. All these steps, equipment setting and process timing are
evaluated to finalise the setting parameter. Limits of all critical parameters shall
put tentatively.
  Thisdraft form of study can lead towards the finalisation of Batch Manufacturing
Record / Batch Packing Record for large scale batches.
 The prospective validation shall take care of following:
1. Process description
2. Investigation summary of critical processing steps
3. Finished product release specification
4. Calibration of equipment
5. Appropriate analytical methods
6. Proposed in process control with acceptance criteria
7. Sampling plan
8. Method for recording and evaluating results and responsibilities.
2. Concurrent validation:
1. This validation comprises of determination and evaluation of process
parameters applicable from scale up to large scale batches.
 Process validation for establishing the predetermined limits of all critical
parameters by conducting three consecutive commercial or large scale batches.
 Validation carried out during routine production or products manufacturing for
sale.
 The tests are finalised based on evaluation of the results of these batches. These
batches were monitored for stability and quality trends.
 Matrix approach can be applied to process validation. The matrix approach means
that a plan to conduct process validation on different strength of same product,
manufactured by the same process and similar type of equipment. e.g. validation
on one strength (preferably smallest) as a representative amongst the multiple
strength of the same product. This approach should be in accordance with cGMP
and should demonstrate that the process is consistent for all the strength.
Note: The batches will not be dispatched unless and until the analysis of the validation
sample is completed.
3. Retrospective validation:
 Historical trending of all critical parameters obtained from analytical results and /
or IPQC results observed after testing of physical, chemical and microbiological
parameters of product manufactured by same process. To ensure that all the
parameters shall be in the limit and in uniform range.
 Retrospective validation shall done yearly of products or batches manufactured in
previous year.
  Minimum first 20 batches shall consider for retrospective validation. If less than
20 batches were manufactured in one year then batches of previous years were
consider for trending.
4. Revalidation:
 Periodic revalidation: This type of revalidation shall be done on periodic basis as
per specified frequency. The revalidation shall be governed by the Change
Control procedure.
 Revalidation after any change : All validated equipment, systems, processes,
products etc. shall be continuously monitored for any change, to be considered
for revalidation of the same.
 Revalidation / Requalification [Verification of validation] shall be considered in
the case of :
 Equipment / Instruments / System:
1) Substitution of existing equipment with a new equipment /instrument/System.

2) Change of site /location of the equipment / instrument / System from qualified existing
place to other place.

3) Any major modification in the existing equipment / instrument /System since purchase
which can have an adverse effect on the quality and efficacy of the finished product.
 Manufacturing Process:
A change in the validated manufacturing process that has an effect on the quality and
efficacy of the finished product, which includes a change in the following :

1) Master formula or manufacturing process.

2) Raw Materials

3) Equipment

4) Batch Size

5) Change in manufacturing site or location.

1. Cleaning validation:
Definition:
· Validation of the process by which the equipment are
cleaned is called as cleaning validation.
Objective:
 Cleaning validation is an important mechanism to protect the pharmaceutical
products from cross contamination. A pharmaceutical product can be
contaminated by previous product residues, traces of cleaning agent, micro-
organisms or any foreign particle as borne particles, dust, raw materials etc.
 This should be performed to provide a documented evidence that the procedure
being followed for cleaning of equipment and accessories is effective and
removes residues of previous batch / product up to a predetermined acceptance
level, using a well defined protocol and acceptance criteria.
 For equipments which are not product specific, cleaning procedure for such
equipment should be able to ensure that it can consistently remove residues to
the predetermined level.
Procedure:
 There are two methods employed for sampling during cleaning validation. These
are Rinse and Swab method. Rinse method will be applicable when swabs are
not practically possible.
 Cleaning procedures for products and processes, which are very similar are do not
need to be individually validated. Representative of similar range can be
selected to justify the validation programme, which addresses the critical issues
relating to selected products and processes.
A single validation study under consideration of the “worst case” can be carried
out on the basis of the maximum strength, potency, solubility and LD50. The
cleaning validation can be evaluated,
1. For highest strength product in multi strength products or all products.
2. For highest potency product in all products.
3. For least solubility in common cleaning solvent i.e. Water.
This “worst case” term can also be referred as “bracketing”. And such approach is called
as matrix approach.
 Three cleaning validations exercise shall be performed and shown to be successful
in order to prove that the method is validated.
 The documentation of cleaning validation shall include validation protocol,
cleaning procedures, sampling plans, surface area calculations, testing
procedures and executed record of the cleaning event, a record of the sampling
 and testing events and a validation report which contains clear conclusions
against acceptance criteria.
 Thisvalidation shall covers sanitation, microbiology as well as removal of
external agents like detergents, using sampling techniques capable of detecting
and measuring to very low levels wherever applicable.
 There are two criteria’s for the cleaning validation, one is dose criteria and second
is 10 PPM criteria.
 Validated analytical methods used for cleaning validation shall have sensitivity to
detect residues or contaminant of previous product . The detection limit for each
analytical method should be sufficiently sensitive to detect the established
acceptance level of residues or the contaminant.
 Equipment surface area calculation:
1. The product contact surface area for each equipment shall be calculated by
theoretically breaking down the equipment in to basic geometric shapes
[cylindrical, cubical, cone, rectangle etc.] and then apply to relevant area
calculation formulae.
2. Amount of contaminant, mix from previous product to next product, depend on
the common surface area of equipment used for both previous and next product.
Responsibility:
 Quality Assurance:
Generation of validation protocol

