The document provides an overview of validation requirements in the pharmaceutical industry. It defines validation and traces its origins back to the 1970s where it began with sterilization processes and has now expanded to all product, process, and facility matters. Validation is important as it assures quality, is a regulatory requirement, reduces costs, and is legally required. The document outlines the various stages of validation from user requirement specification to process validation and continuous process verification. It provides details on what each stage involves and its goals.

1. Overview of Validation Requirements
in
Pharmaceutical Industry
Kaushik Desai
Chairman,
Industrial Pharmacy Division
Indian Pharmaceutical Association
www.ipapharma.org
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2.  A definition
 Where did validation come from ?
 Why do it ?
 What are the benefits ?
 How far do we have to go ?
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3. “ Establishing the documented evidence which
provides a high degree of assurance that a
specific process will consistently produce a
product of predetermined specifications and
quality attributes.”
(FDA Guidelines 1987)
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4. “Process validation is defined as the collection
& evaluation of data, from the process design
stage through commercial production, which
establishes scientific evidence that process is
capable of consistently delivering quality
product.”
(FDA Guidelines, 2011)
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5. “Action of proving, in accordance with the
principles of Good Manufacturing Practice
(GMP), that any procedure, process,
equipment, material, activity or system
actually leads to expected results.”
(EU GMP 1997)
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6.  Began in 1970’s
 Originally sterilized based.
 Now evolved into all Product, Process and Facility
matters.
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7.  Assures Quality
 Regulatory Requirement
 Reduces Cost
 It’s the LAW !
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8. Validation can reduce costs by reducing,
 Rejects
 Reworks
 Reliance on In-process controls
 Down time
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9.  Reliance on product testing
 Loss of confidence
 Possibility of adulterated products
 Inspection : Observations / 483’s
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10.  User Requirement Specification (URS)
 Design Qualification
 Impact Assessment
 Factory Acceptance Testing
 Installation Qualification
10

11.  Calibration
 Site Acceptance Testing
 Operational Qualification
 Standard Operating Procedures
 Performance Qualification
 Process Validation
 Change Control
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12. User Requirement Specification (URS)
 A description of the requirements of the facility
(project) in terms of product to be manufactured,
required throughput and conditions in which the
product should be manufactured.
 Approved statements prepared by the user which
defines what is required by the project.
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13. Design Qualification (DQ)
 Documented review of the design, at an
appropriate stage in a project, for conformance
to operational and regulatory expectations.
(Note : Not an obligation)
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14. Impact Assessment
 The process of evaluating the impact of the
operating, controlling, alarming and failure
conditions of a system on the quality of a
product
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15. Factory Acceptance Testing (FAT)
 Inspection and static and/or dynamic testing of
systems or major system components to
support the qualification of an equipment
system conducted and documented at a
supplier site.
(Note : Not an obligation)
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16.  Documented verification that all aspects of a facility,
utility or equipment that can affect the product
quality adhere to approved specifications and are
correctly installed.
 The process of checking/verifying the installation to
ensure that the critical components meet the
approved specifications and that they are installed
correctly in accordance with design documentation.
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17.  To establish that the critical components are installed
correctly and in accordance with design
documentation requirements (i.e. PO’s, Contracts
etc.), that supporting documentation is in place and of
suitable quality.
 To record the checks and verifications for critical
components in Direct Impact Systems.
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18.  Approval Page
 Objectives
 System Description
 Responsibilities
 Acceptance Criteria
 Engineering Documentation Requirements
 Records of Signatures
 Qualification Test Equipment/Instrument List
 Product Contact Materials Review
 Utilities Verification
 Control System Verification
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19.  Instrument/Control Devices Verification
 Equipment Verification
 Piping Installation Verification
 Discrepancy/Justification and corrective Action
 As built P&I Diagrams
 Specifications
 Conclusions
 References
 Modification/ Change Control
 Attachments / Appendices
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20. Parameters
 Does the vessel meet the design specification?
 Does the agitator assembly meet the design specification?
 Is the motor housing earthed?
 Is the motor over current device set to correct setting?
 Is all the pipe work connected?
