1. 0 Right First Time Six Sigma Project “Improve batch record system for Packaging ” Start Date: 01 Feb 2008 Black Belt: Marina Suryanto Sponsor: Sis Mardini (QO Manager) Process Owner: Raharsih Basrodin (Production) Team Members: Production: Lily, Yaseph, Lely QA: S. Wigati, Yodi, Melissa I-nexus ID: 3,031

2. 1 ControlImproveAnalyzeMeasureDefine The lead time to manufacture to release is too long. Problem Statement Business Case Expected business results: Reliable supply of product Improve quality of records Reduce time and efforts needed to complete batch documentation

3. 2 Scope ControlImproveAnalyzeMeasureDefine The lead time to manufacture comprises of 2 parts i.e: 1.Raw material receipt to bulk film coated tablet and final blend release (Project INX 7724 by JTM) 2.Primary packaging to product disposition Product : Ponstan 500 mg Film Coated Tablet (FCT) and Terramycin (TM) Oph. Oint. START : Ponstan  Blistering TM  Filling ointment STOP : Product disposition by QA Exclude : Batch with deviation and validation

4. 3 Project Goal PROJECT GOALMETRICBASELINE*CURRENTGOAL Reduction of packaging lead time (LT) Working DaysPonstan I : Average 53 TM Oph II : Average 26 TBDPonstan*: Max 20 days/ batch TM Oph*: Max 25 days/ batch ControlImproveAnalyzeMeasureDefine I Data collected from lot released in Jul 2007 to Jan 2008. II Data collected from lot released in Feb 2007 to Feb 2008 * Maximum exclude validation batch and deviation

5. 4 ControlImproveAnalyzeMeasureDefine Process Map Packaging Flow of Ponstan 500 mg FCT (As Is)

6. 5 ControlImproveAnalyzeMeasureDefine Process Map Batch Record Process of Ponstan 500 mg FCT (As Is) Review Batch record = Manufacturing + Packaging batch record

7. 6 ControlImproveAnalyzeMeasureDefine Process Map Packaging Flow of TM Oph. Oint. (As Is)

8. 7 ControlImproveAnalyzeMeasureDefine Process Map Batch Record Process of TM Oph. Oint. (As Is) Review Batch record = Manufacturing + Packaging batch record

9. 8 ControlImproveAnalyzeMeasureDefine DATA PLOT PONSTAN 500 MG FCT Total manufacturing lead time ranges from 59 to 99 days with median of 77 days. Production process LT ranges from 17 to 37 days with median of 25 days. Packaging to disposition LT ranges from 38 to 77 days with average of 52 days which contributes 68% to the total LT. Total Manufacturing LT = Production LT + Packaging to disposition LT

10. 9 ControlImproveAnalyzeMeasureDefine DATA PLOT PONSTAN 500 MG FCT Total lead time ranges from 38 to 77 days with average of 53 days. Packaging process LT ranges from 1 to 12 days with median of 2 days. Final review LT ranges from 35 to 75 days with average of 50 days which contributes 94% to the total LT. LT (Pack – Disposition) = Packaging LT + Final review LT

11. 10 ControlImproveAnalyzeMeasureDefine DATA PLOT PONSTAN 500 MG FCT 79% of the total review LT is contributed by the production review time. Production review LT ranges from 26 – 58 days with average of 39 days. QA review LT ranges from 1 – 28 days with average of 10 days.

12. 11 ControlImproveAnalyzeMeasureDefine DATA PLOT TM Oph. Oint. Total Manufacturing LT = Production LT + Packaging to disposition LT Total manufacturing lead time ranges from 2 to 7 days with average of 30 days. Production process LT ranges from 14 to 45 days with median of 3 days. Packaging to disposition LT ranges from 17 to 48 days with average of 27 days which contributes 90% to the total LT.

13. 12 ControlImproveAnalyzeMeasureDefine DATA PLOT TM Oph. Oint. Total LT ranges from 14 to 45 days with average of 26 days. Packaging LT ranges from 6 to 21 days with median of 10 days. Final review lead time ranges from 5 to 30 days with average of 16 days which contributes 62% to the total LT. LT (Pack – Disposition) = Packaging LT + Final review LT

14. 13 ControlImproveAnalyzeMeasureDefine DATA PLOT TM Oph. Oint. Production review time ranges from 1 – 18 days with average of 8 days. QA review lead time ranges from 1 – 25 days with average of 8 days.

