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cGMP Case Study Training

This is a presentation that I developed and gave to the GMP constituency of a medium-sized biopharmaceutical company to satisfy one of the requirements for ongoing cGMP training. I feel that it very well epitomizes one of my central philosophies surrounding GXP and regulatory topic training -- STORYTELLING.

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cGMP Case Study Training

  1. 1. Chet French Manager, Global Safety Amylin Pharmaceuticals, Inc. November 2007 Lessons Learned: cGMP Case Studies
  2. 2. cGMP Case Studies Training Session Agenda <ul><li>Agenda: </li></ul><ul><li>Introduction </li></ul><ul><li>Case #1 : IV Bottle Contamination (Abbott Laboratories) </li></ul><ul><li>Case #2: Hemodialysis Filters (Baxter Pharmaceuticals) </li></ul><ul><li>Case #3: Albuterol Inhalers (Schering Plough) </li></ul>
  3. 3. 21 CFR Parts 210/211 cGMPs <ul><li>Subparts : </li></ul><ul><li>A General Provisions </li></ul><ul><li>B Organization and Personnel </li></ul><ul><li>C Buildings and Facilities </li></ul><ul><li>D Equipment </li></ul><ul><li>E Control of Components and Drug Product Containers and Closures </li></ul><ul><li>F Production and Process Controls </li></ul><ul><li>G Packaging and Labeling Controls </li></ul><ul><li>H Holding and Distribution </li></ul><ul><li>I Laboratory Controls </li></ul><ul><li>J Records and Reports </li></ul><ul><li>K Returned and Salvaged Drug Products </li></ul>
  4. 4. cGMPs Raising the “Bar of Expectations ” Tragedies Technology Evolution The Bar of Expectations
  5. 5. cGMPs “Raising the Bar”
  6. 6. Regulations: Good or Bad ?
  7. 7. Regulations: Good or Bad ? Medical Mistakes
  8. 8. Regulations: A Good or Bad? Medical Mistakes <ul><li>5% of people admitted to hospitals incur an iatrogenic infection </li></ul><ul><li>3.3% incur Adverse Event </li></ul><ul><li>56% of Adverse Events are attributable to mistakes . </li></ul><ul><li>Medical mistakes kill 44,000 - 98,000 people annually in U.S. </li></ul><ul><li>Your chance of being killed by mistake = 1:500 ! </li></ul><ul><li>Source : National Institute of Medicine Nov 2000 </li></ul>
  9. 9. IV Bottle Contamination Case <ul><li>CASE #1 </li></ul><ul><li>IV Bottle Contamination </li></ul>
  10. 10. IV Bottle Contamination Case Background <ul><li>October 1970 – March 1, 1971 </li></ul><ul><li>150 bacteremias caused by Enterobacter Cloacae </li></ul><ul><li>8 U.S. hospitals </li></ul><ul><li>Commonality Observed </li></ul><ul><ul><ul><ul><li>– All used fluids and IV systems manufactured by Abbott Laboratories </li></ul></ul></ul></ul>
  11. 11. IV Bottle Contamination Case Background <ul><li>Enterobacter Cloacae </li></ul><ul><li>Gram-Negative Organism </li></ul><ul><li>A relatively common “ICU bug” </li></ul><ul><li>Opportunistic pathogen among the vulnerable (i.e. infants and the elderly) </li></ul>
  12. 12. Abbott Laboratories Company Background 1970 <ul><li>A Diversified Company: </li></ul><ul><ul><ul><li>Consumer Goods (Selsun ® , Murine ® , Similac ® ) 1960’s </li></ul></ul></ul><ul><ul><ul><li>Hospital Products (Monitors, IV Equipment, Drug Testing). </li></ul></ul></ul><ul><ul><li>Cyclamate = 30% of Revenue </li></ul></ul><ul><ul><li>Largest Supplier of IV Fluid in U.S. </li></ul></ul><ul><ul><ul><li>45% Marketshare </li></ul></ul></ul>
  13. 13. IV Bottle Contamination Case IV-Associated Septicemias 1970-1971 Week of Onset 9/26/70 3/13/71 1/23/71
  14. 14. IV Bottle Contamination Case Abbott Laboratories IV Bottle - New Cap Design 1970 Abbott Laboratories USP 5% Dextrose Saline
  15. 15. IV Bottle Contamination Case Abbott Laboratories IV Bottle - New Cap Design 1970 Elastomer Liner Old Design Metal Slip Disc Glue Plastic Disc New Design Metal Slip Disc Red Rubber Disc Gilsonite
  16. 16. IV Bottle Contamination Case Contamination Intrusion
