VALIDATION What is the point? Alan Aldcroft Bovis Lend Lease - Pharmaceutical Division

1. VALIDATION What is the point? Alan Aldcroft Bovis Lend Lease - Pharmaceutical Division

2. What was the point?

3. The Devonport Incident • Tue 6th April 1971, Evans Medical in Speke. Transfusion Unit manufacture 5% Sterile Dextrose Solution Lot D1192 • Intravenous Injection therefore required to be sterile • Terminally Sterilised at 115 °C for 30 minutes

4. Disclaimer At that time Evans Medical was a subsiduary of Glaxo and was one of the largest manufacturer of generic pharmaceuticals in the UK. There is still a company trading under the name of Evans Medical, however the company as it exists today, is in no way related in ownership, management, or operations to the Evans Medical that existed then.

5. Sterilisation of Sterile 5% Dextrose T Dial P T Drain 1.7 Bar 115°C Steam 1.7 Bar 115°C Chart 115°C at 1.7 Bar for 30 minutes

6. Sterilisation of Batch D1192/C T Dial T 1.7 Bar 115°C P 115°C Steam 1.7 Bar 47°C 47°C Drain Chart

7. The Devonport Incident • 6th April 1971 Evans Medical manufacture 5% Ster Dextrose Sol. Lot D1192/C • May 1971 Lot D1192/C distributed • 29th Feb 1972: 2 deaths at Devonport Hospital • 1st Mar 1972: 2 further deaths at Devonport • 2nd Mar 1972: 1 further death at Devonport • 6th Mar 1972: Investigation begins • 12th Jul 1972: Clothier Report issued.

8. Findings of the Clothier Report • Lack of instrument calibration • Lack of maintenance activity • Lack of maintenance logs • Inadequate procedures • Lack of procedures • Inadequate equipment • No batch record review • Inadequate equipment cleaning • Poor staff training

9. Effects of the Clothier Report • Ensure that critical instruments were functional and calibrated regularly • Prove that SOP’s were accurate • Prove that operators had been trained • Test and prove that the process would work time and time again • Document that this had been done

10. FDA Guidelines 1984: Validation “Establishing 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.”

11. Do We Have to Validate? VALIDATION IS SPECIFICALLY REFERRED TO IN THE EC DIRECTIVES AND IS A BASIC PRINCIPLE OF GOOD MANUFACTURING PRACTICE (GMP)

12. If Pharma Companies ignore GMP? • Increased attention from regulators • Products withdrawn from market (Recall) • Adverse publicity, patient safety concerns • Loss of confidence by industry peers and regulators • Permission to sell products withheld • Order to stop manufacture and sale of products • (In US) prosecution and prison for individuals

13. The Benefits Of Validation • REDUCING • Rejects • Reworks • Reliance on In-Process Controls • Equipment Downtime

14. What is the point? Validation saves lives!