1. BROMI Variations Training Meeting 8th May 2008 Case Study Session BROMI VARIATIONS.

2. BROMI Variations Training Meeting 8th May 2008 PLAN How this session will work. –A presented example (Case Study 1) to give you an idea of what you should be looking for. –Then there will be up to 3 further case studies for you to work through: More complex than first example. Time for discussions – answer questions. Try to work out how you would do it. BROMI or not and highlighting potential issues.

3. BROMI Variations Training Meeting 8th May 2008 PLAN ‘Model’ answers to all four case studies will be provided in the delegate pack to allow you to train others. Set-up for round-table discussions. Please nominate a table leader to feedback answers to questions during this session. Any questions please ask the industry or MHRA support on hand.

4. BROMI Variations Training Meeting 8th May 2008 CASE STUDY 1.

5. BROMI Variations Training Meeting 8th May 2008 PROBLEM. Company A sells pain reliever tablets Section 6.5 of the SPC describes the current packaging as: –Blister strips consisting of a base layer of 250 micron PVC with lidding foil of 20 micron aluminium foil, in packs of 8 or 16 tablets The company wishes to add a pack size of 12 tablets.

6. BROMI Variations Training Meeting 8th May 2008 QUESTIONS. Could this be a BROMI change, if so which one? What conditions are there for the change and do we meet them? What documentation would be required? Do we have sufficient information available to submit this application as a BROMI change? If not what additional data would we need to provide? Is there anything additional we would submit?

7. BROMI Variations Training Meeting 8th May 2008 ANSWERS. Could this be a BROMI change, if so which one? –Yes, before the BROMI variations this would have been a Type IA now it could be a BROMI Self Certification category 41.a.1

8. BROMI Variations Training Meeting 8th May 2008 ANSWERS. What conditions are there for the change and do we meet them?

9. BROMI Variations Training Meeting 8th May 2008 ANSWERS. What documentation would be required? –Cover Letter –Completed Portal Application Form. –Completed BROMI variations guideline page –Proof of Payment (according to company procedures) PLUS

10. BROMI Variations Training Meeting 8th May 2008 APPLICATION FORM.

11. BROMI Variations Training Meeting 8th May 2008 APPLICATION FORM.

12. BROMI Variations Training Meeting 8th May 2008 APPLICATION FORM.

13. BROMI Variations Training Meeting 8th May 2008 APPLICATION FORM.

14. BROMI Variations Training Meeting 8th May 2008 BROMI GUIDELINE PAGE.

15. BROMI Variations Training Meeting 8th May 2008 ANSWERS. Do we have sufficient information available to submit this application as a BROMI change? If not what additional data would we need to provide? –Yes. As the required pack size is within the current range this can be submitted as a BROMI Self certification. No stability declaration is required. Is there anything additional we would submit? –No

16. BROMI Variations Training Meeting 8th May 2008 DISCUSSION / QUESTIONS Any questions on first case study example?

17. BROMI Variations Training Meeting 8th May 2008 CASE STUDY 2.

18. BROMI Variations Training Meeting 8th May 2008 PROBLEM Company A sells Pain Reliever Tablets. Section 6.5 of the SmPC describes the current packaging as: –Blister strips consisting of a base layer of 250 micron PVC with lidding foil of 20 micron aluminium foil containing 8 tablets, in pack sizes of 8 or 16 tablets. The company wishes to change the lidding foil to a thicker material which consists of 20 micron aluminium foil and 15 micron PVC. –A specification for the new packaging material is available. –The company has also done some work to compare the permeability of the new packaging with the old packaging to show that the product does not interact with either PVC or Aluminium foil. –Stability studies with the new packaging have been started this week

19. BROMI Variations Training Meeting 8th May 2008 QUESTIONS Could this be a BROMI change, if so which one? What conditions are there for the change and do we meet them? What documentation would be required? Do we have sufficient information available to submit this application as a BROMI change? Is there anything additional we would submit? Fill in blank Portal Application form (pertinent sections only)

20. BROMI Variations Training Meeting 8th May 2008 ANSWERS Could this change be a BROMI change, and if so which one? –Yes, it could be a BROMI Type IB change, code no. 29.c : –‘Change in the qualitative and/or quantitative composition of the immediate packaging material - All other pharmaceutical forms – change concerns more resistant packaging and stability data are not yet available’

21. BROMI Variations Training Meeting 8th May 2008 ANSWERS What conditions are there for the change and do we meet them? –The product concerned is not a biological or sterile product. –The change only concerns the same packaging type and material (e.g. blister to blister). –The proposed packaging material must be at least equivalent to the approved material in respect of its relevant properties. –The proposed packaging is more resistant than the existing packaging e.g. thicker blister packaging and three months’ stability data are not yet at the disposal of the applicant. Assurance is given that these studies will be initiated and finalised and that the data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).

