In the pharmaceutical industry, time and productivity are lost due to the lack of scientifically sound and industry-standard approaches to issues such as batch acceptance, equipment qualification, process validation, cleaning validation, and leak-rate acceptance. In the absence of such “best practices,” companies often take overly conservative approaches that lead to rejection of product and lengthy delays in the start-up of new equipment and facilities.
* April 2014: LyoHub initiated development of Best Practices in Instrumentation for Process Monitoring in Pharmaceutical Freeze Drying. Working group is led by Dr. Steve Nail (Baxter BioPharma) and includes lyophilization experts from Pfizer, Allergan, IMA Life, Physical Sciences, University of Connecticut, Purdue University, IMA Life and Millrock Tech.
* April 2015: Best Practices Presentation at 2015 ISLFD Meeting in Chicago, April 9, 2015. Community input requested.
* July 2016: The draft of recommended best practices presented at 2016 CPPR Freeze Drying of Pharmaceuticals & Biologicals Conference in Breckenridge, CO.
* November 2016: Best Practices Brochure for "Process Instrumentation in Freeze Drying" introduced. Click here to download a copy of the brochure to keep in your lab.
* March 2017: Best Practices Paper provided by LyoHUB in open source. To access the complete best practices paper, visit http://link.springer.com/article/10.1208/s12249-017-0733-1
Summary of recommendations - 2016:
1. Recommendations for measuring product temperature in individual vials
A) Thermocouples are preferred to other current methods because of the ability to measure temperature at a precise point. The most appropriate point to measure product temperature is in the center of the vial, with the tip of the thermocouple touching the bottom of the vial.
B) Use fine wire (e.g. 32 gauge) thermocouples because of the flexibility of the wire and the ability to locate the tip of the thermocouple in a precise location.
C) Use a guide tube to hold the thermocouple in place within a monitored vial. The open area of this device should be very close to that of a partially stoppered vial.
D) Be aware of the sources of uncertainty associated with product temperature measurement in a manufacturing setting, and don’t over-interpret such data.
E) Be aware of the bias in freezing and freeze-drying behavior caused by any temperature measuring device. Recognize that monitored vials may freeze dry significantly faster than the rest of the batch.
F) The same best practices that apply at the laboratory scale should also apply in a manufacturing environment.
2. Recommendations for measuring chamber pressure in freeze-drying
A) The capacitance manometer is the instrument of choice for pressure measurement and control in a pharmaceutical freeze dryer. A temperature-controlled sensing head is highly recommended.
B) Best practice would include both a capacitance manometer and a Pirani gauge on both the chamber and the condenser.
C) Use of comparative pressure measurement is highly recommended as a process monitoring tool to determine the end point of both primary and secondary drying.
D) Keep in mind that both repeated exposure to atmospheric pressure and repeated steam sterilization tend to shorten the interval between calibrations of a capacitance manometer. Historical records are useful in establishing the more appropriate time interval between calibrations. In situ calibration is not considered best practice.
Please contact us with your comments and suggestions on best practices in lyophilization/freeze-drying.
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