1. To maximize batch uniformity and minimize radiant energy effects, when processing product in vials:
Use a full tray of vials. The vials in the outer perimeter should be empty to reduce edge effects.*
Thermally shield the product near the door by placing a sheet of aluminum foil inside the product chamber door (shiny side out).** It should be tucked gently around the shelf assembly being careful to avoid getting in between the door and the gasket. This technique will improve batch uniformity for all types of product containers.
*In a recent study, 6 cycles were performed using a solution of 5% sucrose and distilled water. 20cc vials were filled with 3 ml each and lyophilized using the same recipe in cycles 1-5. One set of variables was altered in each cycle. In 3 of the 6 cycles, an empty row of vials was used around the vials with product to better thermally shield them from edge effects. Thermally shielding the vials this way reduced product temperature differences between center and edge vials by an average of 1.7°C at the end of the freezing step and 2.4°C after 15 minutes of stabilization time in the first step of primary drying.
**Using aluminum foil as a radiant energy door shield proved to have the greatest impact in minimizing disparities in rates of drying. While two of the cycles were the same in every other regard, when aluminum foil was used as a thermal shield, the time of thermocouple convergence with the shelf setpoint and the end of primary was 9% closer. If we only have thermocouples as our sole endpoint determination tool, it is very useful if their indication is closer to the true cycle endpoint. It can also be assumed that the heat transfer properties of the product containers may vary. Therefore, with a material that is even better conductor than glass, we may see a more pronounced improvement when using aluminum foil.
Because all cycles produced product that was visually acceptable and very similar across all batches, analysis like this is one of the few ways to determine the very real differences in batch uniformity (and likely frozen structure), GLP such as thermal shielding produces. In comparing key metrics such as length of primary drying time, the two shortest cycles of the 6 performed during this study were the ones where both methods of thermal shielding were utilized.
2. A capacitance manometer is the preferred vacuum gauge with which to configure your lab freeze-dryer because it measures the absolute pressure in the system as it is unaffected by the presence of water vapor. A Pirani gauge by contrast, reads high when water vapor is present.
3. Avoid using vacuum set points below 40 mTorr. Never use 0 mTorr/microbar.
It can be difficult or impossible for some dryers to get down to 40 mTorr(53 microbar)
40 mTorr (53 microbar) equates to a product temp of approx. -45°C. Product that needs to be that cold to successfully freeze-dry should be reformulated.
Vacuum set points below 40 mTorr/53 microbar can set-up the conditions that allow oil back streaming to occur. Oil back streaming is oil from the vacuum pump that migrates into the freeze-dryer because the pressure is lower there than at the vacuum pump.
4. For greatest freeze-drying efficiency, keep container fill volume less than ½ the height of the container or ¾” (19 mm) whichever is lower. Maximizing product surface area relative to product depth is the goal.
5. There is no need to have a multi-step primary drying program with more than 2 shelf set points. If a product can withstand +5°C on the shelf during primary and the freeze-dryer is capable, there is no advantage to performing the initial part of primary at a lower shelf temperature.
6. For maximum repeatability, always use ramp rates to change from one shelf set point to another.
7. Keep the vacuum set point the same throughout primary and secondary drying.
8. Product temperature measurement using T type thermocouples:
Use fine gauge wire (30 gauge or better)
Place thermocouple tip in the bottom center of the vial, just touching the bottom
T type thermocouples are better for placing in vials because they measure a single point
Be aware of the “bias” introduced into product temp measurement by a thermocouple- vials with a TC will freeze sooner and dry faster than vials without a TC
9. Ensure the freeze-dryer is clean, dry and empty to start every cycle. Water from a past cycle remaining in the condenser or condenser drain line can cause sudden pressure excursions.
10. For repeatability in the same freeze-dryer as well as for developing recipes that will be scaled up to other lyophilizers, use “shelf driven mode” (rather than product driven mode). This mode relies on the shelf inlet temperature sensor reaching the recipe set point as the criteria for advancing to the next step of the program. Product driven mode relies on thermocouple readings to advance into primary which may not be consistently placed or representative of the batch.
Author: Leslie Mather, Director Training & Tech Support - SP Scientific