  17. 17. IV Bottle Contamination Case Outcome <ul><li>Contaminated Bottles linked to: </li></ul><ul><ul><ul><li>>434 Infections </li></ul></ul></ul><ul><ul><ul><li>49 Deaths </li></ul></ul></ul><ul><li>Abbott forced to recall 3.5 million bottles of IV fluid </li></ul><ul><li>IV Sales Decrease 84% ($17.9 million to $3 million) </li></ul><ul><li>Abbott redesigns IV bottle seals </li></ul><ul><li>Litigation Ensues </li></ul>
  18. 18. IV Bottle Contamination Case Investigation Findings and Recommendations <ul><li>Abbott Laboratories: </li></ul><ul><ul><ul><li>Facility Cleanup </li></ul></ul></ul><ul><ul><ul><li>Screw Cap Inadequate </li></ul></ul></ul><ul><ul><ul><li>Spun off IV Business </li></ul></ul></ul><ul><li>Hospital Procedures: </li></ul><ul><ul><ul><li>~24 hr Changeout </li></ul></ul></ul><ul><ul><ul><li>Minimize IV Integrity Breach </li></ul></ul></ul><ul><ul><ul><li>Avoid Disrupting Contents </li></ul></ul></ul><ul><ul><ul><li>Never Replace Cap </li></ul></ul></ul>
  19. 19. IV Bottle Contamination Case Applicable cGMPs <ul><li>§ 211.110 Sampling and testing of in-process materials and drug products. </li></ul><ul><li>(c) In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit, during the production process, e.g. at commencement or completion of significant phases or after storage for long periods. </li></ul><ul><li>§ 211.113 Control of microbiological contamination </li></ul><ul><li>(b) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products purporting to be sterile, shall be established and followed. </li></ul>
  20. 20. IV Bottle Contamination Case Summary <ul><li>What went wrong? </li></ul><ul><li>What can we learn? </li></ul>
  21. 21. <ul><li>CASE #2 </li></ul><ul><li>Hemodialysis Filters </li></ul>Hemodialysis Filter Case
  22. 22. Hemodialysis Filter Case Timeline <ul><li>August 2001 </li></ul><ul><li>Dialysis Patient Deaths - Spain </li></ul><ul><li>Cardiac Arrest; 15 min – 7 hrs </li></ul><ul><li>21- 35 age range </li></ul><ul><li>Gas bubbles in blood </li></ul>
  23. 23. Hemodialysis Filter Case Commonality Observed <ul><li>Althane ™ A, AF, AX dialysis filters </li></ul>
  24. 24. Baxter Pharmaceuticals Background Information - 2001 <ul><li>Large hospital supply/medical product company </li></ul><ul><li>45,000 employees </li></ul><ul><li>Mfg & Sales in 110 countries </li></ul><ul><li>$ 6.9 Billion in annual revenue </li></ul><ul><li>OEM Manufacturer </li></ul><ul><li>Renal products ~20% of revenue </li></ul>
  25. 25. Hemodialysis Filter Case Timeline (cont.) <ul><li>Aug-Sept 2001 </li></ul><ul><li>Baxter investigation exonerates filters </li></ul><ul><li>Voluntary Limited Recall by Baxter </li></ul>
  26. 26. Hemodialysis Filter Case Timeline (cont.) <ul><li>Oct 2001 </li></ul><ul><li>Croatia 23 Deaths </li></ul><ul><li>Independent investigation exonerates filters </li></ul><ul><li>JMS/Nikkoso Initiate Recall </li></ul>
  27. 27. Hemodialysis Filter Case Timeline (cont.) <ul><li>Oct-Nov 2001 </li></ul><ul><li>Deaths in Texas & Nebraska </li></ul><ul><li>Worldwide Recall </li></ul><ul><li>Investigation finds root cause </li></ul>
  28. 28. Hemodialysis Filter Case Manufacturing Process PASS Filter Integrity QC Test FAIL PASS Filter Integrity Retest With PF-5070 H 2 O FAIL QC FAIL
  29. 29. PF- 5070 Chemical Properties <ul><li>An Industrial Solvent </li></ul><ul><li>Cooling/heat transfer/cleaning solution for electronic equipment </li></ul><ul><li>Virtually non-toxic </li></ul><ul><li>Fast evaporating </li></ul><ul><li>160 µL = fatal dose* </li></ul><ul><li>* Journal of the American Society of Nephrology Study 2005 </li></ul>
  30. 30. Dialysis Filter Case Outcome <ul><li>Complete Recall of Althane ™ filters </li></ul><ul><li>85 Confirmed Deaths </li></ul><ul><li>2 plants idled/closed </li></ul><ul><ul><ul><li>Ronneby Sweden </li></ul></ul></ul><ul><ul><ul><li>Miami Lakes, FLA </li></ul></ul></ul><ul><ul><li>500 layoffs </li></ul></ul><ul><li>$150 million allocated to date for damages </li></ul>
  31. 31. Hemodialysis Filter Case Summary <ul><li>What went wrong? </li></ul><ul><li>What can we learn? </li></ul>
