INSIGHT - COMMENTS
Vol. 3 No. 11 - Completion of the Primary Drying Process
Dear Mr. Jennings,
First of all I would like to thank you for the regular INSIGHT electronic copies; in frame of my activities (freeze-dried product development and scale-up process) it is a good theoretical and practical working base.
Regarding the last issue (Vol. 3 N°.11) - Completion of the Primary Drying Process- I would like to send to you hereafter a commentary.
I expected also to find in this document, in term of alternative of primary drying completion control method, the determination by product temperature record analyze. Practically primary drying is completed when product probes temperature record is breaking (see attachment). From my point of view it is a method to be take in account. May be this point was threaded in INSIGHT Vol.1 N°5.
Attached Graphic Data
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Fabian Moser
Responsible of Finished Product Manufacture
Debiopharm S.A., rue des Terreaux 17,
1000 Lausanne 9 , Switzerland.
Tél.: 0041 21 321 01 96
Fax: 0041 21 321 01 69
e-mail: fmoser@debio.com
web site: www.debio.com
December 2000
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Response by T. A. Jennings
Yes, I agree with you that the rise in temperature is a result of the ice-gas interface falling below the junction of the sensor and now you are measuring the temperature of the cake. In addition, it would be logical to think that the sharp increase in the product temperature can be taken as the completion of the primary drying. There is, however, one difficulty with such an end-point method and that is there is a frequency distribution to the heat transfer properties of the containers (tray or vial). Not every container will have the same heat transfer property. Thus there will be some containers where the product will dryer faster than the container with the sensor and some that will dry slower. For that reason, we need a method where we can be certain that all of the containers have completed the primary drying process before we start the secondary drying. If we do not take the heat transfer frequency distribution into account then we could have containers with partial meltback. This was the main point that I was trying to get across in the INSIGHT Vol. 1 No. 5.
Let me just state it yet another way. If all of the containers had the same heat transfer coefficients and the shelf surface temperature was uniform, then yes your suggested method of watching for the break point would certainly be very applicable.
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Dear Dr. Jennings
First of all, I would like to wish you a happy Christmas for you and your family.
I hope that in 2001 you will maintain your good advice concerning freeze drying in your INSIGHTs. I think I will be at your seminar in Scotland even if it means that I have to work on the labour day in Europe.
I have a question on your INSIGHT named "Completion of the Primary Drying Process". Don't you think that the best way to know if the primary drying is complete is not pressure rise test probes in the product but the measurement of partial pressure in the device. Water vapor and nitrogen (if it's the gas used for the regulation in primary drying) normally will have a sort of inversion in their value, something like the drawing below. I think that this system is the most reliable even if I don't use it.... if you agree with me do you know of a sensor that could be resistant to freeze drying conditions ?
Philippe Rière
Freeze Drying Manager in Merial Lyon (France).
E-mail: philippe.riere@merial.com
Telephone: 33-04-72-72-34-45.
January 2001
Response by T. A. Jennings
First of all I want to thank you for your kind thoughts and also hope you and your family had a very enjoyable holiday and this coming year will be the best in every way.
I will certainly look forward to meeting you in Scotland and I regret that it will require you working extra time. I will do my very best to make the seminar worth every minute of your extra effort.
Your question regarding the use of the partial pressure of water vapor as a means for determining the completion of the primary drying is well taken. I have measured the partial pressure of water vapor throughout the entire drying process. In a number of cases, I have found that the partial pressure of water vapor was still the predominate gas species until the completion of the secondary drying. So use of the partial pressure of water vapor as a
means of determining the completion of the primary drying must be used with caution.
It is not applicable for every process.
Yet, I must agree with you that one must also use the same amount of caution when using the product temperature or the pressure rise test to determine the completion of the primary drying (see INSIGHT Vol. 3 No. 11).
The only method that will provide an absolute determination of the primary drying
is by the use of calorimetric measurements. The reason that calorimetric measurements would be the preferred method is because of the large difference between the heat of
sublimation of ice and the heat of desorption of water vapor from the cake surface. So the completion of the primary drying is rather well defined. In addition, with calorimetric measurements one can also statistically ascertain the completion of the primary drying which is in itself a major advantage.
If you wish to measure the partial pressures then you should contact one of the major manufacturers of vacuum gauges, e.g., MKS and I believe they market such a system. In order to make partial pressure measurements, the mass spectrometer will have to be housed in a separate high vacuum system. It is suggested that such systems be used in the development of the drying process but not during the manufacturing process because they do require careful handling and a fair amount of maintenance.
