Validation in Biotech Facilities: What ? Why ? How?

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Validation in Biotech Facilities What ? Why ?
How?

• Dr. PK Yegneswaran

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Presentation Outline

• Validation Overview
• Cleaning Validation
• Process Validation
• Sterilization Validation
• Citation Examples
• Regulatory References

3
Typical Project Schedule
YEAR
Phase III
APPROVAL
Scope
Design
Procurement
Construction
IQ/OQ
Startup / Validation
100
APPROVAL
Spent
4
Typical Post OQ Schedule
YEAR
1H Y4
2H Y4
1H Y5
2H Y5
Phase III
APPROVAL
IQ/OQ/Facility/Utility Qualification
Sterilization Dev.
Sterilization Valdn.
Practice Lots
Cleaning Dev.
File License
Cleaning Valdn.
Validation Lots
APPROVAL
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Validation Overview

• To establish documented evidence which provides
  a high degree of assurance that a specific
  process will consistently produce a product
  meeting pre-determined specifications and quality
  attributes.
• (FDA, May 1987)

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Validation Overview

• Why validate ?
• The FDA requires that we validate all of our
  systems and processes according to 21 CFR part
  211
• Improves our understanding of our manufacturing
  processes
• Right thing to do !

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Why Validate?

• Consistent yield quality
• Rapid decisions when mishaps occur
• Fewer discards
• Less time hosting government agencies, more time
  manufacturing

to ensure that the output is consistent first
time, every time!!
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What do we Validate ?

• Process
• Cleaning
• Sterilization
• Filters
• Containers
• Assays

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How do we Validate ?Cleaning, Process,
Sterilization etc.

• Define Critical Process Parameters, Critical
  Quality Attributes
• Develop protocol describing validation studies
• Consider fractional study approach for cleaning,
  sterilization
• Execute studies
• Address deviations
• Compile report
• Review / Approve report
• GMP Documentation all the way.
• This process applies to all validation

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Definitions

• Critical Process Parameter (CPP)
• An input variable that must be controlled within
  a specified range to ensure success.
• Critical Quality Attribute (CQA)
• An output parameter from a unit operation that
  must be within a specified range to demonstrate
  control, consistency, and acceptable product
  quality.
• CPP CQA
• Ionic Strength Ion Exchange Yield
• Column Load Chromatography Purity
• Flow rate Cleaning Conductivity
• Temperature TOC
• Concn.
• Sat. Steam Sterilization BIs
• Time

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Style-ogen Facility BuiltIQ/OQ Complete What
Next ?

• Sterilization Validation
• Development, validation studies
• Practice Lots
• Define validation parameters for process,
  cleaning, cleaning validation
• Validation Lots
• Process validation, cleaning validation
• File license
• Pre-Approval Inspection
• Facility / Product approval

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Typical Post OQ Schedule
YEAR
1H Y4
2H Y4
1H Y5
2H Y5
Phase III
APPROVAL
IQ/OQ/Facility/Utility Qualification
Sterilization Dev.
Sterilization Valdn.
Practice Lots
Cleaning Dev.
File License
Cleaning Valdn.
Validation Lots
APPROVAL
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Presentation Outline

• Validation Overview
• Cleaning Validation
• Process Validation
• Sterilization Validation
• Citation Examples
• Regulatory References

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Cleaning Validation

• Cleaning Validation overview
• Cycle development for Style-ogen equipment
• Validation of cleaning cycles

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What is Cleaning Validation ?
Equipment cleaning validation is the process of
establishing documented evidence that a
particular cleaning procedure will consistently
reduce equipment surface residuals to a
predetermined acceptable level. Residuals
are any product, degradate, intermediate,
excipient, raw material/reactant or cleaning
agent that may reside on any equipment surface
following processing and/or cleaning.
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21 CFR Part 211 Subpart D - Equipment

• 211.67 Equipment Cleaning and Maintenance
• (a) Equipment and utensils shall be cleaned,
  maintained, and sanitized at appropriate
  intervals to prevent malfunctions or
  contamination that would alter the safety,
  identity, strength, quality, or purity of the
  drug product.

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21 CFR Part 211 Subpart F - Production and
Process Controls

• 211.113 Control of Microbiological Contamination
• (a) Appropriate written procedures, designed to
  prevent objectionable microorganisms in drug
  products not required to be sterile, shall be
  established and followed.
• (b) Appropriate written procedures, designed to
  prevent microbiological contamination of drug
  products purporting to be sterile, shall be
  established and followed.