22. BROMI Variations Training Meeting 8th May 2008 ANSWERS What documentation would be required? –Cover Letter –Completed Portal Application Form –Completed BROMI variations guideline page (checklist) –Proof of payment (according to company procedure) –Revised dossier pages (Module 3.2.P.7). –Justification for the omission of stability data and stability commitments. In module 3 or as a separate statement) –Comparative permeability data. –Discussion of the original interaction data and it’s relevance to the new packaging. –Revised SmPC section 6.5 –Present and Proposed Specification

23. BROMI Variations Training Meeting 8th May 2008 ANSWERS Do we have sufficient information available to submit this application as a BROMI change? –Yes, sufficient information is available.

24. BROMI Variations Training Meeting 8th May 2008 CASE STUDY 3.

25. BROMI Variations Training Meeting 8th May 2008 PROBLEM Overview of the proposed changes to be made: –Change in the name and address of the MA holder –Change in the name of the manufacturing site –Addition of a new pack size Impacted Licences –ParaTabs Children’s Tablets –ParaTabs Adult’s Tablets

26. BROMI Variations Training Meeting 8th May 2008 PROBLEM Change 1 - Change the name and address of the MA holder from : ABC Pharmaceuticals 1 High Street Pharmatown UK Company number: 1234 to XYZ Pharmaceuticals 1 The Business Park Pharmatown UK Company number: 1234

27. BROMI Variations Training Meeting 8th May 2008 PROBLEM Change 2 - Change the name of the manufacturing site from: ABC Pharmaceuticals Pharmaplant Paris France to XYZ Pharmaceuticals Pharmaplant Paris France

28. BROMI Variations Training Meeting 8th May 2008 PROBLEM Change 3 - Addition of a new pack size –New pack size: 4 tablets for each licence –Current pack sizes on licence: 2 & 6 tablets –Packaging material remains the same

29. BROMI Variations Training Meeting 8th May 2008 QUESTIONS Can these changes be submitted as BROMI applications? What conditions are there for each change and do we meet them all? What documentation would be required? Do we have sufficient information available to submit these applications as BROMI changes? If not what additional data would we need to provide? What strategy would you use? Fill in blank Portal Application form (pertinent sections only)

30. BROMI Variations Training Meeting 8th May 2008 ANSWERS. CHANGE 1: Could this be a BROMI change, if so which one? –Yes as Company remains the same legal entity –Self certification BROMI No. 1: Change in the name and/or address of the marketing authorisation holder. What conditions are there for the change and do we meet them? –MA holder must remain the same legal entity –The changes are the only changes to be made, other than those stated which are being submitted in parallel.

31. BROMI Variations Training Meeting 8th May 2008 ANSWERS. CHANGE 1(Cont): What documentation would be required? –Cover Letter –Completed Portal Application Form –Completed BROMI variations guideline page (checklist) –Proof of payment (according to company procedure) –Companies House Certificate –Proposed SPC (and fragment) and artwork (as appropriate) – in this case: carton, foil and joint PIL for each product Do we have sufficient information available to submit this application as a BROMI change? –Yes. Is there anything additional we would submit? –No.

32. BROMI Variations Training Meeting 8th May 2008 ANSWERS. CHANGE 2: Could this be a BROMI change, if so which one? –Yes as this remains the same company submit under: –Self certification BROMI No 5: Change in the name and/or address of a manufacturer of the finished product. What conditions are there for the change and do we meet them? –Manufacturing site remains the same –The change is the only change to be made, other than those stated which are being submitted in parallel.

33. BROMI Variations Training Meeting 8th May 2008 ANSWERS. CHANGE 2 (Cont): What documentation would be required? –Cover Letter –Completed Portal Application Form –Completed BROMI variations guideline page (checklist) –Proof of payment (according to company procedure) –Formal document with new name (in this case a GMP certificate) –Updated CTD pages –Updated artwork as appropriate Do we have sufficient information available to submit this application as a BROMI change? –Yes. Is there anything additional we would submit? –No.

34. BROMI Variations Training Meeting 8th May 2008 ANSWERS. CHANGE 3: Could this be a BROMI change, if so which one? –Yes, the new pack size to be added is within the current range so can be submitted as: –Self certification BROMI No. 41, a 1: Change in pack size of finished product within the currently approved range (By referencing the SPC you can see that 2 tablet and 6 tablet pack sizes are currently registered). What conditions are there for the change and do we meet them? –The new pack size is consistent with the posology –Primary packaging remains the same –The smallest and largest pack sizes remain on the licence –The change is the only change to be made, other than those stated which are being submitted in parallel.

