1. Case Studies in Change Management IFF February 2009

2. Analytical Methods – ACN Scope of Change Very comprehensive – many products: stability and release, development: Notification: Regulators /Markets: US, EU (member states), Japan etc. Partners: (API manufacture – all clients) (Contract Manufacture / Contract testing – all clients) Major change Risk: High / Medium / Low could affect impurity profile product is still the same – might not detect an impurity that you previously did methods validation /verification: spiking

3. Packaging – Securitainer - Blister Scope of Change One product : packaging line (new qualification) and stability Risk: High / Medium / Low

4. Key Excipient – Chinese Source Scope of Change Change a key excipient affects 5 different products – specification, finished product stability, impurities, release profile etc. etc. Risk: High / Medium / Low High

5. Possible control measures Quality Agreement Copy of batch manufacturing record Chinese and English versions Copy of QC test procedures Chinese and English versions Samples: to be taken by their personnel during on-site audit On site audit: see production and QC operations taking place

6. Possible control measures Additional QC testing at my company particularly – sample every container for full monograph testing Develop identity tests that can identify potential contaminants Yield controls: reconciliation of materials in vs materials out – even on a batch by batch basis Where do they purchase their raw materials Supply chain – actual site(s) of manufacture – agents and brokers identified and you audit them as well Functionality testing: small scale manufacture and pilot runs using the new supply of excipient and generate some “process validation data” on small scale batches

7. Packaging change: Securitainer - Blister Title: introduction of an existing product to new market Description of the Change: Introducing an additional packaging form of a blister for a (name of product and item number, pack size, dosage form)product already sold in a securitainer in the USA Description of the Current Situation: Product manufactured in securitainers and sold in USA. We have a blister packaging line used for other products therefore we might be able to use existing films / al etc. Reason for the change: The new presentation is for the European Market (!!!!) Signature and date of originator of the change (Marketing department) (Could add at the end of the change management process a “lessons learned” section and “cost assessment for the change”

8. Packaging change: Securitainer - Blister Risk Assessment / consequences of the change: – Impacts packaging specifications and packaging instructions – sampling instructions – (Re) Qualification of packaging line – Process Validation – Stability studies – Transportation studies – Cleaning procedures / validation – Training

9. Packaging change: Securitainer - Blister Controls to be put in place – Revise packaging specifications – Revise packaging instructions – Revise sampling instructions – (Re) Qualification of packaging line – Partial Process Validation – Stability studies – Transportation studies – Cleaning procedures - revised / validation – review Matrix – Training of concerned persons

10. Packaging Change Deadline of 14 days for input from concerned parties – Initiation meeting – outcome defined upfront: do you agree that we can proceed with planning the change 30 days deadline for change plan approval (meeting recommended) Senior Management budget or resources approval if needed

11. Packaging Change Costs associated with the change Communication plan Implementation dates / notification

12. Replacing Tableting Machine with same Principle different manufacturer Description of change: same as above Current situation: manufacturing x 1000 tablets per hour on the existing machine. The machine is old and we are worried that soon it won’t be able to produce any more because we are calling maintenance 6 times a day. Did we do process validation back in those days and how good was it and is it still relevant

13. Replacing Machine Process qualification / validation (comparability) – base on validation on existing machine and data trending in particular SPC and Product Quality Review and Risk Assessment Product hold for first batch or more depending on Risk Assessment and Regulatory requirements / expectations

14. Packaging change: Securitainer - Blister Responsibilities: Overall – Project Leader: Mr X RA – notification of authorities and classification of change: type of variation R&D – information regarding product stability: RH, temp, exposure to light, reaction with Al etc. Stability lab Logistics: Warehouse, shipping Packaging materials sampling and testing QC QA Technical Operations Production and Packaging Purchasing: suppliers Marketing Target Date for Successful completion: 01/01/2011 Review team:

15. Packaging change: Securitainer - Blister Review team:

16. Change Management Plan 1.Description of the (proposed) Change: 2.Description of Current Situation: 3.Reason for the change: 4.Risk Assessment

17. Change Management Plan 5.Change Review Team: 6.Change Plan: Controls Monitoring Acceptance criteria 7.Change Implementation Timetable: 8.Responsibilities 9.Review and approval of change plan 10.Communication

18. Change Management Plan 11.Implementation 12.Follow-up 13.Close-out and product release

19. Case Studies – Day 2 Analytical Methods – ACN needs to be replaced Change a key excipient from EU source to Chinese source (EU stopping manufacture) Define Scope and Complexity of change Define Risk associated with change

20. ACN Scope of change: Replace ACN with a different mobile phase Complexity: Compare old method with new – method validation and qualify impurities – maybe new additional or different impurities might show up – ID them and quantify Ongoing stability would be affected? Risk: (Low / Medium / High)

21. Key Excipient – Chinese Supplier Scope of change: affects 5 products Complexity: Straightforward change – we know what to do – the problem is the Chinese Supplier Risk: (Low / Medium / High – because of the Chinese element)

22. When do we fill out a Change Request Form?

23. Do we have sufficient information? WHY? Is the change being made WHO? Initiated the change WHEN? Time table for implementation – is it urgent e.g. Regulatory requirement (e.g. change to pharmacopoeial method for Heparin) WHICH? Products / department / people are involved WHAT? Samples / tests need to be performed

24. Packaging Change – from Securitainer to Blister Pack Description of change: Addition of a new presentation / Change of primary packaging material for one product Current Situation: Have an approved packaging line for securitainers and we have an existing blister packaging line which we can use for the additional product. The securitainer includes silica gel – so product has some sensitivity to humidity Reason for Change: Marketing believes that it will boost sales by 200%

25. Packaging Change – from Securitainer to Blister Pack Change Review / Analysis: Reg Affairs: New stability will be required Variation: Type II Process validation ? Increased in-process / packaging sampling Package Integrity Cleaning Quality: Artwork will need preparation, review, approval, control of printers, specifications, testing Packaging materials specifications Leachables and Extractables (compatability) Standard Operating Procedures updated Master Packaging Instructions revised Supplier qualification for packaging materials Sampling instructions

26. Packaging Change – from Securitainer to Blister Pack Responsibilities: Project Manager – Marketing Manager - Production and planning: evaluate capacity of current blister line and validation - documentation dept to update relevant docs - engineering dept for new tooling if needed - R&D for packaging materials and stability and compatibility - Purchasing for primary and printed pack materials, supplier evaluation - Reg Affairs

27. Replace Tableting Machine – same operating principle different manufacturer Description of the Change: Replacement of tableting machine with a new one that operates on same principle but different manufacturer – new machine has three times the capacity of the old Current situation: existing machine is 35 years old with frequent breakdowns, lack of capacity Reason for the Change: increase capacity and save operational resources

28. Replace Tableting Machine – same operating principle different manufacturer Change Review: Back to development to understand what the change will do the product(s) and processes before deciding on regulatory strategy URS Involve technical department, maintenance and validation for qualification of the machine Make a project team with Manufacturing Manager at helm