Right First Time M 1 Laboratory Related Method

Right First Time M 1 DEFINE 2 Copyright © 2002 Aon Consulting. All rights

Right First Time Who to invite? ? • Laboratory analysts that normally perform this test- must include analyst that performed testing which resulted in OOS results, as well as other analysts. • Laboratory supervisor. • Technical Services Chemist. • Quality Assurance support for laboratory. • Quality Control Team Leader (as it is such a significant issue for lab). 3 Copyright © 2002 Aon Consulting. All rights reserved. M 1

Right First Time Questions Asked in Define • What: Unknown impurity band >0. 1% in the reference standard & samples. • Where: Preparation in OSP 4 QC lab and testing in OSP 1 raw materials lab. • When: 14/9/05 and intermittently in the past. • Significance: Cannot release batches that are failing on unknown impurity (9 batches). • Desired state: No unknown impurity in batches tested. Specification is max 0. 1% unknown Impurities. 4 Copyright © 2002 Aon Consulting. All rights reserved. M 1

Right First Time M 1 MEASURE 5 Copyright © 2002 Aon Consulting. All rights

Right First Time Process Mapping/Flow Charting M 1 • Having the right people in the room is critical to the success of any method 1 but especially laboratory method 1’s where mapping the process is extremely important. • Different analysts indicated different ways of performing some parts of the preparation for the test. • The detailed mapping in this method 1 provided many ideas for the brainstorm session in analyse. 6 Copyright © 2002 Aon Consulting. All rights reserved.

Right First Time Ammonia can be added with other reagents or added at a

Right First Time M 1 ANALYSE 8 Copyright © 2002 Aon Consulting. All rights

Right First Time Brainstorm/Fishbone Diagram 9 Copyright © 2002 Aon Consulting. All rights reserved.

Right First Time Prioritisation of Potential Root Causes • Prioritized Potential Root Causes: – Contamination - reagents – Auto-spotter – Plastic contamination 10 Copyright © 2002 Aon Consulting. All rights reserved. M 1

Right First Time Actions to Confirm Root Cause. Reagent Contamination M 1 • Tests Conducted: – Original diluent used, spotted using auto-spotter – Fresh diluent prepared, spotted using auto-spotter – Blank track (nothing spotted) • Results: – There was no impurity seen in any of the tracks • Conclusion: – Tests ruled out contamination of the ethanol wash, solvents, iodine bath & the auto-spotter 11 Copyright © 2002 Aon Consulting. All rights reserved.

Right First Time Actions to Confirm Root Cause. Plastic Contamination • Tests Conducted: – Prep Vials and plastic pipettes used as per standard procedure and spotted both manually and using auto-spotter – Glass volumetric flasks and glass pipettes used in place of plastic normally used, samples spotted both manually and using auto-spotter 12 Copyright © 2002 Aon Consulting. All rights reserved. M 1

Right First Time Actions to Confirm Root Cause • Results: 13 Copyright © 2002

Right First Time Confirmed Root Cause • From tests conducted it was established that the root cause of the unknown impurity seen in both standards and samples was: • Degradation of the plastic equipment used during testing. 14 Copyright © 2002 Aon Consulting. All rights reserved. M 1

Right First Time M 1 IMPROVE 15 Copyright © 2002 Aon Consulting. All rights

Right First Time Use of glassware rather than plastics Analysts were asked to use: a. 2 ml volumetric flasks b. Glass pipettes when carrying out Sildenafil 3 HPTLC analysis 16 Copyright © 2002 Aon Consulting. All rights reserved. M 1

Right First Time Results of Improve • The nine batches were retested using recommended glass equipment. • No impurity was seen-All batches released for shipment. • The material usage variance associated with the rework of the 9 batches of Sildenafil API, had these lots been rejected was $ 514, 500. 17 Copyright © 2002 Aon Consulting. All rights reserved. M 1

Right First Time M 1 CONTROL 18 Copyright © 2002 Aon Consulting. All rights

Right First Time Controls • Addendum written, to STP I 19. 5, stating that plastic pipettes & TLC prep vials are not to be used in this test. • Process map generated during investigation is to be used when training new analysts on this test. 19 Copyright © 2002 Aon Consulting. All rights reserved. M 1