Process Validation

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Process Validation

• Case Study Heat Sealing Operation for Sterile
  Product An Approach to Process Validation

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Regulatory Requirements (21CFR 820.75)

• Validate It
• Control It
• Revalidate When Appropriate
• Document Throughout

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Benefits of Validation

• Requires thorough understanding of a process
• Provides basis for Process Control
• Improves Product Quality and Reliability
• Reduces risk of patient hazard
• Improves Productivity
• Reduces adverse Regulatory Inspection Findings
• Reduces Field Actions / Complaints

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What Needs Validation?

• Where in-process tests have insufficient
  sensitivity to verify the desired safety and
  efficacy of finished devices
• Where clinical or destructive tests are required
  to verify the process produces the desired result
• Where in-process tests do not reveal all
  variations in safety and efficacy of finished
  devices
• Where process capability is unknown, or is
  suspected barely capable
• From FDA 1996 Compliance Guide

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Examples of Processes That Should Be Validated

• Sterilization Methods
• Clean Room Ambient Condition
• Aseptic Filling Procedures
• Sterile Packaging Sealing Processes
• Lyophilization Process
• Heat Treating Processes
• Plating Processes
• Plastic Injection Molding Process
• Welding Process

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Process Validation Decision Tree
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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Pre-Validation
• From Design Requirements What aspects of the
  product play a role in the process, e.g.
• Sterilization Method
• Packaging
• Equipment Required to Seal
• Shipping Container
• Economics
• Identified Through the Manufacturing Plan Which
  Is Developed in Early Design Stages

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Prepare Validation Plan
• Installation Qualification
• Software Validation
• Operational Qualification
• Process Characterization/Screening Experiment
• Gage RR as needed
• Performance Qualification
• Ongoing Process Controls

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Develop and Approve Protocols
• Approvals should include the appropriate
  functional areas and levels
• Define Success Criteria
• What do you expect from the process
• Prepare and Approve Reports
• Executive Summary and/or Conclusion Statement
• Was Success Criteria Met
• When to Revalidate
• Monitor the Process

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Installation Qualification (IQ)
• Confirm proper equipment installation, utilities,
  and configuration/setup
• Establish Maintenance and Calibration Needs
• Identify Worker Training/Safety Requirements
• Perform Tooling Qualifications Mini-IQ (if
  applicable)
• Define the tool/jig/fixture typically through a
  drawing
• Confirm it matches the drawing
• Are there any maintenance requirements for it
• Are there any utilities associated with it
• Are there any safety concerns
• Are there any measuring gages associated

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Sealer IQ protocol
• Engineering Documentation/Specification
  (Instruction Manual, Standards e.g. ASTM, peel
  pouch specs, etc.)
• Electrical Utility Verification (Voltage, Safety
  Cutoff, Overload Protection, Circuit Breakers,
  etc.)
• Instrument List Within Sealer (Thermocouple and
  Timer Calibrations)
• Preventive Maintenance Established (Manufacturer
  Recommendations)

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Sealer IQ protocol cont
• Equipment Operation Procedure Drafted
• Software Validation Is a separate validation
  needed
• If the software is embedded factory software, it
  shall be considered validated as a result of the
  overall validation as long as all fault
  conditions, alarms, and functionality is tested
  within the validation program
• If the software is a separate package such as a
  Windows-based application, then a separate
  software validation protocol may be required

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Sealer IQ protocol cont
• Equipment Control System Installation (on/off
  switch, indicator lights, stops, breakers,
  guards)
• Test Instrument Control System Installation
  (multimeter)
• Any Discrepancies Resolved

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Process Characterization/Screening
• Designed experiment to identify key input
  variables
• Run process at different settings for the inputs
  (trials) and measure the outputs
• Determine which inputs affect the outputs
• For this example, the process inputs are in the
  form of manufacturers recommendations for
  temperature, hot dwell, and cool dwell
• Outputs will be burst pressure and visual
  examination of the seal

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• One example of characterization techniques is the
  L-8 Array

Center Point
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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• The trials then are

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Operational Qualification (OQ)
• From the screening experiment you can determine
  the inputs that contribute to the maximum output
  variation, i.e., your worst-case condition
• The OQ further challenges the process by
  subjecting it to conditions such as anticipated
  breakdowns like cleaning and maintenance, as well
  as unanticipated conditions like a power failure,
  etc.

