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 1970s
Originally sterilized based.
Now evolved into all Product, Process and Facility
matters.
6
WHY VALIDATE ?
Assures Quality

Regulatory Requirement

Reduces Cost

Its the LAW !
7
BENEFITS
Validation can reduce costs by reducing,
Rejects
Reworks
Reliance on In-process controls
Down time
8
WHEN IT GOES WRONG ..?
Reliance on product testing

Loss of confidence

Possibility of adulterated products

Inspection : Observations / 483s
9
VALIDATION TERMINOLOGY
User Requirement Specification (URS)
Design Qualification
Impact Assessment
Factory Acceptance Testing
Installation Qualification
10
VALIDATION TERMINOLOGY
Calibration
Site Acceptance Testing
Operational Qualification
Standard Operating Procedures
Performance Qualification
Process Validation
Change Control
11
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.
12
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. POs, 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.
17
IQ PROTOCOL (CONTENTS)
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
18
IQ PROTOCOL (CONTENTS)
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

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.
24
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)
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
26
OPERATIONAL QUALIFICATION (PROTOCOL)
Sequence testing
Test data sheets
SOPs
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

27
OQ MFG. VESSEL
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.
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.
30
PERFORMANCE QUALIFICATION (PROTOCOL)
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
SOPs
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
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 SOPs
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 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
42
VALIDATION MASTER PLAN
43
Introduction Qualification Personnel Schedule
Preventive
Maintenance
Installation
Operation
Process
Responsibilities
Training
Change
Control
Procedures
Documents
Appendices
VALIDATION POLICY
The companys 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

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 SOPs
Acceptance criteria
- defined to prevent cross contamination
- definition of residue limits
47
PRIOR TO CLEANING VALIDATION
ESTABLISH SPECIFIC SOPS
Cleaning procedure for each piece of equipment
- Flow charts and diagrams
- Cleaning agents, concentration, volume
- Frequency
- time left dirty



48
CLEANING VALIDATION
Sampling procedures
- swabs, rinse, location

Residue limits

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).
53
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.
54
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
55