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Clean In Place Technlogies BioPharma Facilities

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  • 1. Cleaning Technologies in BIOPHARMA PROCESSES August 29, 2007 Ranjeet Kumar M Tech (Chemical)
  • 2. Cleaning Overview
    • Cleaning a challenge in Biopharmaceutical facility
    • Steps of CIP
    • Factors affecting Cleaning efficiency
    • Effects of Turbulence
    • Cleaning Mechanisms
    • Validation
  • 3. Principles
    • Cleaning can be defined as removal of the previous active ingredients to the acceptable level.
    • Carry over of dirt is influenced by:
      • Nature of dirt.
      • Nature of the surface of equipment – Vessel surface, centrifuge, filters
      • Accessibility to cleaning – vessel top, agitators, valve body, hold up
    • Typical Biopharma residues
      • Proteins, Lipids
      • Sugars, Salts
      • Nucleic Acids, Viable Organisms
      • Endotoxins
  • 4. Challenges in Cleaning
    • Cleaning can be done by any method so long as it cleans.
      • Manual cleaning
      • Semi-manual
      • Automated
    • Automation is required to –
      • Track cleaning procedure & record data
      • Assurance of repeatability
    • Automation is to ensure repeatability and confidence and is not a necessity.
    21 CFR Part 211.67 – guidelines for Equipment Cleaning & Maintenance.
  • 5. Clean In Place a Step Ahead
    • Consistent Cleaning Process
    • Resource Savings (water, electricity, chemicals)
    • High Quality Result
    • Time Saving
    • Less Manual Work
    • Higher Safety for Personnel
    • Documented Process
    • Minimum load on Waste Treatment.
  • 6. Steps of CIP
    • Wash and drain (Ambient Temp)
    • Alkali Wash (High Temp, Recirculation)
    • Rinse - Purified water
    • Acid Wash (Cleaning & Neutralization)
    • Rinse – Purified water
    • Rinse – WFI
    • Rinse – WFI (Conductivity Check)
      • AIR BLOW AFTER EACH RINSE TO REMOVE PREVIOUS SOLUTION
  • 7. Factors Affecting Cleaning Efficiency
    • Cleaning Solution Temperature
    • Cleaning Solution Concentration
    • Cleaning Time
    • External Energy (Spray Device, Agitation, Baffle, Turbulence)
  • 8. Solution Temperature
    • Chemical cleaning is a chemical process & Increased Temperature ↔
      • Increases – Solubility, Reaction Rates & Precipitation
      • Decreases – Bond Strength & Viscosity
    • Optimum temperature should be defined for different type of equipment.
    • Range – Alkali Rinse – 50-80 ° C & for Acid Rinse – 30-60 ° C.
    • Defined on residual characteristics.
  • 9. Cleaning Agents
    • Concentration of chemical increases Cleaning Efficiency
    • Alkali Concentration- 0.25 M
    • Acid Concentration- 0.1 M
    • Adjustable for each cleaning operation based upon Residue Characteristics
    • Chemical should be efficient in cleaning action – simple or formulated chemical
    • Not a part of manufacturing process – should be rinsed off completely or up to a defined level
  • 10. Cleaning Time
    • Cleaning duration should be enough to remove process residue & chemicals
    • Increased Contact Time ↔ will improve cleaning process but have more cost.
    • Ensure repeatable results
    • Alkali Wash : 5 – 40 min
    • Acid Wash : 5 – 20 min
    • Adjustable for each cleaning operation based upon residue characteristics
    • Time should be based on –
        • Specified turn over volume
        • Monitoring return conductivity
    • Rinse volume –
        • Volumetric flow rate
        • Circuit hold up volume
  • 11. Fermentor & Its Transfer Lines
  • 12. CIP Solution Collection
  • 13. Recirculation Of CIP Solution
  • 14. Cleaning of Transfer Lines
  • 15. Design of CIP system
    • Capable of heating through heat exchanger.
    • Should have a pump to deliver flow at the rate of 1.5 m/ sec.
    • Capable of adding Alkali & Acid and measuring concentration using conductivity.
    • Capable of recycling
    • Capable of repeating if temperature and velocity is incorrect.
    • Capable of performing self CIP
    • Capable of SIP if infectious organisms are handled.
  • 16. CIP Cycle Development (CD)….
    • It is a three stage program of
        • Water run to check CIP Path
        • Chemical run to check rinsing of alkali
        • soiled CIP
    • Contamination Risk Management strategy - to determine control & alarm set points, and ensure cleaning cycle robust, repeatable & efficient.
    • The purpose of the CIP CD program is to identify and resolve cleaning challenges prior to beginning the cleaning validation & Production.
    CIP CD is also a Project Execution Strategy
  • 17. CD an Investment on
    • Practical lessons learned from a CIP CD program –
    • case study, parameters setting, safety study, SOP practice, etc.
    • What efficiencies can be gained which demonstrate a Return On Investment (ROI), in a CIP CD program?
    • Cost of problem solving, benefit of manufacturing improvement, research investment.
  • 18. CIP CD program should have
    • System boundaries & mechanical configuration.
    • Automation specification.
    • Rationale for the configurable parameters.
    • Understanding – Equipment, CIP circuit, & residue grouping strategies.
    • Pre approved Protocol / checklist.
    • Project management.
    • Assurance for Cleaning Validation priorities – cleaning, repeatability, cycle time & “DONE?”
  • 19.  
  • 20. Validation
    • Riboflavin test for Coverage
    • Conductivity for Cleanliness
    • T.O.C for residual matter
    • Swab test
    • Flow Measurement
    • Temperature stabilization
    • Dead Leg & Drainability check
      • Validation Assumes That Cleaning is: -
      • Effective,
      • Reliable,
      • Repeatable