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Operational Qualification (OQ)
• Measuring equipment needs to be appropriate for
  intended use. One technique to determine this is
  a Gage RR (Reference ASTM F1469-99 standard for
  Repeatability and Reproducibility)
• Gage Repeatability Reproducibility (Gage RR)
• Measuring instruments are subject to variation,
  therefore, a process validation study cannot be
  meaningful unless the process measuring equipment
  possesses accuracy and precision

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• A Gage RR measures
• Repeatability Amount of variation obtained by
  measuring the same unit (precision) with the
  measuring equipment and same operator
• Reproducibility Amount of variation observed in
  the average of the measurements made by different
  operators using the same unit and same equipment

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Sealer OQ protocol
• Process Characterization complete showing worst
  case parameters
• Process Challenges by generating fault conditions
• Power Failure
• Overload
• Gage RR Completed
• Any Discrepancies Resolved

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Performance Qualification (PQ)
• Demonstrate the process will consistently produce
  acceptable product under normal operating
  conditions
• The PQ then challenges the process by performing
  replicate runs at the defined worst case
  acceptable condition
• Multiple runs/lots captures lot to lot
  variability including raw materials
• Multiple operators captures operator to operator
  variability
• Multiple runs also captures any tear down, setup,
  cleaning, and maintenance activities routinely
  required

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Performance Qualification (PQ) cont
• Running at this worst case condition assures that
  the product will meet all defined requirements
  through all anticipated conditions of
  manufacturing
• Provides data for calculation of process
  capability - Can the process consistently
  produce product that meets specification

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Sealer PQ
• Replicate Runs/Lots Performed
• No Visual Seal Failures
• All Seals Burst Greater Than Spec
• Process Capability Determined to Be ? Cpk of 1.33
• Multiple Operators
• Any Discrepancies Resolved

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Final Validation Report Almost Done
• Summarize and reference all protocols and results
• Conclude the validation status of the process
• State routine monitoring parameters and range
• Criteria for revalidation

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Revalidation Requirements the following are
  examples of conditions in which revalidation may
  be necessary or at least evaluated
• Changes in the actual process that may affect the
  quality of the product
• Negative trends in your quality indicators
• Change in product design affecting process
• Transfer of process to another facility

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Revalidation Requirements cont.
• Changes in external requirements (regulations,
  standards)
• New piece of equipment or modification of
  existing equipment
• Revalidate entire process?
• Not necessarily
• Dependent upon the extent of change
• New equipment may only require an IQ
• Document Decision

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Quality System Mechanism for Revalidation
• Change Order Process
• Are questions built into the CO process to force
  a decision on revalidation, e.g.
• Change to Equipment
• Change to process
• Change to Design
• Change to Supplier
• Nonconformance System
• Calibration/Preventive Maintenance Systems
• Corrective/Preventive Action System

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CASE STUDY Heat Sealer Validation for Sterile
Packaging

• Continuous Monitoring and Process Control
• Ensure the process remains within the established
  parameters
• Control Charts if applicable
• Use the data
• Process shifting, evaluate and adjust while it is
  in range and before there is a need to revalidate
• Nonconformance reports
• Investigate to determine if there is a need for
  corrective action or revalidation

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Conclusions

• Dont be like this
• Engage the validation activities early

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Regulatory Requirements (21CFR 820.75)

• Validate It
• Control It
• Revalidate When Appropriate
• Document Throughout