Sampling during validation

Review and compilation of validation data & certification

 Production:
Ensuring cleaning of equipment

1. Utilities Validation:
 Equipments / Machineries used for plant utility as,

1. HVAC system
2. Water system
3. Pure steam generator
4. Compressed air system
 1. HVAC system:-
 Air Handling Unit system, ventilation system, and evaporating system are the part
of HVAC system which is one of the utility have directly or indirectly impact on
products.
 Total ____ number of independent air handling units, _____ number of ventilation
systems with supply and exhaust duct have been provided in the facility. Each
critical operational area has a dedicated air-handling unit (AHU) and has
temperature and humidity controls. Each room is provided with terminally
filtered air, as per the requirement of operation, to be carried out in the room.
Total ___ number of evaporating units in service floor are provided.
 The core corridors are provided with controlled environment. Pressure balancing
of each room has been done to avoid any cross contamination, by any ingress of
air / drug product from adjacent areas.
 There is provision to automatically control and record temperature and percentage
relative humidity & monitor and record the pressure differential across Rooms,
by means of a computer interface.
 Thissystem is qualified initially, monitored at regular intervals and revalidated
once in a year in oral dosage form area.
 InitiallyTemperature control test, Humidity control test, Air velocity & number of
air changes test, Differential Pressure Control test, Air borne Particle Count test,
Microbial count test, Air flow direction test shall be conduct to perform the
system.
 Limits for each test shall mentioned in the validation protocol as acceptance
criteria.
2. Water system:-
 Water system is one of the utility which have directly or indirectly impact on
products. There are mainly three types of water system as follows,
Raw water system [Potable water]

DM water system [Deionised water]

Purified water system

 New water system shall be established and use for regular purpose after one year
validation study includes the results of chemical and microbiological quality of
the water.
 o For qualifying the DM water system & purified water system,
Chemical and Microbiological Test shall be conduct mentioned as
follows.
o Temperature, PH, Conductivity, Colour, Total hardness, Total
dissolved solids, Turbidity, Alkalinity and presence of ions or minerals,
Microbial counts, pyrogens and endotoxins. Test method for each tests
shall be mentioned in the protocol.
o Location of sampling points shall be done as per specified in
Validation protocol or as per SOP.
o Frequency for all above mentioned tests shall be mentioned in the
individual validation protocol.
o Validation of water system shall divide in to three different phases as
follows. Frequency of sampling, number of samples taken and no. of
sampling locations are reduces from phase I level to next phase level.
Phase – I –

Phase – II –

Phase – III –

 Following acceptance criteria:

1. Raw water circulation and its storage shall be requalified if microbial load is
if,more than 500 CFU / ml and chemical water quality shall confirms to In-
house standards.
2. Demineralised water circulation and its storage shall be qualified if microbial load
is if, more than 100 CFU / ml and chemical water quality shall confirms to In-
house standards.
3. Purified water circulation and its storage shall be qualified if microbial load is
if,more than 10 CFU / ml and chemical water quality shall confirms to In-house
standards.
4. For acceptance criteria of chemical and microbiological tests of purified
water,USP – 41 [NF – 36] shall be refer.
 Sanitization of purified water system shall be done after 15 days
 Water system shall be revalidate if there is any major change, replacement or
modification in existing system. It shall be periodically revalidate or verified
once in a year on the basis of monthly, weekly or daily testing data as per
scheduled trend.
 3. Pure steam generator:-
 Pure steam is one of the utility which have directly or indirectly impact on the
quality of the product.
 Conductivity, PH, Total organic carbon, Bacterial endotoxin and Microbial count
test of pure steam condensate shall be carried out during validation.
 Frequency for sampling and testing shall be mentioned in the protocol.
 Sampling locations of pure steam shall be carried out from pure steam generator as
per specified in the validation protocol.
 Data of chemical and microbiological analysis of all months shall be reviewed and
trend shall be prepared for year.
 Based on the trend data of the year summary report shall be prepared and shall be
approved at unit levels.
 Limits or Acceptance criteria for each tests shall defined in the validation protocol.
 Pure steam generator shall be revalidate if there is any major change, replacement
or modification in existing system. It shall be periodically revalidate or verified
once in a year on the basis of monthly, weekly or daily testing data as per
scheduled trend.

