1. Modifying Alert Levels Adam Walker

2. Appropriate alert Why? Trend Monitoring EU GMP Chapter 6: 6.9 Some kinds of data (e.g. tests results, yields, environmental controls) should be recorded in a manner permitting trend evaluation. Any out of trend or out of specification data should be addressed and subject to investigation. EU GMP Annex 1: 20. Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action. Traditionally Alert levels have been 0.5 x action level Is this an appropriate level? Modifying Alert Levels – A Discussion

3. Modifying Alert Levels Moving on from Trend Monitoring Use to educate appropriate Alert Limits What are the options? Fixed value Assigned automatically based on trend analysis over previous (x) results Assigned individually, or to a group Suggested by MRS based on trend analysis over previous (x) results and implemented by site user Assigned manually based on trend data Over what period do we trend the data? Variable value Assigned automatically based on trend analysis over previous (x) results

4. Fixed Values- Pros and Cons ProsCons Simple to administerMay not be appropriate to current trend Can be calculated by MRS and ‘suggested’ at e.g. annual micro review Requires input to assess appropriateness of limit Will identify a slowly increasing trend (eventually) Requires regular (annual?) maintenance Little validation requiredWill not respond to a decreasing trend until review

5. Variable Values- Pros and Cons ProsCons Simple to administer (automated) Need to ensure slowly increasing trend will trigger alert Responds to real time data based on previous (x) results Challenging to validate appropriately One method will ensure compliance for all (if MHRA agree methodology) May not identify a slowly increasing trend Needs agreement on calculation method and allowable ‘slack’

6. Fixed alert level of 0.5 x action levelFixed alert level of mean +2 SDFixed alert level of Mean +3 SD Plate #05/11/201512/11/201520/11/201527/11/201511/12/201518/12/201523/12/201512/01/201620/01/201628/01/201605/02/201608/02/201616/02/201624/02/201602/03/201611/03/201616/03/201624/03/201605/04/201615/04/201621/04/201629/04/201606/05/201609/05/201617/05/201625/05/201602/07/201607/06/201615/06/2016 1 15 37202313100 778 0631641136873010 2 6 161011774 734 142107216254114 3 38100001210013 201156205531010 4 14131410111154071145 4337134118388240 5 27317403210631962721 146130 78428220510 6 5543152519270301514185647 2540350401920107392501860 7 365737217624502813171302637 1656920 126103 2706713 8 111480221220627332116 1481201841313042170154 9 10004000000114 3016140005010 100 1000003571652 34401602202751410 11 4010100210015 4111310830304310 12 0000102202001 100023032062100 13 2010232403124 10111601986321100 14 021233002250500000317052208102083 15 29061422410002100010114 90020001323271415 16 12081016300007111001603 270013001927111016 17 290110182047001911003218 20008600171519123 Plate #05/11/201512/11/201520/11/201527/11/201511/12/201518/12/201523/12/201512/01/201620/01/201628/01/201605/02/201608/02/201616/02/201624/02/201602/03/201611/03/201616/03/201624/03/201605/04/201615/04/201621/04/201629/04/201606/05/201609/05/201617/05/201625/05/201602/07/201607/06/201615/06/2016 1 15 37202313100 778 0631641136873010 2 6 161011774 734 142107216254114 3 38100001210013 201156205531010 4 14131410111154071145 4337134118388240 5 27317403210631962721 146130 78428220510 6 5543152519270301514185647 2540350401920107392501860 7 365737217624502813171302637 1656920 126103 2706713 8 111480221220627332116 1481201841313042170154 9 10004000000114 3016140005010 100 1000003571652 34401602202751410 11 4010100210015 4111310830304310 12 0000102202001 100023032062100 13 2010232403124 10111601986321100 14 021233002250500000317052208102083 15 29061422410002100010114 90020001323271415 16 12081016300007111001603 270013001927111016 17 290110182047001911003218 20008600171519123 Plate #05/11/201512/11/201520/11/201527/11/201511/12/201518/12/201523/12/201512/01/201620/01/201628/01/201605/02/201608/02/201616/02/201624/02/201602/03/201611/03/201616/03/201624/03/201605/04/201615/04/201621/04/201629/04/201606/05/201609/05/201617/05/201625/05/201602/07/201607/06/201615/06/2016 1 15 37202313100 778 0631641136873010 2 6 161011774 734 142107216254114 3 38100001210013 201156205531010 4 14131410111154071145 4337134118388240 5 27317403210631962721 146130 78428220510 6 5543152519270301514185647 2540350401920107392501860 7 365737217624502813171302637 1656920 126103 2706713 8 111480221220627332116 1481201841313042170154 9 10004000000114 3016140005010 100 1000003571652 34401602202751410 11 4010100210015 4111310830304310 12 0000102202001 100023032062100 13 2010232403124 10111601986321100 14 021233002250500000317052208102083 15 29061422410002100010114 90020001323271415 16 12081016300007111001603 270013001927111016 17 290110182047001911003218 20008600171519123 Real world examples – Basic models

7. Real world examples – Advanced (EMA)

10. User Requirements What do we need to decide? What is the right method? How sensitive must this be (1 x SD, 2 x SD etc.) What time period do we consider (t=5, 10, 13, 52?) How is this applied to existing limits (automatic/manual?) How often should the limits be changed (monthly, annual?) What will regulators be happy with? What will we be happy with- do we need a range within which a variable value can operate? Is there anything else we need to consider?

11. Future Developments What else is possible? ‘Area’ alerts If several plates from within the same product ‘path’ have raised levels which are under the alert levels- could we be notified? Trending by ID- the same contaminant in several locations within limits- could we be notified? ‘Informative information’ not necessarily to take action on, but to make us aware of a developing trend

12. Thank you