INSIGHT - Comments
Volume I No. 2 Role of Product Temperature in the Lyophilization Process
No, we do not monitor product temperature in commercial lots. Why? Because the aseptic risk of placing them in a lyophilizer and the problems that we might encounter with our automatic loading system. Besides, the inaccuracy even of thermocouples due to the conduction of heat and the inaccuracy due to the erratic positioning of the thermocouple tip within the cake also influences the results. But, yes, we do use product temperature as a parameter in scale-up and technical runs. We believe that with a proper process development, we can do without the product temperature measurements in commercial lots.
J.Z. of Germany - August 1998
Response by T. A. Jennings
For years equipment manufacturers of freeze-drying equipment have advocated the measurement of the product temperature. Only when they found that the automatic loading system would not accommodate the loading of product sensors did the product temperature suddenly not become an important measurement. Is the measurement of the product temperature not important because it really is not important or is not important because it can’t be measured?
Lets look at a hypothetical example. Suppose that the engineers had come up with a magnetically driven transmission for automobiles. Instead of being limited to about 5 different gear ratios, this new transmission can control the gear ratio electronically so that a million gear ratios are now possible. The saving on fuel alone would make purchasing this car worthwhile. There is only one small problem. They were not able to build in a reverse mode. But backing up is dangerous because the driver often does not have a clear view of the rear of the car. Every year in the States, parents are horrified to learn that they just backed over and killed their own child or pet. Isn’t the latter fact alone enough evidence for justifying doing away with the reverse gear? How many people are killed each year as a result of thermocouples being used to measure the product temperature?
The answer to the first question is well documented but it is very doubtful that you would purchase an automobile that has no reverse gear. But there is, to the best of my knowledge, no statistics or proof of a patient dying or a product batch being recalled as a result of monitoring the product temperature. Strange, in one case one would continue to use the reverse gear in spite of known accidents, whereas, product temperature is now considered to be a hazard in spite of the lack of any supporting evidence.
A common pitfall is that by using a properly developed lyophilization process, based on product temperature, is sufficient to manufacture without product temperature measurements. The problem with that argument is that equipment and instruments, like people, to which I can attest, do age and do not continue to function like they did when they were in their prime. It is for this reason that we must continually check the performance of the dryer by knowing the product temperature.
================================================================
I have found your homepage in February this year. The information on this page was very interesting for me. I think it is a very good media to learn more about lyophilization.
I have two questions regarding insight volume 1 no. 2 "Role of Product Temperature in the Lyophilization Process".
1. In this article you have explained the relationship between product temperature, shelf temperature and chamber pressure. If we have a constant shelf temperature during primary drying we can adjust product temperature in dependence to chamber pressure. Do you have any experience of the pressure distribution inside the cake? Is the pressure inside the cake noticeable dependent of the filling height?
2. This article also describes the important role of product temperature measurement. We have different sizes of lyophilizers and different product temperature measurements. We use resistance thermal devices (PT 100) and thermocouples. Do you have any data about the energy entry into the cake during lyophilization? Is there a possibility to measure product temperature without direct contact to the cake, perhaps with infrared temperature measurement?
Nicole Denkinger May 1999
Boehringer Ingelheim Pharma KG
Biopharmaceutical Manufacturing
Birkendorfer Str. 65
88397 Biberach
Germany
E-mail: nicole.denkinger@bc.boehringer-ingelheim.com
Reponse by T.A. Jennings
In your first question you ask if you can, with a constant shelf temperature, adjust the product temperature by changing the pressure. In order to answer this question, I must break it down into two parts.
Constant Shelf Temperature: If the shelf temperature is really constant, then the product temperature will be directly related to the chamber pressure. If we were to increase the shelf temperature, the product temperature would increase and a decrease in pressure would result in a decrease in product temperature.
Which Shelf Temperature: The term shelf temperature can be ambiguous and that was brought out in INSIGHT Vol. 1 No. 7. If the shelf temperature that you are referring to is the fluid temperature that is passing through the shelves then the actual shelf-surface temperature seen by the product will also vary with pressure. This is because by changing the chamber pressure you are also changing the heat transfer rate between the shelf-surface and the product. For example, if the heat transfer rate were to decrease, the shelf-surface temperature will increase while the shelf-fluid temperature will remain the same. One must always be cognizant of just exactly what they are measuring and not what they think they are measuring. If there is heat transfer between the shelf-surface and the product, then there must be heat transfer between the shelf-temperature and the shelf-fluid temperature. In order for heat transfer to occur, there must be a difference in temperature between the shelf-surface and the shelf-fluid.
The second part of your question deals with the pressure differential within the cake. The pressure differential will be dependent on a number of factors. Let me just touch on some key ones at this time. First of all, the pressure differential will be strongly dependent on the cake structure. If you have a very fine structure cake, the gas conductance from the gas-ice interface, where the sublimation is occurring, will decrease as the cake thickness increases. As a result, even for a constant shelf-surface temperature and chamber pressure, there will be an increase in the product temperature. The reason for this is that the pressure at the gas-ice interface has increased. Another important factor is the fill-height. As the aspect ratio (fill-height to vial diameter) increases, so will the product temperature increase as the drying proceeds. But perhaps the most important factor is the formation itself. It will be thermal properties like the degree of supercooling and degree of crystallization that will have a major impact on the variation of the product temperature at a given shelf-surface temperature and chamber pressure.
