1. © Institute for International Research, Inc. 2006. All rights reserved. Module 6: Manufacturing Throughput

2. 2 international Module 6 Purpose and Objectives  Module Purpose:  Process optimization requires understanding the process. The student will examine the variables involved with sublimation and then review “whole manufacturing cycles”.  Module Objectives:  After this module, you will be able to  Look at a lyophilization cycle in the broader context of a manufacturing cycle.

3. 3 international Throughput  Vials per Year  Manufacturing Cycle: (related to Lyo)  Sterilize Lyo and Cool the shelves.  Perform the leak test.  Fill vials  Load Lyo (Close Door)  Lyophilize vials  Unload Lyo  Run CIP  Verify cleaning via swab testing

4. 4 international Step Timing  Sterilize Lyo – 3 hours, including cool down.  Assumes the lyo is clean at start  Includes performing filter integrity.  Assumes a 30 minute steam exposure at 121  C.  Allows some time for cool down.  [Do not start a lyo load with frozen shelves.]  Leak Test – automated cycle. If a leak is detected, there is time in the manufacturing schedule to find, fix and repeat sterilization.

5. 5 international Vial Filling  Lyo should be ready to use at the beginning of a fill shift. – When the product is “committed”.  Loading will likely occur throughout the filling period.  Filling period will be 4 to 12 hours.

6. 6 international Lyophilize Vials  Can there be “planned variable length cycles”? What about validation?  Option 1: Stay in freeze mode (lowest shelf temperature) without vacuum for a variable length of time?  Option 2: Hold vials (pre-stoppering) at some defined temperature (e.g. -5  C) until it is “convenient” for manufacturing?  Option 3: Hold vials (post-stoppering) inside the lyophilizer and at their designated storage temperature?

7. 7 international Unload & CIP  Unloading may go slowly and include capping.  Some products require a post filter integrity test. If so, it can be done during the unloading.  CIP cycles are pre-built and validated, so the time is known.  Verify cleaning. Are test results required (due to product changeover) before proceeding?

8. 8 international Example Lyo Cycle

9. 9 international Lyo Cycle Segment Compare

10. 10 international Unload & Clean  Stoppering will take about 30 minutes.  Unloading/Capping may take 4 or more hours.  CIP (if the water is ready) may take 1 to 2 hours.  Swab sampling: 2 hours (includes gowning)  Swab testing: up to 8 hours if started immediately.

11. 11 international Scheduling Constraints: Filling begins on the day shift. Ergo: The complete lyo manufacturing cycle has to be an integral number of days. Slack Time: Some built in slack time may be needed in order to keep to a schedule.

12. 12 international Cycle Optimization – 3 day turn Making the Lyo Cycle shorter can’t really help.

13. 13 international PQ Validation Considerations  Freeze Holds.  Perform one PQ cycle with an extended freeze hold.  Does vacuum or not matter to the validation?  Perform one media fill where vials see an extended time in the lyophilizer ?  Might the media dry out?  Media fills are not normally exposed for the time that a vial is open in the lyophilizer.  In the cycle state a freezing time range from X to Y hours.  Why? Vacuum and Condenser and Shelves have to reach set points.

14. 14 international PQ Validation Considerations  Perform all PQ cycles with a hold prior to stoppering.  Why? Stoppering is manual and 3AM is inconvenient for the Manufacturing personnel.  Why? Stoppering is a critical activity and a lot of errors are made at 3AM.  Why? The actual cycle start time is variable due to lot size, variable filling times, unknowns holds during the fill, etc. Consequently, the stoppering time isn’t known soon enough to permit scheduling personnel.  Rational: This is the same as defining a longer “secondary dry” with a new temperature.

15. 15 international An “Optimized” Machine Cycle A longer “secondary dry” with a new temperature permits the design of a “convenient” cycle.

16. 16 international PQ Validation Considerations  Perform one (or all) PQ cycles with a hold post – stoppering.  Why? Vial is closed and sterility is assured.  Why? Storage condition can be the final storage temperature.  Why? Cycle can be defined such that it begins and ends at convenient work times.  Why Not? Stoppering may require alert personnel during a night shift.

17. 17 international Exercise: 6.1 Recommend a manufacturing cycle for a vaccine filling operation that has an optimized drying cycle of 12 hours. Assume  The market cap is limited by manufacturing.  There are currently two lyophilizers for one filling line.  Filling for one dryer takes 6 hours.  Fill room clearance and re-set takes 4 hours.  Indicate the risks associated with your recommendation.