1. 6/11/2016 SIP I NOE Reduction Project Ann - Marie Ward Lab Services Group Leader

2. 26/11/2016 Definitions Notice of event (NOE): A laboratory error or event representing a departure from cGMP, SOP’s, manufacturing /testing instructions, applicable regulations, applicable standards or established product limits that is deemed to be minor in nature. Analytical Test Method (ATM): An authorised analytical test that is used in the testing of materials in the analytical laboratory.

3. 36/11/2016 Project Title : Reduce the number of “method not followed” NOE’s. Deliverable: Reduce “method not followed” NOE’s by 30-40%. Objectives: –To redesign & implement a more concise analytical test method (ATM). –To perform analysis right first time. –To reduce the number of “method not followed” NOE’s using the updated ATM. –Reduce compliance risk and ongoing cost associated with repeat testing.

4. 46/11/2016 Supply Improvement Process

5. 56/11/2016 Identify Process The Process is to perform analysis right first time with the use of the updated ATM template. Expected Benefits:  Analysis performed right first time.  Reduce repeat analysis time.  Reduced scheduled down time.

6. 66/11/2016 Appoint Process Owner StepAction/TaskResponsibleAccountableConsultedInformed 1Streamline ATM’sGroup LeadersManagerSenior AnalystsAnalysts RACI Chart

7. 76/11/2016 Define Process Project Scope : Reduce method not followed NOE’s. Key Business Triggers : Analysis to be performed right first time and within lead times. Key Customer (s) : Analytical Laboratory, Business Units, QP Group, Planning. Business Values (internal) : Reduce compliance risk and ongoing cost associated with repeat testing. Deliverable : Streamline ATM template and update ATM’s – May 2009

8. 86/11/2016 “As is” Reference Standard Preparation

9. 96/11/2016 “To Be” Reference Standard Preparation SAFETY NO. OF PREPARATIONS EXPIRY

10. 106/11/2016 Define Requirements CUSTOMER INTERNAL/ EXTERNAL CUSTOMER’S EXPRESSED REQUIREMENTS TRANSLATED REQUIREMENTS AnalystsInternalATM Template DesignFlow of ATM to be in the order the task is performed Laboratory ManagerInternalIncrease focus on safetyInclude chemical hazard symbols Quality SystemsInternalReduce number of NOE’sPerform analysis right first time

11. 116/11/2016 Define Metrics Process Map VOC Identify Metrics: No of method not followed NOE No of repeat tests Identify Metrics: No of method not followed NOE No of repeat tests

12. 126/11/2016 Analyse and Challenge  Used Quantitative Analysis to analyse data.  Identified products and tests using Pareto analysis to identify which had the most “method not followed” NOE’s.  Applied Talsico Human Error reduction techniques to design the new ATM template e.g. left to right, sequence, pictures

13. 136/11/2016

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17. 176/11/2016 Multiproducts ATM’s Based on the above pareto analysis the following Products/Tests ATM’S were updated to the new ATM template: –Estradiol/Dissolution + Assay –Testosterone/Dissolution –Ovestin/Dissolution + TLC –Deca-Durabolin/Assay –Orgalutran/Assay + TLC

18. 186/11/2016 Parenterals “method not followed” NOE by Product 0 2 4 6 8 10 12 14 16 18 PSV+CartridgeSodium ChloridePuregon LyosphereZemuron Type Number

19. 196/11/2016

20. 206/11/2016 Parenterals ATM’s Based on the above pareto analysis the following Products/Tests ATM’s were updated to the new ATM template: –Puregon/L-Methionine + Benzyl Alcohol Assay –Zemuron/Assay

21. 216/11/2016

22. 226/11/2016

23. 236/11/2016 Tablets ATM’s Based on the above pareto analysis the following Products/Tests ATM’s were updated to the new ATM template : –Cerazette/Assay + Degs, Dissolution –Desogen/Assay + Degs, Dissolution –MarvelonAssay + Degs, Dissolution –Mercilon/Assay + Degs, Dissolution –Mircette/Assay + Degs, Dissolution –Gracial/Assay + Degs, Dissolution –Livial/Assay + Degs, Dissolution

24. 246/11/2016 Implement Changes DateStep May 2009Update ATM’s using new template. Aug 2009Perform customer survey. Sep 2009Update ATM template following customer survey feedback.

25. 256/11/2016 Verify, Monitor and Control  The number of “method not followed” NOE’s for May – Nov 2008 were compared to the number for May - Nov 2009.

26. 266/11/2016 Verify, Monitor and Control  Over 5 months a reduction of 36% of “method not followed” NOE’s was obtained. Therefore 50 repeat tests were avoided which equates to a saving = €8,000. (Potential for a full year savings = €20,000)  Project goal is a 30 - 40% reduction – on schedule to achieve project goal.  Continually monitor “method not followed” NOE’s for reoccurrence following implementation updated ATM template.  NOE’s are reviewed monthly using an NOE database by the Analytical Lab Manager (presented at monthly metrics meeting).  Action will be taken where a recurring method NOE occurs or when the number of NOEs increases.

27. 276/11/2016 Voice of the Customer Survey results  An initial customer survey was performed in Aug 2009 with analysts in the Analytical Laboratory.  Good response: “Safety symbols and no. of preparations was better”. “Expiry dates are clearer” “Notes highlighted in bold were more obvious” “Overall method is more visual and easier to follow” “Change the flow of the ATM e.g. Testing overview and Glossary at the start of ATM”.

28. 286/11/2016 LIMS worksheets/Logbook update  Remove human error elements e.g. missing references  Populate static data to avoid transcription errors.

29. 296/11/2016 LIMS worksheets update

30. 306/11/2016 LIMS worksheets update Specification Instrument details Column Type Testing requirements Sample prep Comply

31. 316/11/2016 LIMS worksheets update

32. 326/11/2016 LIMS worksheets update

33. 336/11/2016 Logbook Update

34. 346/11/2016 Logbook Update

35. 356/11/2016 Logbook Update