Sensors: In using any type of temperature sensor one must be careful not only about placement of the sensor in the vial or tray but also on its mass. The mass of the sensor may not be a factor during the freezing and the primary drying when the mass of the product far exceeds the mass of the sensor. It is during the secondary drying that one must be careful that the mass of the sensor does not greatly exceed that of the cake. In such a case, there would be a tendency for the output of the sensor to read false high.
Heat Transfer: You can find energy input data into a product in the following two publications.
T. A. Jennings and Henry Duan "Calorimetric Monitoring of Lyophilization",Journal of Parenteral Science and Technology, Vol. 49, No. 6 pp. 272-282 (1995).
T. A. Jennings, Lyophilization - Introduction and Basic Principles, Interpharm Press, Inc., Buffalo Glove, IL (1999).
Infrared Temperature Measurement: You asked if there is a possibility of determining the product temperature using infrared spectroscopy. The answer would be yes but just how it would be done is another question to which I have no answer at this time. The noninvasive measurement of the product temperature still presents an elusive problem.
===============================================================
Dear Dr. Jennings
I am a Mechanical Engineer, I work as a project manager for an A&E firm that designs Pharmaceutical facilities. We are currently working on several aseptic filling areas. I wanted to brush up on my understanding of lyophilization.
I found your articles very helpful and informative. Thanks for the book coupon, I will most certainly purchase the book when it comes out in July. I already researched it at Amazon.com, I was a little disappointed that I had to wait, but the articles have tied me over until it is published.
From the tone of your articles you seem to have a good sense of humor, so I am not embarrassed to ask the following questions:
1. Why does lowering the chamber pressure reduce the ice surface temperature. It has been a while since freshman thermo, so can you give me a quick lesson.
2. Why would monitoring the pressure rise give an indication of the completion of primary drying. I understand you disagree with the approach, but I just want to understand the concept.
3. Where exactly are the temperature probes placed during the manual filling of the LYO? where on shelve? in the product?
4. You seem to be against automatic loading of the LYO. Does this also mean that you would not recommend barrier technology of the fill line. It would not seem practical to have one without the other.
5. During secondary drying is the temperature of the product above its collapsed temperature? and if so why does meltback not occur?
6. Why is secondary drying needed, can't all the drying occur in primary drying. Can you explain what is desorption, is this what happens during regular everyday drying.
I am only half way through the articles, so I am sure I will have more questions later. Thanks for the help and good luck with the Book.
Brian M. Flynn, PE June 1999
Response by T. A. Jennings, Ph.D.
I will answer your questions in the order in which you asked them.
Reduction of the Ice Temperature. When sublimation (solid to gas phase change) occurs there is a loss of both mass and energy. If there is not a source of energy to replace that lost by the sublimation process, the temperature of the ice will be lowered. The temperature of the ice-gas interface will be governed by the phase diagram of water.
Pressure Rise Test. The pressure rise test is when the drying chamber is isolated from the condenser and one observes the rate at which the pressure increases in the drying chamber. If there is ice present in the system and the shelf temperature is higher than that of the product temperature, then by isolating the drying chamber the pressure will rise rapidly because there is no longer a steady state between the energy going into the ice that dissipated by the heat of sublimation. Thus a sharp increase in chamber pressure can be an indication that ice is still present in the chamber. A word of caution. Increasing the pressure will also cause an increase in the product temperature and one must insure that the temperature at the gas-ice interface does not exceed the collapse temperature of the formulation. It is not that I disagree with this method of determining the completion of the primary drying process as much as there are other means by which once can ascertain the completion of primary drying without jeopardizing the integrity of the final product.
Temperature Probes. First of all, I do not agree that there is an exact location for either the product or shelf temperature probes. I have found that best placement of the product temperature probe in a vial was about in the center of the vial and 1/16” to 1/8” from the bottom. It is in this region where the last remaining ice will be during the completion of the primary drying.
When you speak of “on” the shelf, I assume you are referring to the shelf-surface temperature. The answer to this question is that the probe can be positioned anywhere on the shelf-surface that is representative of the shelf-temperature that provides energy to the product. Placement of the probe on the side or the underside of the shelf will give values
approaching that of the shelf-fluid temperature.
Automatic Loading and Barrier Technology. As you will see in Chapter 13 of my book titled Lyophilization - Introduction and Basic Principles, I fully support the concept of automation and complete barrier technology. What you may be missing is that if such loading equipment does not provide means for measuring the product temperature then one has no way of verifying that a lyophilization process was conducted within the validated process specifications. You now have a process that is based on art and not science. The product temperature serves as a check on the chamber pressure and shelf temperature.
Meltback and Collapse. Meltback and collapse occur during primary drying when there is mobile water present in the interstitial region of the matrix. Consequently, upon removal of the ice, the interstitial region can become deformed under its own mass.
Secondary Drying. First of all, you should realize that there is not a sharp demarcation between the primary and secondary process. Secondary drying is the desorption of water vapor from the resulting cake. This desorption process commences during the primary drying. However, in most products, the moisture content of the cake is too high at the end of the primary drying and the product will not have the desired stability. The rate of desorption of the water from the cake can be enhanced by increasing the product temperature so that the final moisture content in the cake will have the desired stability.
I realize that the above explanations are brief but they should give you some idea as to the general answer to your questions. I am sure you will find the detail that you are seeking when you read the book.