 Are all instruments installed as per P&I diagram?
 Have all the temperature indicators been calibrated?
 Is calibration procedure available?
 Are operation and maintenance manuals available?
 all electrical connections securely and safely fitted?
 Is insulation complete?
 Is vessel clean and free from dirt?
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21.  After protocol execution is complete and
deviations evaluated, post execution approval
is required.
 Requires sign off by original signatories.
 IQ execution should be complete and approved
prior to the start of OQ.
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22. Calibration
 Demonstrating that a measuring device
produces results within the specified limits of
those produced by a reference standard over
an appropriate range of measurements.
 The devices are normally tagged and
supported by a maintenance procedures.
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23. Site Acceptance Testing (SAT)
 Inspection and dynamic testing of systems or
major system components to support the
qualification of an equipment system
conducted at a client site.
(Note : Not an obligation)
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24.  Documented verification that all aspects of
a facility, utility or equipment that can affect
product quality operate as intended
throughout all anticipated ranges. It is the
process of testing to ensure that individual
components and systems operate as
specified, and how that information is
recorded.
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25.  To establish through documented testing, that all
critical components and direct impact systems are
capable of operating within established limits and
tolerances.
 To test parameters that regulate the process or
product quality. To verify the proper operation of
controllers, indicators, recorders, alarms and
interlocks, is performed and documented during the
operational qualification testing.
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26.  Approval page
 Pre-requisites
 Objectives
 System Description
 Responsibilities
 Acceptance Criteria
 Records of signatures
 Qualification test Equipment/Instruments list
 Alarm and Interlocks test
 Operation testing
 Capacity testing
 Power failure testing
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27.  Sequence testing
 Test data sheets
 SOP’s
 Conclusions
 Modification / change control
 Discrepancy/Justification and corrective action
 Operational Qualification Summary
 References
 Attachments/Appendices
- Verification of test instruments
- Chart recordings
- P&I diagrams
- Printouts
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28. Parameters
 Have all Installation Qualification been completed for this system?
 Is the system clean and free from dirt?
 Is the direction of the rotation of agitator correct?
 Check the operation of the agitator emergency stop?
 Check the operation of all agitator controls, both on the main and local
panels?
 Check that the agitator in the vessel free to turn?
 Pressurize the vessel and record the pressure drop for 10 min.
 Perform a vacuum test and record the vacuum drop.
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29.  Documented verification that all aspects of
a facility, utility or equipment that can
affect the product quality perform as
intended in meeting the predetermined
acceptance criteria.
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30.  To integrate procedures, personnel, systems
and materials to verify that the utility /
environment / equipment / support systems
produces the required output. This output
may be a product contact utility, sterilization
condition or environment.
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31.  Approval page
 Pre-requisites
 Objectives
 System Description
 Responsibilities
 Acceptance Criteria
 PQ test plan
 Challenge test plan
 Records of signatures
 Test equipment/Instrument list
 Test data sheets
 SOP’s
 References
 Conclusions
 Attachments
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32. Process Validation
 The documented verification providing a high
degree of assurance that a specific process will
consistently produce a product meeting its
predetermined specifications and quality
attributes.
 The new guidelines aligns process validation
activities with a product life cycle concept.
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33.  211.42, 211.63, 211.68, 211.84
 211.100(a) , 211.110(a),
211.110(b)
 211.160(b), 211.165(c),
211.165(d), 211.180(e)
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34. Life Cycle of the product & the process
 Stage 1 – Process Design
 Stage 2 – Process qualification
 Stage 3 - Continuous process verification
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35.  It is the activity of defining the commercial manufacturing
process that will be reflected in planned master production
and control records.
 The goal of this stage is to design a process suitable for
routine commercial manufacturing that can consistently
deliver a product that meets its quality attributes.
 It is based on the knowledge gained through development &
scale-up activities.
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36. During this stage, the process design is evaluated to
determine if the process is capable of reproducible
commercial manufacturing. The products
manufactured during this stage, if acceptable , can be
released for distribution.
Two Aspects
 Design of facility and qualification of equipment and
utilities.
 Process Performance Qualification ( PPQ).