  32. 32. Proventil ® Asthma Inhaler Case <ul><li>CASE #3 </li></ul><ul><li>Proventil ® Asthma Inhaler Case </li></ul>
  33. 33. Schering-Plough Company Background <ul><li>$9.8 Billion Annual Sales </li></ul><ul><li>Areas of Focus: </li></ul><ul><ul><li>Allergy & Respiratory </li></ul></ul><ul><ul><li>Anti-Infection </li></ul></ul><ul><ul><li>Cancer </li></ul></ul><ul><ul><li>Cardiovascular </li></ul></ul><ul><ul><li>Consumer Division: </li></ul></ul><ul><ul><li>Dr. Scholl's ® , Coppertone ® , Bain de Soleil ® </li></ul></ul>
  34. 34. Schering-Plough Proventil ® Asthma Inhaler Timeline 1998 1999 2000 2001 … Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 … Puerto Rico IRE Kenilworth NJ Puerto Rico Kenilworth NJ 190K Units 60MM Units FDA FDA AAC FDA
  35. 35. Schering-Plough Proventil ® Asthma Inhaler Deaths 1998-2000 1998 1999 2000 Recall 1 Recall 2
  36. 36. Schering-Plough AAC Audit Findings -- Kenilworth, NJ Plant <ul><li>Personnel : </li></ul><ul><li>Inordinately high turnover </li></ul><ul><li>Employee Lack of experience/knowledge </li></ul><ul><li>Lack of Accountability </li></ul><ul><li>Systems : </li></ul><ul><li>No “Culture” of Quality Evident </li></ul><ul><li>No in-process Testing for Active Ingredient </li></ul><ul><li>Outmoded Equipment </li></ul>
  37. 37. Schering-Plough Public Citizen’s Health Research Group Letters <ul><li>March 1, 2001 </li></ul><ul><li>Urges Investigation Regarding Asthma Inhalers Knowingly Shipped w/o Active Ingredient </li></ul><ul><li>August 9, 2001 </li></ul><ul><li>Alleges Criminal Intent </li></ul><ul><li>August 15, 2001 </li></ul><ul><li>Schering-Plough Rebuttal: “ Every inhaler involved in a patient’s claim of injury that has been tested by the company has been shown to date to contain active ingredient ”. </li></ul>
  38. 38. Proventil ® Asthma Inhaler Case Outcome <ul><li>Consent Decree $500 Million Fine </li></ul><ul><li>Stock Plummets -- >$10 Billion Market Value Lost </li></ul><ul><li>Reduced Earnings Expectations </li></ul><ul><li>Delayed Product Approval </li></ul><ul><li>CEO, COO Resign </li></ul><ul><li>$50 Million Equipment/Facilities Investment </li></ul><ul><li>3 ½ years “Climb to Compliance” </li></ul>
  39. 39. Proventil ® Asthma Inhaler Case FDA Compliance Inspectional Outcomes FDA 483 Form Establishment Inspection Report Warning Letter Consent Decree NOIR Regulatory Action Continued Operation No Regulatory Action Criminal Charges
  40. 40. Proventil ® Asthma Inhaler Case Applicable cGMPs <ul><li>§ 211.22 Responsibilities of Quality Control Unit </li></ul><ul><li>(a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred. </li></ul><ul><li>§ 211.110 Sampling and Testing of In-Process Materials and Drug Products </li></ul><ul><li>(c) In-process materials shall be tested for identity, strength , quality , and purity as appropriate, and approved or rejected by the quality control unit. </li></ul>
  41. 41. How Could This Happen? <ul><li>Inertia </li></ul><ul><li>Group Anonymity </li></ul><ul><li>“ Legacy” Effects </li></ul><ul><li>Bureaucracy </li></ul><ul><li>Corporate Arrogance </li></ul>
  42. 42. What About Amylin? <ul><li>What controls do we have in place that would prevent the following? </li></ul><ul><li>Bacterial contamination in our product? </li></ul><ul><li>An apparent “innocuous” change in raw materials adversely impacting patient safety? </li></ul><ul><li>Product produced/shipped without active ingredient? </li></ul>
  43. 43. Why Follow cGMPs? <ul><li>Protects the patient </li></ul><ul><li>Protects the company </li></ul><ul><li>Protects our jobs </li></ul><ul><li>It’s the law! </li></ul>
  44. 44. Some Final Thoughts… <ul><li>We are empowered with an awesome responsibility -- the work we do has the power to heal or injure patients. </li></ul><ul><li>cGMP compliance is our assurance that the work is performed the right way, each and every time. </li></ul>
  45. 45. Q & A <ul><li>Questions/Comments </li></ul>? ? ?  ? ?