1. © Institute for International Research, Inc. 2006. All rights reserved. Module 5: Quiz & Exercise Answers

2. 2 international Question 1a of 3  Collapse Temperature for a product has been measured at -41  C. Decision has been made to keep the ice at -43  C.  What vial pressure (mTorr) will cause the ice to be at -43  C in the absence of heat input?

3. 3 international Answer 1a of 3  Using a table, -43  C = 68.9 mTorr. (with linear interpolation)  Or, using the Clausius Clapeyron Equation:  torr

4. 4 international Answer 1b of 3  Why would a lyo cycle developer care? Chamber pressure needs to be well below the ice vapor pressure at the target temperature. How easy/hard is it to get well below 68 mTorr?

5. 5 international Answer 2 of 3  Use the empirical equation given in the presentation to determine a target chamber pressure for a target temperature of -43  C. P c = 44.2 mTorr

6. 6 international Answer 3 of 3 With a 50 mL fill of immunoglobulin in a 60 mL vial (OD = 41.6 mm; wall thickness = 1.6mm) you are asked to set a primary cycle length in hours. The primary segment chamber pressure will be 150 mTorr and the shelf temperature will be +5  C. No further information is available. Pick time in hours to program for primary drying. The number of vials doesn’t really matter – except for choked flow and we will assume that to be a non issue.

7. 7 international Answer 3 of 3  The Area is Weight in one vial is approximately The cycle is likely to be Not optimal, so use a Rate of 0.02 gm/cm 2 ∙hr

8. 8 international Answer to Exercise p1  Select a Cycle for a small molecule product with a collapse temperature of -10  C. There will be 25 liters of product (40 mg/mL) and a dose is 20 mg. The fill will be 1 dose/vial. Excipients include only 3mM Glycine for pH control at 4.2.  Select a vial size.  Consider the number of vials and size of the lyophilizer.  Select a freezing temperature and time.  Select a primary segment  chamber pressure  Shelf temperature  Time in primary  Select a secondary segment  Shelf temperature & time.

9. 9 international Answer to Exercise p2  This is just 1 of many right answers.  Select a 2cc vial since we only need 0.5 mL in each vial.  Product height will be

10. 10 international Answer to Exercise p3  25 L x 40 mg/mL = 1 kg of product  1 kg / 20mg = 50,000 vials  For the 2cc vial size, each 1 x 2 tray holds 874 vials.  50,000 / 874 = 57.2 trays  So, we need at least 115 ft 2 lyophilizer.

11. 11 international Answer to Exercise p4  Freeze to -40  C and hold for 3 hrs.  Freeze rate can be ~-1  C/min  Don’t bother annealing. Product height suggests that dry layer resistance will be negligible.

12. 12 international Answer to Exercise p5 Choose a chamber pressure by selecting a target temperature that is 2 deg below collapse and then use the empirical equation.

13. 13 international Answer to Exercise p6 Use Clausius Clapeyron to determine what ice temperature this chamber pressure would cause.

14. 14 international Answer to Exercise p7  The difference between the Clausius ice temperature, -34.75  C and the target ice temperature, -12  C is a lot and will permit substantial heat input from the shelves.  We haven’t discussed how to select a shelf temperature, and it requires more information than is given in the problem. For now, we will guess one at +5  C.  Ramp to +5C from -30C at ~1  C/min.

15. 15 international Answer to Exercise p8  Calculate a time in primary by assuming a rate of 0.04 gm/cm 2 ∙hr

16. 16 international Answer to Exercise p9  Choose +50  C for secondary because it is a small moleucule.  Ramp to +50  C at 0.1  C/min  Hold at +50  C for 3 hours.  Return to room temperature before stoppering and unloading.