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SAPRAAMarch 2013
Validation
Presentation
What will be covered in this presentation….. Why do we validate? What do we validate? Approach to validation Qualification Process validation – a look at the FDA guidelines
Purpose of Validation
GMP Guide Chapter 5, Annex 11, Annex 15 In compliance
Dossier submission
Ever look at those files…..
Factors affecting quality
Raw Materials
Personnel
ProceduresValidated processes
Equipment
PremisesEnvironment
Packing Materials
OR
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 useo comply with registered requirementso 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 GMPo are installed in compliance with design criteriao 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 resultsQualification 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
Facilities, systems and equipment qualified prior to process validation being completed
What gets validated
Utilities / Services / Systems Critical systems with direct impact e.g.
Purified Water HVAC Compressed air (in contact with product or
primary containers) Steam (if used for cleaning product contact
surfaces)
What gets validated
Processes Non-sterile manufacturing Sterile manufacturing – media fills Sterilizing loads Waste
Sequencing of Validation Stages
Validation Master Plan
Design Qualification
User Requirement Specification
Installation Qualification
Operational Qualification
Performance Qualification
Site Master File
Overall Validation Master Plan
Documents that are required to be in place and are routinely updated
Process ValidationValidation SOP
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 ValidationPlanning
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 non-critical, 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. 1.1ISPE Pharmaceutical Engineering Baseline Guide: Commissioning and Qualification Vol. 5 March 2001
Impact Spectrum
Fig. 2.1ISPE 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 Systems 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)
Direct Impact Components
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 ValidationVerification 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 ValidationEngineering 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 ValidationVerification Execution
Verification confirms critical aspects meet acceptance criteria
Extent of verification commensurate to risk to product quality
Execution: 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
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. 2.2ISPE Guide: Science and Risk-Based Approach for the Delivery of Facilities, Systems and Equipment (2011)
Sequencing of Validation Stages
Validation Master Plan
Design Qualification
User Requirement Specification
Installation Qualification
Operational Qualification
Performance Qualification
Site Master File
Overall Validation Master Plan
Documents that are required to be in place and are routinely updated
Process ValidationValidation SOP
User Requirement Specification (URS)
Details of requirements from an operational and GMP perspectiveOne 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: 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: 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 ValidationFDA Process Validation: General Principles and Practices
‘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 ValidationFDA Process Validation: General Principles and Practices
Guidance covers: 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 excludedFDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process ValidationFDA Process Validation: General Principles and Practices
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 in-
process and final product inspection and testing
FDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process ValidationFDA 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…’
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 ValidationFDA Process Validation: General Principles and Practices
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 ValidationFDA Process Validation: General Principles and Practices
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 ValidationFDA Process Validation: General Principles and Practices
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 ValidationFDA 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 consideredFDA Guidance for Industry
Process Validation: General Principles and Practices
January 2011 Revision 1
Process ValidationFDA 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 ValidationFDA 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 ValidationFDA 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 ValidationFDA 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 ValidationFDA Process Validation: General Principles and Practices
Stage 2 – Process Qualification PPQ protocol:
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 ValidationFDA 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 ValidationFDA 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
Timing 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 Prospective vs. concurrent Availability of design data and initial validation data Risk
Challenges / Issues
Multi-disciplinary teams PPQ performed when equipment / utilities have
not Robust Change Control process Data collection and review
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