Comments on INSIGHT Vol. 6 No. 6
“Why do We Use RTD’s to Monitor the Freeze Drying Process?”
The following are comments sent in by readers regarding the above INSIGHT. I have not made any response to these comments but will publish any supporting or opposings views.
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Dear Mr. Jennings,
Even if the length of my message will make it less appealing I hope you will find some of your precious time to read it and hopefully to consider it at least funny.
.First, I have to say that I am a doubting type of person (“dubito ergo cogito, cogito ergo sum” Descartes). Even so, I will make an exception in this case saying that I am positive that there is no good answer to your question… Instead of this “non-existing” answer I have some other questions…
.The temperature gradient in the product being freeze dried (in liquid, ice or cake form) is an obvious fact for me (us); is it for everyone ?… I mean production people, QA, R & D, regulatory bodies experts and anybody else that use to “chat” on the freeze drying process.
.If this gradient is accepted, how many and which temperatures should be monitored ? (top, bottom, center, side…)… which should be considered necessary, relevant, useful…
.If the “product temperature” becomes “product temperatureS” what are becoming the usual relationships / equations used to describe, monitor or control the process….
.Even if it is possible to build “punctual” temperature measurement systems can we imagine a system to consistently position this probes in the predefined positions with the needed precision in manual and automatic loading freeze dryers ?
.In my opinion the vials subject to temperature monitoring are already “altered” with respect to the other ones for several reasons (temperature probe(s) mass, heat loss or gain through the temperature probe wire and last but not least the different pressure drop at the neck / rubber stopper level resulting in a different pressure at the product surface level). If we start thinking about a more complicated system for the temperature monitoring, is this going to make the above mentioned situation even worse ?
.Is the fact that the freeze drying process is a “statistical” one accepted ? If so, which are the tolerances accepted / expected for the temperature measurement ? On the same line… which is the relevance of all this values for the other vials ?
.Starting from the above mentioned “statistical” aspect, after a certain process / product has been validated (don’t ask me how…) can we content ourselves with monitoring / controlling the parameters that can be really, consistently, and precisely measured / determined, like shelves fluid temperature, chamber pressure, ice condenser temperature & pressure, vacuum pump head pressure, chamber “atmosphere” temperature etc. to ensure that any vial in any batch is “exposed” to the same “external” conditions (values and time evolution) ?… Anyhow, in real life, there is little more that can be done…
.Speaking of “equal conditions” I have another question mark: it happened to me very often to meet people that consider that the rubber stopper position during the freeze drying process is totally irrelevant as long as the vial is not completely closed. In my opinion this position is important (I can give the explanation if needed) as much as to be considered one of the process parameters. What is your opinion on this ?
.Coming back to the initial point I would say that with specially designed PT100 or other temperature probes, the “punctual”, precise measurement of the temperature in different points of the product would be very “nice” during the development of the process. Still, I am wondering if this will make more complicate the passage from R&D stage to mass production…
Bogdan Oghina July 2003
E-mail: boghina@fx.ro
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Dear Tom,
I enjoyed (As in each month) to read the insight article. In the present article you discussed the disadvantages of PT-100 . I would like here to mention the advantages.
Normally thermocouples are fragile. For industrial lyophilizer my experience with Pt100 is of better durability. Industrial lyophilization is a process where we employ an accurate defined process to a very large population of vials or trays. equipped with large variety of qualities which influencing its heat conductance properties. The variety is so high that process is also different while we compare the process in the left side to the right and bottom to top of the. Different locations shows different drying pattern.
As you mentioned measuring temperature using Pt 100 giving us kind of rough average which is proportional to the phase of the process. After few FD cycles operators or plant managers might study this proportional ratio thus feeling the general trend of at each point. In case of equipment malfunction they can see the general trend and this trend can be used as a tool for decision making. I agree that it is not necessary tool for good FD. It is a nice to have option. (Can you imagine what problem these probes are making to automatic loading and unloading systems?) But still I think that the benefit of having it is superior to all other possibilities.
