Validation
SAPRAA
March 2013
Presentation
What will be covered in this presentation…..
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Why do we validate?
What do we validate?
Approach to validation
Qualification
Process validation – a look at the FDA guidelines
Purpose of Validation
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GMP Guide
Chapter 5, Annex
11, Annex 15
 In compliance
Dossier
submission
Ever look at
those files…..
Factors affecting quality
Personnel
Validated processes
Procedures
OR
Raw Materials
Equipment
Packing Materials
Premises
Environment
Validation
Change Control
FDA Warning Letters
Why do we validate
 Manufacturers must assume responsibility for
the quality of products & ensure they are:
o fit for use
o comply with registered requirements
o do not place patients at risk
Why do we validate
 Validation establishes & provides documented
evidence that premises, utilities and equipment:
o are designed in accordance with GMP
o are installed in compliance with design criteria
o operate in accordance with design criteria
 Validation establishes that a specific process
will consistently produce a product meeting its
pre-determined specification
Validation
 Validation a requirement not an option
 Is validation a ‘tick box’?
 Validation documentation always checked in GMP
inspection (the ‘action of proving..’)
 MCC and PIC/S….. design, installation, operational
and performance…. qualification
 MCC and PIC/s…. validation of processes, cleaning
and analytical methods…. validation
 A system or equipment must be qualified in order to
operate in a validated process
 Process validation protocols required for dossier
submission
Validation / Qualification
Validation:
Proving procedures, processes, equipment, materials,
activities, systems lead to the expected results
Qualification:
Proving and documenting premises, systems, equipment
properly installed and/or work correctly & lead to the
expected results
Qualification often initial stage of validation, individual
steps alone do not constitute process validation
What gets validated
Facilities
 Utilities / Services / Systems
 Equipment
 Computer systems
 Analytical methods
 Cleaning methods
 Processes
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Facilities, systems and equipment qualified prior to
process validation being completed
What gets validated
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Utilities / Services / Systems
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Critical systems with direct impact e.g.
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Purified Water
HVAC
Compressed air (in contact with product or
primary containers)
Steam (if used for cleaning product contact
surfaces)
What gets validated
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Processes
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Non-sterile manufacturing
Sterile manufacturing – media fills
Sterilizing loads
Waste
Sequencing of Validation Stages
Site Master File
Overall Validation Master
Plan
Validation SOP
Documents that are
required to be in
place and are
routinely updated
Validation Master Plan
User Requirement Specification
Design Qualification
Installation Qualification
Operational Qualification
Performance Qualification
Process Validation
Approach to Validation
Validation requires:
 Collaboration between the all relevant
parties (validation, QA, production,
engineering, consultants, contractors)
 Resources – time, budget, people
 Planning (including defining scope of
work) and control
Approach to Validation
Planning
 Risk-based approach to validation; not all components
need to be validated
 Avoids making validation unnecessarily complex
 A Risk Assessment or Impact Assessment
determines which components are critical and noncritical, or have a direct impact or indirect impact on
product quality
 Critical Process Parameters & Critical Quality
Attributes
These decisions have implications on the extent,
cost and time of the qualification process
ISPE Commissioning and
Qualification
Fig. 1.1
ISPE Pharmaceutical Engineering Baseline Guide: Commissioning and Qualification
Vol. 5 March 2001
Impact Spectrum
Fig. 2.1
ISPE Pharmaceutical Engineering Baseline Guide: Commissioning and Qualification
Vol. 5 March 2001
Qualification Requirements
Direct Impact Systems
 Direct impact on product
quality
 Designed &
commissioned in line with
GEP
 Also subject to
qualification
Indirect Impact Systems
 No direct impact on
product quality
 Designed &
commissioned in line with
GEP
 No qualification required
Impact Assessment
Indicators
Direct Impact
Components
Direct Impact Systems
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Direct contact with product
(e.g. air)
Produces an excipient /
ingredient (e.g. WFI)
Used in cleaning / sterilizing
- malfunction could result in
failure which poses risk
Controls a risk to the
product (e.g. Nitrogen
blanket)
Produces data used to
accept / reject product
Produces identification
information (e.g. expiry
date)
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Used to demonstrate
compliance with registered
process (e.g. hardness tester)
Has a direct effect on product
quality (e.g. blister embossing)
Failure or alarm of component
having a direct effect on
product quality (e.g. in-line
TOC)
Information from component
recorded as part of batch
record (e.g. drying
temperature)
Has direct contact with product
Approach to Validation
Verification and GEP
 Verification and GEP – processes that function
within the engineering environment
 Support the validation effort
 Operate continually, not only at one point in
time
 Based on quality management principles e.g.