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One-Third Of Recent Drug GMP Warning Letters
Cite Cleaning Practices (2002 survey)
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Cleaning Validation Where Do I Start?
Define The Process To Be Validated
Manufacturing Process
Cleaning Process
Mfg. Equipment Design
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Manufacturing Process
Considerations

• Obtain a Process Flow Diagram
• Is Product Inactivation Required ?
• (Important to ensure inactivation procedure
  is defined before starting validation)
• Define Applicable Hold Times
• Dirty End of Process to Start of Cleaning
• Clean End of Cleaning to Next Process Use
• Sterile End of SS/SIP to Next Process Use
• What Residuals Need to Be Cleaned by the CIP ?
• Product (includes degradates, excipients, raw
  materials, etc.)
• Cleaning Agents
• Are the Residuals Representative of the
  Process ?
• (Important to consider when validating
  during Practice Runs or Demonstration)
• Is the Equipt. Sanitized or Sterilized after CIP
  ?

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Cleaning Process
Considerations

• Define CIP Type (Manual, Automated)
• Are the Individual Steps of the CIP Procedure
  Defined ?
• Critical Process Parameters Defined ? (e.g.
  Flow, Temp.)
• Is the Cleaning SOP available ?
• Does CIP Procedure Clean All Product Contact
  Surfaces?
• (Highlight and Compare Mfg Process to CIP
  Process on Same PID)
• What CIP Cycle Development Work is Planned?

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Mfg. Equipment Design
Considerations

• Are All Equipt/Systems IQ/OQd ?
• Define Surface Materials of Construction (Prod.
  Contact)
• Ensure General CIP Design Principles Followed
• Minimal to No System Deadlegs
• Turbulent Flow Maintained During CIP
• Full Coverage to Vessel During the CIP
• Lines Flooded Completely During the CIP
• Complete System Drainability
• Assess Validation Sample Locations
• Accessibility
• Availability

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Validation Strategy
Defined in a Protocol and Includes

• Challenge Strategy
• Hold Times
• Fractional Cycle Approach
• No. of Lots Tested
• Product/Equipment Matrix Required
• Test Methods and Sampling Plan
• Rinse Sampling
• Swab Sampling
• Visual Inspection
• Analytical Methods
• Assay Selection (Chemical/Micro)
• Assay Validated (Includes Swab Recovery)
• Acceptance Criteria

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Typical Acceptance Criteria

• Overall surface evaluation final rinse
  sampling analysis
• USP chemical- purified water methodology
• pH 5.0 - 7.0
• Conductivity lt 3 µS/cm
• Endotoxin lt 0.25 EU/mL to lt 10.00 EU/mL
• TOC lt 1.0 ppm(based on system capability)
• Bioburden lt 100 cfu/10mL
• Product specific varies, typically non-detect
• Over Negative Control
• Bioburden sampling is performed in systems
  that are not steamed or sterilized for bioburden
  control

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Back to Style-ogen Bulk Portable Tanks CIP

• Manufacturing Process

• Product is Inactivated with Hypochlorite Prior
  to CIP (SOP)
• Only 100L Portable Tanks Cleaned at Bulk PTS
• One Tank Can Be Cleaned At A Time At Bulk PTS
• Each Tank Can Contain One of the Following
  Product Soils
• Active Ingredient Manny
• Active Ingredient Moe
• Active Ingredient Jack
• 25 Sucrose
• Tank is Not SS/SIP After Cleaning

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Style-ogen - BULK PTS CIP

• Cleaning Process

• Automated CIP Cycle
• Cycle Steps Defined
• Cleaning SOP Available
• Cycle Development
• Planned Concurrent to
• OQ Engineering Lots

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Styleogen - BULK PTS CIP

• Validation Strategy

• How Many Validation Lots?

• 3 Lots Moe (Hardest to Clean)
• 1 Lot Equivalency Each Others

• Use a Fractional Cycle Approach
• Caustic Wash Time Reduced 33
• Final Rinse 5 Eliminated

• Dirty Clean Hold Times Challenged During
  Validation

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Style-ogen - Bulk PTS CIP

• Execute Protocol
• Document deviations
• Collect samples
• Analyze samples
• Check vs Acceptance Criteria
• Pass / Fail / Investigation
• Write Report
• Address deviations
• Review / Approve Report Stakeholders
• Include summary in license document

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Presentation Outline

• Validation Overview
• Cleaning Validation
• Process Validation
• Sterilization Validation
• Citation Examples
• Regulatory References

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Process Validation - Definition
2001-ms-3767

• To establish documented evidence which provides
  a high degree of assurance that a specific
  process will consistently produce a product
  meeting pre-determined specifications and quality
  attributes.
• (FDA, May 1987)

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Why Validate the Process ?