While making the research or cycle development the information achieved by PT-100 is useless. It is better using thermocouples at different locations and height in the cake. They developed magnificent research tools: vials equipped with micro thermocouples embedded in its glass for achieving data, helping you to know the cycle very intimately. But once the ice front passes the thermocouple head you do not know what happens in the layer below. While with PT100 you certainly know because the average is different from shelf temperature- lower. How much is not that important. when you have 10-20 thermoelements in each cycle the information and experience operators and plant managers can achieve is huge.
Can I offer that in case that you are not publishing INSIGHT in one month on the next month you will publish 2? I am really looking forward to them. I appreciate your monthly effort in publishing this important information, your drawings and editing are super. the collection of these articles is a valuable source of information about lyophilization.
All the best to you and I wish you continue publish INSIGHT for long years.
Yossi Shapira
Technology & Projects
API Division
TEVA Pharm. Industries
Tel: 00972-50-321712
June 2003
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Dear Tom,
The most important question I have is it fair to claim that we measure the actual PROCESS product temperature when we insert a relatively large RTD sensor in our product?
In my opinion crystallisation speed and direction, and the herewith-associated temperature front(s) are significantly influenced by an insertion in SVP. Especially a conductive (steel), rather large unit as a RTD head/wiring. Additionally the probe is often inserted in the middle, thus replacing the critical liquid heart area by glass/stainless steel....
Is the additional volume of the head compensated by filling less product, or is the filling height different than in vial without a probe?
Usually we gain knowledge by measurement, but sometimes we have to wonder in what way we alter the process we want to measure, by the very act of performing the measurement. Until now I have always concluded that I'm not sure that we are able to measure the actual freeze drying process by inserting probes, thus I always do not claim to measure "actual" product T's, but I present them as process "trending" data.
Regards,
Michel Croes.
June 2003
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Hi Tom,
It's a credit to you and your colleagues that the site attracts so many people. I'm sure you are right about people enjoying reading other people's comments - especially if those comments fit with their own experiences!Anyway, regarding TMDs for product
monitoring, may I offer the quote below?
"With more and more formulations having a low fill volume, and the trend for many not to be freeze-dried in vials but rather in more unusual formats (particularly diagnostic kits and medical devices), the issue of accurate product temperature monitoring (whether for cycle development purposes or in production) is becoming more pressing.It may be argued that right now, thermocouples (giving a "point measurement" of temperature) are the only practical option for low fill products (compared to typically more bulky RTDs). However, even with small probes, we still risk making the probed sample quite atypical - possibly causing it to both freeze and dry before the remainder of the batch. This can give "false positives", perhaps causing secondary drying conditions to be adopted too early in the cycle, or even a run to be stopped prematurely, possibly with disastrous consequences!The future is surely in non-invasive, non-destructive temperature monitoring, but there is some way to go before this is (a) commercialised, and (b) validated and allowed by the regulatory authorities! In the meantime, we just have to work with what is tried and tested..... and for now, I guess that means RTDs and thermocouples!"
Kevin R. Ward, Ph.D.
MRSCResearch & Development Manager
Biopharma Technology Ltd.Winchester, U.K.
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Dear Mr. Jennings,
It appears to me as if the answer to your question may be at least two-fold.
Firstly, RTDs are said to be the most stable and most accurate of temperature sensors (compared to thermocouples and thermistors). Does the inaccuracy for an RTD, that results from the arguments you made in your article, outweigh the inherent accuracy of an RTD compared to these other sensors?
Secondly, perhaps the problem isn't so much the sensor type but rather the sensor placement or orientation (90 deg. rotation). It seems to me that, after reading your article, changing material fronts and inherent temperature gradients that occur throughout the lyophilization process may make the desired temperature measurement difficult no matter which sensor type you use. Perhaps a linear profile of 3 or 4 sensors would span the changing conditions. In the case of low product contact mass compared to the RTD mass yeilding inaccurate measurements, perhaps a low mass thermocouple would indeed be the best alternative.
Take care,
Richard Wheeler
June 2003