4. Compressed air system:-

 Compressed air system is one of the utility which have directly or indirectly
impact on the quality of the product.
 Sampling locations shall be mentioned in the validation protocol. Sampling
method of Compressed Air shall be carried out as per respective Standard
Operating Procedure.
 Followingtest shall conduct to qualify compressed air system. Limits or
Acceptance criteria for each tests shall defined in the validation protocol.
1. Water vapour: Dew point and moisture content in air shall identify.
1.1 Pressure Dew point : 0 to + 3° c.

1.2 Atmospheric Dew point : – 15 to – 20° c.

2. Compressed Air must be oil free so during the course of generation it

does not comes in contact with Oil.

3. Hydrocarbons should be less than 5 mg / m3.

4. Micro organisms should be less than 3 CFU/ m3.
 5. Particulate matter such as fibres and metal particles should be NMT 100
particles of 0.5 mper cubic feet of air.
6. Compressed air system should meet the class 100 requirement.
 Frequency of different tests of different frequency should be specify in to the
validation protocol.
 Data of chemical and microbiological analysis collected monthly or quarterly shall
be reviewed and trend shall be prepared for year.
 Based on the trend data of the year summary report shall be prepared and shall be
approved at unit levels.
 Compressed Air System shall be revalidate if there is any major change,
replacement or modification in existing system. It shall be periodically
revalidate or verified once in a year on the basis of monthly and yearly testing
data as per scheduled trend.
Note: During validation program of above described utilities some tests were conducted
by external party and some tests were in-house, specified in validation protocol.

10.0 ACCEPTANCE CRITERIA

10.1 The specific acceptance criteria for the experimentation results, during validation,
shall be defined in detail in the respective validation protocol. Recognised national or
international standards shall be cited for reference.

11.0 RISK MANAGEMENT STRATEGY

11.1 Risk: It is defined as the combination of like hood and consequences of
specified hazardous event occurring.

11.2 Hazards: It is defined as the source or situation with potential for harm in
terms human injury or ill health, damage to property, damage to work place, damage to
environment, or a combination of these.

11.3 Any aspect of the operation that can affect the quality attributes i.e. Identity,
purity,strength, safety of the product directly or indirectly, obviously that can affect the
health of customer, that’s why, assessment of impact of risk requires.

11.4 This shall be based on the comprehensive understanding of the product,

process,system and components. Where possible this assessment of impact shall be
defined in the user requirement specification & process validation.

11.5 Risk and issue management strategy:-

Sources of risks: Risk sources are broadly categorized into,

 New project
 Introduction of new equipments in to the existing facility
 Changes in the existing facility or utility or equipments
 Introduction of new product
 Change in the approved vendor.
11.6 Method of Risk identification and Evaluation:

Impact assessment : The risk is identified and categorized in to impact and no impact.

Identify the system

Develop system boundaries

Does the system have an direct impact on product quality

Is it linked with direct Direct impact

impact system

No impact system Indirect Impact Develop supporting rational

11.7 Based on the findings, if the impact of the risk is direct or indirect one, then
the extent of validation is decided i.e. whether it requires a process, equipment, analytical
method, cleaning process or vendor qualification.

11.8 Risk categorization, validation priorities, schedule preparation, depth of

validation including timelines shall be determined by the functional team members from
the production, QA, QC and Engineering.

11.9 When a new product is introduced in to the existing system, the risk is assessed
by using matrix vs. does form which is evaluated in the product development plan for the
process validation and cleaning validation.

11.10 Impact assessment: The applicability of any thing of the following criteria
was taken as an indication that the system has direct impact or indirect impact on the
product. Systems such provides Utility which has direct contact with the product are
compressed air, purified water, Pure stem and HVAC system
 Name of System / Equipment / Direct Indirect
Description Remark
Instrument impact impact

Area — Y — —

HVAC System Y — —

Compressed air Y — —

Utilities Purified water Y — —

Potable water N Y —

Pure steam Y Y —

All equipments used in the

Y — —
manufacturing processes
Equipments
All equipments or machineries
N Y —
used for storage

12.0 STANDARD OPERATING PROCEDURES

12.1 The Standard Operating Procedures relevant to the equipment, process,and
analytical methods shall available at individual site.
13.0 CHANGES AND MODIFICATIONS:
13.1 Changes and modification to the validation systems:
Any changes or modifications to the validation protocol, test reporting formats and other
related documents must be approved by the validation team prior to becoming effective
through a ‘Change Control’ system.