• Demonstrate process control and consistency
• Comply with regulatory requirements for licensure
• Provide assurance that release tests will be met
  the need for some release testing may be
  eliminated.

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Process Validation requires a rational approach
Key Process Variables
Lab-scale process
Optimization/Process Understanding
Process Characterization
Phase I/II Clinical process
Robustness Worst case challenges?
Lab Scale Validation
Manufacturing process
Process Validation
Process Validation at Full-scale
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Characterization vs. Validation

• Characterization
• Validation studies at bench-scale using
  scaled-down models, if possible.
• Well-documented in Lab notebooks and key
  technical reports (no protocol)
• Learning, not Validating
• Validation
• Usually at Full-scale in actual process equipment
  (except for viral clearance and resin/filter
  re-use)
• Conducted by Manufacturing under Protocol
• Testing what we already know, NOT EXPERIMENTING!

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Understand Your Process

• Ruggedness
• Multiple lots of raw materials
• Multiple lots of resins/filters
• Explore failure limits at laboratory/pilot scale
• Scaled-down process should reflect full scale
  manufacturing performance as closely as possible
  so that data generated are relevant.

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Definitions

• Critical Process Parameter (CPP)
• An input variable that must be controlled within
  a specified range to ensure success.
• Critical Quality Attribute (CQA)
• An output parameter from a unit operation that
  must be within a specified range to demonstrate
  control, consistency, and acceptable product
  quality.
• CPP CQA
• Ionic Strength Ion Exchange Yield
• Column Load Chromatography Purity

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Example-Homogenization Step
Function in the manufacturing process Cell
breakage - cell breakage must be ? 70 by
Hematocrit assay.

• Process knowledge
• Scientific rationale
• Tools are simply to provide a basis for
  discussion
• and to facilitate the PV process.

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Back to Style-ogen Process Validation

• 1. Select CPPs, CQAs
• 2. Process Validation Protocol
• 3. Execute
• 4. Assay
• 5. Report
• 6. File

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Process Mapping Step Purpose
Fermentation Thaw/Cell Breakage Microfiltratio
n/Chromatography 1 UF/Chromatography
2 Sterile Filtration Dilution/Adjuvant
Addition
Antigen Release Antigen capture Polishing
purification Sterilization Dose/ adjuvant
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Detailed Step Description
Step Goal Primary purification
Chromatography
Other parameters Feed properties/composition,
salt concentration, temperature, lot-to-lot
feed/resin variability, feed concentration, load

• Equipment constraints
• flow rate
• pressure drop
• Cycle time
• Column size
• Flow distribution

• Sampling plan
• Feed
• Flow-through
• Product

• Characterization
• Size
• Potency
• Lipid
• Carbohydrates
• Yield
• Purity

• Monitoring
• Flow-pressure
• UV
• Conductivity
• HETP

• Support Documents
• Technical memos
• Effect of load
• Cleaning/reuse
• SOPs
• Batch summaries
• Equipment FRS

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Select CPPs, CQAs Factors to Consider

• Impact on product quality
• does the parameter have an impact on a CQA?
• Controllability
• how easy is the parameter to control?
• Recovery potential
• is there a redundant downstream step?
• Use tools such as Criticality Index Analysis

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Example of a Criticality Index Analysis
Cell breakage
Enzyme treatment
Microfiltration
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Process Validation Protocol

• CPPs, CQAs w/ acceptance criteria
• Background / rationale for ranges
• How will they be sampled / monitored ?
• How many validation lots ?
• How will deviations be handled ?
• Define Roles and Responsibilities
• Manufacturing, Quality, Technology

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Process Validation Protocol
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Style-ogen - Process Validation

• Complete 3 Validation Lots
• Obtain, Analyze data
• Address deviations
• Transient deviations
• Equipment malfunctions
• Additional lots if needed
• Complete / approve report
• Include in license

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Presentation Outline

• Validation Overview
• Cleaning Validation
• Process Validation
• Sterilization Validation
• Citation Examples
• Regulatory References

46
Sterilization Validation

• Sterilization Validation overview
• Validation of sterilization cycles (Protocol,
  Acceptance criteria,.)

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Steam Sterilization

• Cell death by protein denaturation
• Simple, reliable economical
• Spores are more resistant than cells
• Spores 100x more resistant to dry heat than
  steam
• Typical cycle gt121ºC for 5-45 minutes
• Saturated steam is critical!

