1. Pre-Approval Inspections A Case Study Steve Pondell 28 Nov 2007

2. Topics Pre-Inspection The Inspection Outcome

3. Pre-Inspection - Situation API manufacturer in Sweden Second site Process transferred from first site Process validation underway First inspection (of four that ultimately happened)

4. Supply Chain Primary API Manufacturer (US) Secondary API Manufacturer (Sweden) Formulator (US) Packager (Canada) INSPECTIONS FDA (3) FDA (1) FDA (2) EMEA (MHRA) NONE

5. Pre-Visit Inspection Notification received approximately 2 months prior to inspection –Four days planned, two inspectors Two day site pre-visit planned with Encysive and manufacturer All major systems reviewed Validation documentation reviewed Major issues discussed and strategized Final check

6. Pre-Visit Inspection Logistics of inspection discussed –Who would be with inspectors –How would information be processed –What would sponsor’s role be

7. Planned Logistics - People Two inspection rooms prepared Two site people in each room –One QA person as direct interface –One scribe Back room headed by QA with ample support staff Selected sponsor representatives permitted in inspection room and back room

8. Planned Logistics – Communications Dedicated chat room set up for site Scribe in inspection rooms set up with interface All key site departments to monitor continuously Back room set up with individual monitors as well as projection to screen

9. Planned Logistics - Roles Site QA – primary response to all questions Sponsor – –in inspection room, only as requested by site QA –For questions related to filing –In back room, to provide input as needed and requested

10. Planned Logistics - Information All process documents, SOPs and validation documents collected into back room One copier dedicated for inspection team, loaded with “confidential” watermark paper Two copies made of any requested information Dedicated person for copies Dedicated runners for information transmission

11. The Inspection Two sponsor representatives arrived one day early –Final check on arrangements FDA arrived with two inspectors After introduction, immediately separated

12. How It Worked Wonderfully! Chat room was successful beyond expectations –Back room had heads-up on incoming information requests –Information was being prepared as FDA request was being voiced –Frequently had information or person available outside of room within seconds of request

13. How It Worked Sponsor in back room was able to see flow of information from both rooms in real time (but in Swedish!) Site had people assigned to both FDA and sponsor for breaks and meals –Segregation was assured

14. Sponsor Role Discussion of filing topics Discussion of site transfer activities Excused from topics regarding other products

15. Major Unresolved Topic Technical Transfer Protocol –Not a specific requirement –Topic addressed by sponsor each day –Protocol did not exist as specific document

16. Outcomes Inspection lasted most of four days Site answered all topics Site committed to change tech transfer SOP Sponsor committed to issue final tech transfer report at end of validation

17. Outcomes NO FDA-483 OBSERVATIONS “Approval” letter recommended and later received

18. Observations Site was completely engaged with inspection –All personnel –Entire QA group Interaction with sponsor seen as positive by all End result achieved Model used successfully for other audits

19. Who is This Manufacturer Cambrex Karlskoga –Karlskoga, Sweden

20. Questions or Comments?