documentation control, change management,
authorization processes, deviations /
discrepancies
Approach to Validation
Engineering Risk-based Verification
 Risk Management applied - identifies critical
aspects for product quality & patient safety
 List of critical aspects approved by QA
 Acceptance criteria specified for the critical
aspects
 Non-critical aspects may be included (do not
require same level of involvement by QA)
 Acceptance and release must provide
documented confirmation of fitness for
intended use
Approach to Validation
Verification Execution
 Verification confirms critical aspects meet
acceptance criteria
 Extent of verification commensurate to risk to
product quality
 Execution:
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Design review
Factory Acceptance Test (FAT)
Site Acceptance Test (SAT)
Installation testing
Functional testing
Performance testing
Handling of discrepancies, change management
Acceptance and release
Good Engineering Practice
 Focus on practices that add value - providing
evidence of fitness for use & proper
performance
 GEP is expected in pharmaceutical
enterprises; it is not required by GxP
regulations
 However value of effective GEP is supported
by regulatory and engineering guidance /
standards
Qualification Approaches
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International regulations: facilities, equipment &
systems qualified and automation systems validated
ISPE Guide: ensures facilities, equipment, systems,
and associated automation are ‘fit for intended use’
ISPE Guide: states critical aspects, and the
installation & operational acceptance criteria
documented in the final risk assessment / design
review could be labeled as the IQ / OQ
Emphasis on ensuring fitness for use through
verification activities during the life cycle rather than
‘incidents’ that represent qualification
Life Cycle
Fig. 2.2
ISPE Guide: Science and Risk-Based Approach for the Delivery of Facilities,
Systems and Equipment (2011)
Sequencing of Validation Stages
Site Master File
Overall Validation Master
Plan
Validation SOP
Documents that are
required to be in
place and are
routinely updated
Validation Master Plan
User Requirement Specification
Design Qualification
Installation Qualification
Operational Qualification
Performance Qualification
Process Validation
User Requirement Specification (URS)
Details of requirements from an operational and GMP
perspective
One of the most important documents but usually drafted
as an after thought!
Examples:
 Speed e.g. 200 bottles per minute
 Temperature e.g. drying temperature range 50 to 80ºC
 Finishes e.g. SS304
 Safety features e.g. guards
 Documentation required e.g. manuals
Design Qualification(DQ)
Verification that what is to be supplied is in line with the
requirements specified in the URS and will meet GMP
requirements
Does the design incorporate sufficient provisions to
control all risks to the end user?
Examples:
 Speed e.g. 50 to 200 bottles per minute
 Temperature e.g. drying temperature range 35 to 90ºC
 Finishes e.g. mild steel (does not meet requirements)
 Safety features e.g. guards present
 Documentation required e.g. manuals available
Installation Qualification (IQ)
Installation complies with design specification and
manufacturer’s recommendations
Examples:
 Correct make / model installed
 All components present
 Connections made
 Instruments calibrated
 As-built drawings available and correct
 Materials of construction correct
Installation Qualification (IQ)
A thoroughly executed IQ process ensures:
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A fully verified installation that complies with the
documented design
All deviations and changes recorded, assessed and
approved
Accurate ‘as built’ drawings available and verified
Calibration of measuring instruments completed
Materials of construction verified
Operational Qualification (OQ)
Installation performs as intended throughout the
anticipated operating ranges
Examples:
 Test, for example, speeds / temperatures / fill volumes
through full operating range & comparable load (inert
material used if required)
 Test alarms
 Test safety mechanisms
 Test interventions, stoppages, start-up etc.
 Operational and maintenance procedures available
 PPM and calibration schedules are drafted
 SOPs are compiled & authorized
 Training performed & documented
Operational Qualification (OQ)
A thoroughly executed OQ process ensures:
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Formal commissioning reports available
Ability of systems to maintain set points in all operational
modes demonstrated
Correct functioning of the control system demonstrated
All alarms verified as functioning correctly
Operational ranges, specific alert and action limits
identified
Operational and Maintenance manuals available
PPM and calibration schedules available
SOPs available and authorized
Personnel training successfully completed
Performance Qualification (PQ)
Effective and reproducible performance, based on the
approved process method and product specification
Does the qualification provide assurance that the system /
equipment is fit for use and any deviations from
specification have been identified and evaluated?
Examples:
 Performance of filling equipment:
 Consistent fill volume within registered specification
using placebo product
 Performance of Purified Water system:
 Microbial contamination within specification
 Performance of HVAC:
 Non-viable particle count within specification
Performance Qualification (PQ)
A thoroughly executed PQ process ensures:
 Demonstration of consistent delivery of process /
product specification
 Demonstration that the systems have been
successfully validated and will not contribute any
risk to the quality of products routinely produced
 Re-validation criteria, where required, have been
formalized
Process Validation
FDA
Guidance for Industry
Process Validation: General Principles and
Practices
January 2011 Revision 1
 ‘…aligns process validation activities with a
product lifecycle concept…’
 ICH Q8 Pharmaceutical Development
 ICH Q9 Quality Risk Management
 ICH Q10 Pharmaceutical Quality System
Process Validation
FDA Process Validation: General Principles
and Practices
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‘The lifecycle concept links product and process
development, qualification of the commercial
manufacturing process, and maintenance of the
process in a state of control during routine
commercial production.’