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Kinetics of Microbial Death

• Generally observed to be first-order kinetics
• Non-logarithmic behavior is known
• Kinetic models

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Kinetics of Cell Death
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Kinetics of Cell Death

• Logarithmic decline most applicable to vegetative
  cells
• Spores can show non-log rates
• Spore germination
• Sequential events for death

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Kinetics of Cell Death
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Temperature Effect

• Kinetic rate is a function of temperature
• Arrhenius model typically employed
• Linear correlation between ln(k) and 1/T

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Temperature Effect
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Characterization of Steam Sterilization Cycle
Lethality

• Organism-related
• D-value (log reduction time)
• Z-value (deg. of temp. to reduce D by 1 log)
• Cycle-related
• F-value (integrated lethality delivered)
• Log reduction F/D
• Typically, TR 121.1º C, D 1-3 min (spores)
• Target Fo 36-72 minutes (full cycle)

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D-value

• A measure of the sensitivity of an organism to a
  sterilization method
• Decimal reduction time - time at a given
  temperature required to reduce a population by 1
  log

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Z-value

• A measure of sensitivity of organism to different
  temperatures
• Number of degrees needed to alter the D-value by
  one log
• Allows for integration of the lethal effect of
  heat as the temperature changes.
• Depends on sterilization method
• Steam Z 10º C
• Dry heat Z 21º C

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Z-value

• Spores, Z 8 - 12ºC
• 10º C usually assumed

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F-value

• Integrated amount of lethality delivered during a
  sterilization cycle
• For TR 121º C and Z 10º C, F Fo

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F-value

• Extremely sensitive to temperature
• Fo 1 min at 121º C for t 1 min
• Fo 2 min at 124º C for t 1 min
• Fo 8 min at 130º C for t 1 min
• Log reduction F/D
• D 2 min, Fo 16 min, Log reduction 8
• For SAL 10-6, initial population lt102

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Typical SIP Cycle

• Come-up
• Purge air
• Add steam
• Wait to reach sterilization temperature
• Dwell
• Hold at Tgt121 C for fixed time or Fo
• Cool-down
• Turn steam off and cool system down
• Pressurize with air

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Sterilization Validation

• Fractional cycle approach
• Challenge with 106 G. stearothermophilus spores
• Run validation studies to obtain a 6 log
  reduction of G. stearo. spores
• Production cycle will be based on a theoretical
  12 log reduction
• Establish continuing validation schedule and
  change control for validated cycle.

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Sterilization Validation (SIP)

• Place spore challenges throughout the system
  targeting worst case locations (Geobacillus
  stearothermophilus)
• Run a fractional sterilization cycle (reduced
  temperature and/or time)
• Evaluate the temperatures (Fo) at each location
• Evaluate saturated steam conditions
• Evaluate the kill/inactivation of the spores
• Perform 3 fractional cycle studies followed by 1
  production cycle study

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Sterilization Validation Positioning of
Thermocouples
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Validation Complete What Next?
YEAR
1H Y4
2H Y4
1H Y5
2H Y5
Phase III
APPROVAL
IQ/OQ/Facility/Utility Qualification
Sterilization Dev.
Start Change Control
Sterilization Valdn.
Practice Lots
Cleaning Dev.
File License
Cleaning Valdn.
Validation Lots
APPROVAL
65
Implement Change Control

• Changes happen.
• Need to
• Document changes
• Assess impact on validation
• Revalidate as necessary
• File as necessary

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Presentation Outline

• Validation Overview
• Cleaning Validation
• Process Validation
• Sterilization Validation
• Citation Examples
• Regulatory References

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Recent FDA Observations - Cleaning
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Recent FDA Observations - Sterilization
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Recent FDA Observations - Process
70
Regulatory References

• FDA guidance documents
• CMC Guidance
• http//www.fda.gov/cber/gdlns/cmcvacc.pdf
• Sterilization Validation
• http//www.fda.gov/cber/gdlns/sterval.pdf
• Process Validation
• http//www.fda.gov/cder/guidance/pv.htm
• PAT approach
• http//www.fda.gov/cder/guidance/6419fnl.htm

• FDA guidance documents
• CMC Guidance
• http//www.fda.gov/cber/gdlns/cmcvacc.pdf
• Sterilization Validation
• http//www.fda.gov/cber/gdlns/sterval.pdf
• Process Validation
• http//www.fda.gov/cder/guidance/pv.htm
• PAT approach
• http//www.fda.gov/cder/guidance/6419fnl.htm