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37. Def.: “Releasing for distribution a lot of finished
product, manufactured following a qualification
protocol, that meets the standards established in
the protocol, but before the entire study has been
executed”.
 Orphan Drugs
 Specific drug for specific use
 Shor t Shelf-life radio pharmaceuticals
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38.  The goal of this stage is continual assurance that the
process remains in a state of control ( the validated state)
during commercial manufacture.
 The cGMP requirements, specifically the collection &
evaluation of information & data about the performance
of the process will allow detection of undesired process
variability.
 This stage is also applicable for legacy products.
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39. Change Control
 Formal evaluation of the potential impact of
planned modifications on the validated status
of a product, process or facility.
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40.  Training personnel for IQ/OQ execution.
 The purpose of the equipment/ system.
 Use of test equipment
 Applicable SOP’s
 cGMP documentation of training
 Document all training
 Periodically review training requirements
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41.  A document that summarizes and analyses
the test results at the end of PQ.
 Provides a conclusion about the ability of the
system to consistently meet acceptance
criteria.
 May be a stand alone document at each
stage of IQ/OQ and PQ to summarize results.
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42. Commissioning and Qualification
Project Phases Validation Phases
Technology Transfer Collecting data
Conceptual Design
Basic Design Preliminary VMP
Detailed Design Detailed VMP
Procurement Detailed planning,DQ
Construction IQ
Pre commissioning
Commissioning OQ
Process operation / Validation
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43. 43
Introduction Qualification Personnel Schedule Preventive
Maintenance
Installation
Operation
Process
Responsibilities
Training
Change
Control
Procedures
Documents
Appendices

44. The company’s overall policy, intentions and
approach to validation, including :
 Validation of production processes
 Cleaning procedures
 Analytical methods
 In-process control test procedures
 Computerized systems
 Persons responsible for design, review, approval
 Documentation of each validation phase
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45.  Product validation is NOT ……
- just 3 batches that meet specifications
 Product validation is ……
- an ongoing process to build confidence into
the manufacturing activities
- an ability to demonstrate consistency at any
time.
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46.  Cleaning validation is establishing
documented evidence that the equipment
is consistently cleaned from product,
microbial and cleaning agent residues to
predetermined acceptable levels.
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47. A written procedure for cleaning validation
which includes :
 Responsibility for development, performance and
approval of the validation study.
 Establishment of SOP’s
 Acceptance criteria
- defined to prevent cross contamination
- definition of residue limits
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48.  Cleaning procedure for each piece of equipment
- Flow charts and diagrams
- Cleaning agents, concentration, volume
- Frequency
- time left ‘dirty’
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49.  Sampling procedures
- swabs, rinse, location
 Residue limits
 Analytical methods
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50.  Validation report
- Results Vs. acceptance criteria
- Deviations and how handled
- Conclusion that cleaning process is
validated
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51.  Major change in cleaning procedure
 Change in cleaning agent
 New equipment
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52.  Knowledge of the materials
- Potency of the drug
- Pharmacological and toxic properties
- Degradation products
- Cleaning agents
- Micro residues
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53. Residual Limits must be………….
 Practical
 Achievable
 Verifiable
 Safe
FDA does not set acceptance specifications
(limits).
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54. MAC = TD x BS x SF / LDD
MAC = Maximum Allowable Carryover
TD = Single Therapeutic Dose
BS = Batch size of next product to be
manufactured on the same equipment.
SF = Safety Factor
LDD = Largest Daily Dose of the next product
in the same equipment.
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55. Ranitidine Tablets - Ibuprofen Tablets
TD = Single Therapeutic Dose = 150 mg Ranitidine-Tab
BS = Batch Size = 100 kg of Ibuprofen
SF = Safety Factor = 1/1000
LDD = Largest Daily Dose of the next product in the same
equipment = 200 mg X 5 tablets of Ibuprofen
MAC = Max Allowable Carryover = 150 X 100 X 1000 x
1000 X 1/1000 X 1/1000
i.e 15000 mg in 100 kg Batch size
i.e 150 mg in 1 kg = 150 ppm
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