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
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Guidance covers:
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Human drugs
Veterinary drugs
Biological and biotechnology products
Finished products and APIs/drug substances
The drug constituent of a combination (drug &
medical device) product
Medical devices, dietary supplements, human
tissues, medicates feeds excluded
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
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Products should be produced that are fit for their
intended use
Quality, safety and efficacy are built into the product
Quality cannot be adequately assured through inprocess and final product inspection and testing
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
‘… process validation is defined as the collection and
evaluation of data, from the process design stage through
commercial production, which establishes scientific
evidence that a process is capable of consistently
delivering quality product…’
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Stage 1- Process Design: Commercial manufacturing process
defined through development & scale up activities
Stage 2 – Process Qualification: Process design evaluated to
verify capability of reproducible commercial manufacturing
Stage 3 – Continued Process Verification: On going assurance
during routine production that process remains in state of control
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
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Gain high degree of assurance in performance of
manufacturing process before any commercial batch is
distributed for use
 Attributes consistent
 Identity
 Strength
 Quality
 Purity
 Potency
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
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Successful validation depends on information /
knowledge from product & process development
 Understand sources of variation
 Detect presence & degree of variation
 Understand impact of variation
 Control variation (commensurate with risk to process
& product)
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
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Focus on qualification without understanding the process
and variation may not lead to quality assurance
Continue to maintain state of control during lifecycle
regardless of changes (materials / equipment / facilities /
personnel)
On-going programs collect and analyze data to evaluate
state of control
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
Stage 1 – Process Design
 Do not need cGMP conditions
 Sound scientific methods & principles, good
documentation practices (ICH Q10)
 Decisions & justification of controls documented and
reviewed – value for use and later adaptation
 Product development provides key inputs to quality
attributes and manufacturing process
 Functionality & limitations of commercial manufacturing
equipment considered
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
Stage 1 – Process Design
 Predicted variability considered
 Strategies for process control:
 Reduce input variation
 Adjust for input variation (to reduce impact on output)
 Both
 Process controls address variability → assures quality
 Controls:
 Examination of material quality
 Equipment monitoring
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
Stage 2 – Process Qualification
 Determine capability for reproducible commercial
manufacture
 Two elements:
 Facility design & equipment / utilities qualification
 Process Performance Qualification
 Successful completion before distribution of product
(FDA expects concurrent release to be rarely used)
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
Stage 2 – Process Qualification
 Qualification: Demonstrate utilities and equipment are
suitable for intended use and perform properly
 Qualification must precede Process Performance
Qualification (PPQ)
 PPQ combines facility, utilities, equipment, trained
personnel, commercial manufacturing process, control
procedures and materials / components
 Successful PPQ required before distributing product
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
Stage 2 – Process Qualification
 PPQ has:
 Higher level of sampling
 Additional testing
 Greater scrutiny of process performance
 Above could be extended in certain cases e.g.
complexity of process, production volume
 Manufacture under normal conditions using routine
personnel
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
Stage 2 – Process Qualification
 PPQ protocol:
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Manufacturing conditions (including operating parameters,
processing limits, materials)
Data to be collected (when, how, evaluation)
Tests to be performed and acceptance criteria
Sampling plan (sampling points, number of samples, frequency
of sampling)
Process performance indicators (statistically based)
Status of qualification & analytical method validation
Process for addressing deviations
Review & approval
FDA Guidance for Industry, Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
Stage 3 – Continued Process Verification
 Objective: Continual assurance that process remains in
a state of control / validated state
 Managing change
 Routine monitoring systems, maintenance, calibration
 Data collection & review (product reviews)
 Evaluation of process – identify problems, corrective /
preventative actions
 Statistical process control techniques
FDA Guidance for Industry, Process Validation: General Principles and Practices
January 2011 Revision 1
Process Validation
FDA Process Validation: General Principles
and Practices
Stage 3 – Continued Process Verification
 Changes include:
 API supplier
 Excipient physical properties
 Primary packaging material
 Equipment
 Process
 Facility / plant
 Changes require documented description, well-justified
rationale, implementation plan, QA approval
Concurrent & Retrospective
Validation
 Concurrent: Validation carried out during routine
production of products intended for sale
 Exceptional cases
 Justified, documented, approved
 Retrospective: Validation based on historical /
collected data (manufacturing, testing, control
data)
 Only for well established processes
 Inappropriate where changes to
composition, equipment & processes made
 Suggested source data
Challenges / Issues
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Timing
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Generating the protocol for submission
Technology transfer from design to commercial
PPQ batches manufactured but cannot be released
Time for regulatory approval
Launch
New sites for existing products - protocol and
results
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Prospective vs. concurrent
Availability of design data and initial validation data
Risk
Challenges / Issues
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Multi-disciplinary teams
PPQ performed when equipment / utilities have
not
Robust Change Control process
Data collection and review