13.2 Changes and modification to the validated systems:

All changes or modifications to a validated systems must be evaluated and

approved by following ‘Change control system’. A supplement to be attached to the

revised protocol to reflect the approved changes as it may be deleted part or additional
part in the validation protocol.
14.0 VALIDATION SCHEDULE
14.1 The Validation for equipment, instruments, systems and processes which requires to
be periodically revalidated at defined frequency as per individual validation protocol
within ± 1 month of the due date.

15.0 ANNEXURE (To be prepared and attached)

 1. Annexure – I Product list
2. Annexure – II Equipment list
3. Annexure – III Process flow
4. Annexure – IV Equipment validation schedule
5. Annexure – V Process validation schedule

16.0 GLOSSARY
1. Acceptance criteria:
The product, equipment, and /or process specifications and limits, such as acceptable
quality level and unacceptable quality level, that is necessary for making a decision to
accept or reject.

2. 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.

3. Change control:
A formal system by which qualified representatives of appropriate discipline reviewed
proposed or actual changes that might affect a validated status. The intent is to determine
the need for action that would ensure and document that the system is maintained in the
validated status.

4. Certification:
Documented testimony by qualified authorities that a system qualification, calibration,
validation or revalidation has been performed appropriately and that the results are
acceptable.

5. Critical variable study:

A study that serves to measure variables or parameters , critical to the satisfactory
operation of a piece of equipment or plant and to assure their operation within monitored
and controlled limits. Examples of variables are pressure, Temperature, Flow rates , Time
etc.

6. Limit of detection:
The lowest amount of analyse in a sample which can be detected but not quantitiated as
an exact value. The limit of detection is mostly a parameter of the limit test.

7. Limit of Quantitation:
The lowest amount of analyse in a sample which can be quantitatively determined with
defined precision and accuracy under the stated experimental condition. The limit of
detection is mostly a parameter of the limit test.
8. Inspection:
The process of measuring, testing or otherwise comparing the item to requirement.

9. Installation Qualification:
Documented verification that all key aspects of the installation adhere to appropriate
codes and approved design intentions and that manufacturer’s recommendations are
suitably considered.

10. Operational Qualification:

Documented verification that the system or subsystem performs as intended throughout
all anticipated operating ranges.

11. Performance qualification:

Documented verification that the equipment performs as intended for the process,as
specified by operating ranges .

12. Process optimisation:

To optimise the process for maximum efficiency while maintaining quality standards.

13. Process validation :

Establishing documented evidence that a process does what it purports to do. It is an
documented verification that the integrated system functions as intended in its normal
operating environment. The term performance qualification may also be used.

14. Pre determined acceptance criteria:

The criteria assigned before undertaking testing to allow evaluation of test results to
demonstrates compliance with test phase of delivery requirement.

15. Protocol:
A document that gives a direction or guideline for any process as what , where, when,
who, why and how to do.

16. Proven acceptable range:

All values of a given control parameter that fall between proven high and low worst case
conditions.

17. Qualification:
The performance of tests to determine if a component of a manufacturing process
possesses the attributes required to obtain a specified quality of a product.

18. Quality assurance:

The activity of providing , to all concerned , the evidence needed to establish confidence
that the quality function is being performed adequately .

19. Quality control:

The regulatory process through which industry measures actual quality performance ,
compares it with standards and acts on the difference .

20. Quality function:

The entire collection of activities from which industry achieves fitness for use, no matter
where these activities are performed .

21. Revalidation:
Repetition for verification of the validation and qualification process or a specific portion
of it.

22. SOP: Standard Operating Procedure.

23. State of control:
A condition in which all operating variables that can affect performance remain within
such ranges that the system or process performs consistently and as intended .

24. Validation change control:

A formal monitoring system by which qualified representatives of appropriate
disciplines review proposed or actual changes that might affect validated status and cause
corrective action to be taken that will ensure that the system retains its validated state of
control .

25. Validation task report:

A scientific report of the results derived from executing a validation protocol A brief
summary of conclusions from a specific task conclusions report, usually indicating
validation success and designating proven acceptable ranges that have resulted. The
conclusions are formally approved .

26. Validation Master Plan:

A document providing information on the company’s validation activities. It should be
define details of and time scales for the validation works to be performed.
Responsibilities relating to the plan should be stated.
 27. Worst case:
A condition or set of conditions encompassing upper and lower processing limits and
circumstances within standard operating procedure, 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.

28. Critical Part:

Part of an equipment which can affect the quality of product directly is known as critical
part.

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