Overview of Validation Requirements
in
Pharmaceutical Industry
Kaushik Desai
Chairman,
Industrial Pharmacy Division
Indian Pharmaceutical Association
www.ipapharma.org
1
AGENDA
A definition
 Where did validation come from ?
 Why do it ?
 What are the benefits ?
 How far do we have to go ?

2
DEFINITION ( FDA)
“ 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)
3
DEFINITION ( FDA)
“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)
4
DEFINITION (EU GMP)
“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)
5
WHERE DID VALIDATION COME FROM ?

Began in 1970’s
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Originally sterilized based.
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Now evolved into all Product, Process and Facility
matters.
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WHY VALIDATE ?

Assures Quality

Regulatory Requirement

Reduces Cost

It’s the LAW !
7
BENEFITS
Validation can reduce costs by reducing,

Rejects
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Reworks
Reliance on In-process controls
Down time
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8
WHEN IT GOES WRONG …..?
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Reliance on product testing
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Loss of confidence
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Possibility of adulterated products
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Inspection : Observations / 483’s
9
VALIDATION TERMINOLOGY

User Requirement Specification (URS)

Design Qualification

Impact Assessment

Factory Acceptance Testing

Installation Qualification
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VALIDATION TERMINOLOGY
Calibration
 Site Acceptance Testing
 Operational Qualification
 Standard Operating Procedures
 Performance Qualification
 Process Validation
 Change Control
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VALIDATION TERMINOLOGY
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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VALIDATION TERMINOLOGY
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)
13
VALIDATION TERMINOLOGY
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
14
VALIDATION TERMINOLOGY
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)
15
INSTALLATION QUALIFICATION (DEFINITION)

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.
16
INSTALLATION QUALIFICATION (PURPOSE)

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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IQ PROTOCOL (CONTENTS)
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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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IQ PROTOCOL (CONTENTS)
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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
19
BASIC IQ – MFG. VESSEL
Parameters
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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?
20
IQ PROTOCOL APPROVAL

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.
21
VALIDATION TERMINOLOGY
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.
22
VALIDATION TERMINOLOGY
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)
23
OPERATIONAL QUALIFICATION (DEFINITION)

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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OPERATIONAL QUALIFICATION (PURPOSE)

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.
25
OPERATIONAL QUALIFICATION (PROTOCOL)
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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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OPERATIONAL QUALIFICATION (PROTOCOL)
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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OQ – MFG. VESSEL
Parameters
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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.
28
PERFORMANCE QUALIFICATION (DEFINITION)

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.
29
PERFORMANCE QUALIFICATION (PURPOSE)

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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PERFORMANCE QUALIFICATION (PROTOCOL)
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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
31
VALIDATION TERMINOLOGY
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.
32
US FDA (21 CFR)– PROCESS VALIDATION

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)
33
PROCESS VALIDATION
Life Cycle of the product & the process

Stage 1 – Process Design

Stage 2 – Process qualification

Stage 3 - Continuous process verification
34
STAGE 1 - PROCESS DESIGN

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.
35
STAGE 2 – PROCESS QUALIFICATION

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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).
36
CONCURRENT RELEASE
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

Short Shelf-life radio pharmaceuticals
37
SATGE 3 – CONTINUED PROCESS VERIFICATION

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.
38
VALIDATION TERMINOLOGY
Change Control

Formal evaluation of the potential impact of
planned modifications on the validated status
of a product, process or facility.
39
TRAINING
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

40
FINAL SUMMARY REPORT

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.
41
BASIC IQ/OQ/PQ
Commissioning and Qualification
Project Phases
Technology Transfer
Conceptual Design
Basic Design
Detailed Design
Procurement
Construction
Pre commissioning
Commissioning
Validation Phases
Collecting data
Preliminary VMP
Detailed VMP
Detailed planning,DQ
IQ
OQ
Process operation / Validation
42
VALIDATION MASTER PLAN
Introduction
Qualification
Personnel
Installation
Responsibilities
Operation
Training
Schedule
Preventive
Maintenance
Change
Control
Procedures
Documents
Appendices
Process
43
VALIDATION POLICY
The company’s overall policy, intentions and
approach to validation, including :
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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
44
PRODUCT VALIDATION

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.
45
CLEANING VALIDATION

Cleaning validation is establishing
documented evidence that the equipment
is consistently cleaned from product,
microbial and cleaning agent residues to
predetermined acceptable levels.
46
FDA EXPECTATIONS
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

47
PRIOR TO CLEANING VALIDATION
ESTABLISH SPECIFIC SOP’S
Cleaning procedure for each piece of equipment
- Flow charts and diagrams
- Cleaning agents, concentration, volume
- Frequency
- time left ‘dirty’
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48
CLEANING VALIDATION
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Sampling procedures
- swabs, rinse, location
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Residue limits
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Analytical methods
49
CLEANING VALIDATION

Validation report
- Results Vs. acceptance criteria
- Deviations and how handled
- Conclusion that cleaning process is
validated
50
REVALIDATION

Major change in cleaning procedure

Change in cleaning agent

New equipment
51
ESTABLISHMENT OF LIMITS

Knowledge of the materials
- Potency of the drug
- Pharmacological and toxic properties
- Degradation products
- Cleaning agents
- Micro residues
52
ESTABLISHMENT OF LIMITS
Residual Limits must be………….
 Practical
 Achievable
 Verifiable
 Safe
FDA does not set acceptance specifications (limits).
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SETTING OF LIMITS
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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EXAMPLE
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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