35. BROMI Variations Training Meeting 8th May 2008 ANSWERS. CHANGE 3 (Cont): What documentation would be required? –Cover Letter –Completed Portal Application Form –Completed BROMI variations guideline page (checklist) –Proof of payment (according to company procedure) –Proposed SPC (and fragment) –Proposed carton, foil & leaflet for each product –Updated CTD pages –Stability data is not required as the stability parameters are not affected. Do we have sufficient information available to submit this application as a BROMI change? –Yes. Is there anything additional we would submit? –No.

36. BROMI Variations Training Meeting 8th May 2008 ANSWERS. CHANGE 3 (Cont): STRATEGY: –The 3 changes can be submitted in parallel

37. BROMI Variations Training Meeting 8th May 2008 CASE STUDY 4.

38. BROMI Variations Training Meeting 8th May 2008 PROBLEM Company A sells pain reliever tablets It would like to use paracetamol manufactured by Active P Supplier Inc in their tablets. This is a new supplier. Active P Supplier Inc has a European Pharmacopoeia Certificate of Suitability (CEP) for paracetamol. It has a number of suppliers of paracetamol on its licences, however it would also like to remove Paracetasupply Ltd from the licence. Paracetasupply Ltd is listed as an API (Active Pharmaceutical Ingredient) manufacturer on three other of company A’s licences.

39. BROMI Variations Training Meeting 8th May 2008 QUESTIONS Could the above changes be handled as BROMI changes, if so which one(s)? What conditions are there for the changes and do we meet them? What documentation would be required? Do we have sufficient information available to submit relevant applications? If not what additional data would we need to provide? What is the most efficient way of removing Paracetasupply Ltd from all three licences? Fill in blank Portal Application form (pertinent sections only)

40. BROMI Variations Training Meeting 8th May 2008 ANSWERS Could this be a BROMI change, if so which one? –The addition of a new CEP could be submitted as a BROMI Self Certification change code 15 a 2 if the manufacturer is currently approved (Updated CEP) but in this case the manufacturer is not currently approved and so the variation should be submitted via the standard Type I A route, change code 15 b 2. –The deletion of Paracetasupply Ltd on the 3 licences can be done as a BROMI change code 9a.

41. BROMI Variations Training Meeting 8th May 2008 ANSWERS What conditions for the changes and do we meet them? Type I A Code 15 b –The finished product release and end of shelf life specifications remain the same. –The active substance will be tested immediately prior to use if no retest period is included in the European Pharmacopoeia certificate of suitability or if data to support a retest period is not provided. –The manufacturing process of the active substance, starting material/reagent/intermediate does not include the use of materials of human or animal origin for which an assessment of viral safety data is required. BROMI Change code 9a –An appropriately authorised site remains registered on the authorisation to undertake the manufacturing operation concerned.

42. BROMI Variations Training Meeting 8th May 2008 ANSWERS What documentation would be required? Type I A Code 15 b –Copy of the current (updated) European Pharmacopoeia certificate of suitability. –Amended page(s) of Part IIC and IIF (old Part IIE) or equivalent in the CTD format, if applicable –Where applicable, a document providing information of any materials falling within the scope of the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products including those which are used in the manufacture of the active substance. The variation application form should clearly outline the “present” and “proposed” manufacturers as listed in section 2.5 of the (Part IA) application form. –A declaration by the Qualified Person (QP) of each of the manufacturing authorisation holders listed in the application where the active substance is used as a starting material and a declaration by the Qualified Person (QP) of each of the manufacturing authorisation holders listed in the application as responsible for batch release. Cover Letter –Proof of payment (according to company procedure) –Completed application form –Completed variations guideline page (checklist) –Cover Letter

43. BROMI Variations Training Meeting 8th May 2008 ANSWERS What documentation would be required? BROMI Change code 9a –Cover letter –Completed BROMI variations guideline page (checklist) –Completed Portal Application Form –Proof of payment (according to company procedure) –The “present” and “proposed” manufacturers should be clearly stated on the variation application form. –Updated Module 3 pages in CTD format

44. BROMI Variations Training Meeting 8th May 2008 ANSWERS Do we have sufficient information available to submit this application as a BROMI change? If not what additional data would we need to provide? –No, for the addition of the API supplier. We have the current European Pharmacopoeia certificate of suitability but we require a signed QP declaration before submission. –Yes to remove the API manufacturer, Paracetasupply Ltd. The licences still include an API supplier Paracetamol Supplies Ltd. Is there anything additional we would submit? –No

45. BROMI Variations Training Meeting 8th May 2008 ANSWERS What is the most efficient way of removing Paracetasupply Ltd from all three licences? –As with standard, non-BROMI variations bulk applications are acceptable.