15. CAPABILITY ANALYSIS 14 ControlImproveAnalyzeMeasureDefine 100% of the batches cannot meet the lead time of max 20 days. Data is approx. normal

16. CAPABILITY ANALYSIS 15 ControlImproveAnalyzeMeasureDefine 58% of the batches cannot meet the lead time of max 25 days. Data is approx. normal

17. 16 Value Stream Map Analysis (Ponstan 500 mg FCT) ControlImproveAnalyzeMeasureDefine Total Packaging Lead Time ranges from 24 – 29 days. Total processing time (P/T) ranges from 3 – 3.5 days (23 – 26 hours) Total delay time ranges from 21 – 26 days. Delay time was 89% of total LT Processing time in batch record review ranges from 6 – 8 hours per batch with delay time 19 - 24 days. Delay time in review process needs to be minimized. Note: Data taken from measurement of 3 batches

18. 17 Value Stream Map Analysis (TM Oph Oint) ControlImproveAnalyzeMeasureDefine Total Packaging Lead Time ranges from 22 - 33 days. Total processing time (P/T) ranges from 15 – 18 days (113 – 134 hours ) Total delay time ranges from 6 - 15 days (45 – 113 hours). Delay time was 37% of total LT. Processing time in batch record review ranges from 7 – 10 hours per batch with delay time 2 – 10 working days. Delay time in review process needs to be minimized. Note: Data taken from measurement of 3 batches

19. 18 Brainstorming Why batch record review lead time is too long? 1.Structure and content of batch record is not user friendly/ complicated 2. Effort and time needed for correcting documentation errors 3.Flow of batch record review process is not efficient. Review level that is labor intensive involving several personnel. The overall documents of the batch record from manufacturing to packaging is reviewed at the end of the process. 4. Standard lead time for batch record review and product release is not clearly defined. Delay time during final review is high. 5.Batch record is accumulated waiting for review and sent to QA including waiting time for approved QAP for TM Oph. Oint. ControlImproveAnalyzeMeasureDefine

20. 19 Batch record is accumulated waiting for review and sent to QA Numbers of Batch Record sent to QA per month was variable ranges from 1 – 23 batch records per receiving day with median of 5/ day. ControlImproveAnalyzeMeasureDefine

21. 20 Waiting time for QAP Availability The QA review lead time, which ranges from 1 – 25 days, includes the waiting lead time for QAP from lab. QAP LT ranges from -19 to 11 days. Minus value means that the QAP has been received prior to the batch records sent to QA. QAP LT = Batch record receive date – QAP receive date ControlImproveAnalyzeMeasureDefine

22. 21 Improvement Matrix ControlImproveAnalyzeMeasureDefine Potential X’sProposed SolutionSupporting Data Structure and content of batch record is not user friendly/ complicated: Excessive data entries, excessive signatures, Many separate forms are linked to the batch record for data recording. Excessive data verification during IPC between Production and QA Re-structure of batch record both contents and format. The content is also analyzed and some improvements are made to comply with PQS & regulatory requirements. Some of IPC activities and data verification will be transferred from QA to Production as per risk assessment. QA Risk assessment: New IPC matrix: Numbers of signatures for the new format of batch packaging records are reduced by approx. 50% (Ponstan FCT: 52%; TM Oph: 58%)

23. 22 Improvement Matrix ControlImproveAnalyzeMeasureDefine Potential X’sProposed SolutionSupporting Data Documentation error- Re-structure batch record as above. - Training Operator on documentation practice for the new batch record - Flow of batch record review process is not efficient. Review level that is labor intensive involving several personnel. The overall documents of the batch record from manufacturing to packaging is reviewed at the end of the process New flow of packaging process including IPC and batch record review process: - Batch record will be reviewed at each defined stage. - Reviewers include Prod Spv, Prod Manager, QA Spv, QA Manager  Delete non-value-added activity i.e., Prod Admin function to check and record doc error. These functions will be integrated to all reviewers. See proposal of new flow in the next slides.

24. 23 Improvement Matrix ControlImproveAnalyzeMeasureDefine Potential X’sProposed SolutionSupporting Data Waiting time for approved QAP of TM Oph Oint The Lab Spv will also sign off the batch record at each stage (Before radiation & after radiation) to confirm whether the test result meet or doesn’t meet spec. The QAP will be inserted into the batch record after the Lab Spv sign off the BR at the after radiation stage, then the batch record will be circulated to the Prod and QA Manager for final approval. This avoid the delay due to QAP documentation. - Batch record is accumulated waiting for review and sent to QA. Define standard lead time for review: 1) Review at each stage: Max 1 business day per reviewer per batch. 2) Final review: : Max 2 business day per reviewer per batch. - Standard lead time for batch record review and product release is not clearly defined. Delay time during final review is high.

25. 24 Proposal for New Process Flow Off-Line Printing ControlImproveAnalyzeMeasureDefine

26. 25 Proposal for New Process Flow Folding Leaflet ControlImproveAnalyzeMeasureDefine

27. 26 Proposal for New Process Flow Filling & Packaging of TM Oph Oint 3.5 g Korea ControlImproveAnalyzeMeasureDefine

28. 27 Proposal for New Process Flow TM Oph Oint 3.5 g Batch Record Review Process ControlImproveAnalyzeMeasureDefine

29. 28 Proposal for New Process Flow Blistering & Packaging of Ponstan 500 mg FCT ControlImproveAnalyzeMeasureDefine

30. 29 Proposal for New Process Flow Ponstan 500 mg FCT Batch Record Review Process ControlImproveAnalyzeMeasureDefine