Clean In Place Technlogies BioPharma Facilities


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Clean In Place Technlogies BioPharma Facilities

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