* * * INSIGHT * * *

How important is the flatness of the shelves of a freeze dryer?

by Thomas A. Jennings, Ph.D. It has been my experience when talking to company personal who are engaged in purchasing a freeze dryer, that the main focus is often on the refrigeration system, i.e., the range of shelf temperatures and condenser temperature and the vacuum capabilities of the pumping system. Without question these and other considerations like process controls and data acquisition are some of the more important issues to be addressed. And yes the shelf surface is a key factor for that will relate to product capacity of the dryer. It then becomes a matter of just engineering the dryer in accordance with the process specifications required by the purchaser. Yet, it is often surprising to me to find that with so many details listed often little or no attention is given to flatness of the shelves. Although I must give credit to others like the Novice who asked the question Are they flat? in INSIGHT Vol. 2 No. 11 and also following references [1-3]; however, little heed is often given to such advice and the shelf flatness tends to be overlooked. Therefore it is the objective of this INSIGHT to make the reader more aware of the important role that the flatness of the shelves play in the lyophilization or freeze drying process.

Heat Transfer: The entire lyophilization or freeze drying process (freezing, primary
drying and secondary drying) is strongly dependent on heat transfer between the shelf surface and the product container. Ampoules, bottles and vials: Given that the temperature across the shelf surface is uniform (which we are aware is not) then the flatness of shelves would not seriously affect the heat transfer between the shelf surface and the container surface in the case of the vials, ampoules or bottles. The reason being is the bottom configuration of these types of container will have far greater impact on the heat transfer than that of the flatness of the shelf (see INSIGHTs Vol. 1 (No. 2, No. 3 and No. 5) Vol. 2 No. 5, Vol. 3 (No. 4, No. 9 and No. 11) and Vol. 5 No. 2. and ref [3]). It is frequency distribution of the heat transfer coefficient ( Co ) of these containers that will have a far greater impact on the energy transfer between the shelf and the container than actual flatness of the shelves. So it is my opinion, that the flatness of the shelves will not play a major role in the heat transfer to these latter type of containers when they rest directly on the shelf surface. Trays:

However, when it comes to larger containers such as trays now the flatness of shelves could play a major role in the heat transfer between the container and the shelf surface. It is true that full bottom stainless steel trays are notorious for often having poor thermal contact with the shelves. In some cases, I have observed where the trays only contact the shelf at three points which would represent the worse possible scenario heat transfer during the lyophilization or freeze drying process. Yet in the case of bottomless trays, the bottom of the tray is not removed. Since the bottom portion of this type of tray is often a flat sheet of metal and is not subject to such warping and the flatness of the shelf can now be quite critical. When such a tray is placed on a shelf having a non-uniform flatness, now the bottom of the tray will only come in contact with hills on the surface and not make thermal contact with any valleys. While the presence of such hills and valleys will no doubt affect all aspects of the lyophilization or freeze drying process, none are more affected than that of the primary drying. For it is during the primary drying that heat transfer involves the most energy (see INSIGHT Vol. 3 No. 8). Since during the primary drying the main source of energy is the direct contact with the shelf, even a shallow valley could have a major on impact on the heat transfer. The reason being is that under vacuum, a valley of just a thousandths of an inch could have the same effect on the heat transfer if the valley were an inch in depth. That is because the amount of energy transported by thermal conductivity of the gases in the dryer would represent only a small faction of the necessary energy transfer to conduct the drying process. Thus when using trays, even with perfectly flat bottoms, the flatness of the shelf becomes an important consideration. The effect of flatness will be direct function of the dimensions of the shelves and the trays. Dimensions of the shelf. As the size of the dryer ( shelf surface area) increases so does the problem with its construction. In the case of small research dryers with shelf areas ranging say from 2 ft2 (0.2 m2) to 10 ft2 (0.9 m2) the manufacturer will often use a relatively thick sheet of stainless steel to form the top and bottom surface of the shelf. The thickness of such a shelf is sufficiently flat that there are no significant hills and valleys on the surface. So the placement of a perfectly flat bottom tray on the shelf will form a system in which there is good overall thermal conductivity between the shelf surface and the bottom of the tray. Of course if the bottom of the tray is not flat or is distorted in some fashion, then one would still be faced with non-uniform heating of the tray but here the heat transfer is dependent on the configuration of the tray and not that of the shelf surface. Now as the dryer size increases, e.g. > 220 ft2 (20 m2) one starts to run into some serious problems. The mere weight of the shelves soon becomes an important factor. For example, if the product is being processed in ampoules, bottles or vials, those containers on the bottom must be able to withstand not only the total weight of the shelves above them but also the force that must be exerted by the stopper mechanism in order to fully seat the stoppers on the top shelf without being crushed. It is not only the mass of the actual shelves that one must take into consideration but also the heat transfer fluid in the shelves also adds to the problem. In order to meet the force limitations imposed by the

containers on the bottom shelf, one must find means of reducing the weight of the shelves. Since the top and bottom plates of the shelf represent the major portion of the mass of the shelves, the manufacturer may be forced to reduce their thickness. The reduced thickness will certainly improve heat transfer between the heat transfer fluid and that of the shelf surface but if the plates become too thin construction of the shelves becomes more difficult. The manufacturer must attach the shelf surface to a grid work that will be used to generate the serpentine path for heat transfer fluid and now must do with a rather flexible sheet of metal. Hence the unfortunate generation of hill and valleys on the shelf surface. The problem only gets worse as the size of the dryers increase because of the demand to enhance the batch volume. It is only a matter of time when the manufacturer can no longer reduce the weight of the shelves by reducing their total mass. When that point is reached then industry has to finally realize that the day for the continuous freeze dryer has indeed arrived (see INSIGHT Vol. 3 No. 8) [3]. Measurement of the flatness of the shelves. Laser technology has made it quite easy to determine the flatness of the shelf. There are at present many very economical systems for determining the flatness of a surface. Many of these systems can be easily found on the Internet [4]. Possible solution to drying on a non-uniform surface or with warped trays If you are faced with the problem of having a dryer which has a surface that is not flat or you are using trays that are not flat, then you may want to look into the possibility of heating the trays solely by radiant energy. This would mean that you would phyically raise each tray so they do not contact the surface of the shelf. In order to obtain the necessary transfer energy (E) from the shelf to the bottom of the tray, one would have to depend mainly on Stefans Law which is defined as E = 5.7 x 10-12 ( es (Ts4 - Tt4 ) watts/cm where es is the emissivity of the shelf surface and tray surface ( assumed to have the same value), Ts is the temperature of the shelf surface, and Tt is the temperature of the bottom of the tray. There are some obvious advantages and disadvantages to using such a technique. The main advantages are that energy transfer would not be dependent on the configuration of the tray or the contour of the shelf surface. A second advantage is that all trays would receive the same amount of energy and there for there would be uniform drying (eq. 1)

throughout a given shelf. Finally, variation in shelf to shelf temperature would less impact on the amount of energy transferred than that found in systems when the trays would be in direct contact with the shelves. There will be, as with any system, some draw backs. The first and obvious one is that the freezing time could be greatly extended. The second is that one would have to carefully monitor the secondary drying process in order to prevent possible overheating of the product. The reason being is that the shelf temperature that may be required during primary drying could greatly exceed that of the intended final product temperature. And last, the shelf temperature required for primary drying may well exceed those specifications of the dryer. As with any significant process change one would have to first validate the process in a development freeze dryer before attempting to transfer it into a production dryer.

Stoppering: The presence of an uneven shelf surface can also have an impact on the
stoppering of the ampoules, bottles or vials. In order to form a proper seal, the closure must make good contact with the surface as defined by the rim of the container [3]. Any container that fails to form such a seal, depending on the nature of the product, may have to be discarded. As a result, not only must the surface upon which the container rests must be flat but so too must the bottom surface above the shelf above. One can see that if the container rests in a valley and the contour of the shelf above it is a hill then one would might form a proper seal. A proper seal may also occur if container is on a hill the contour of the surface above is also a hill then a seal may well occur. However, one may not form a seal if the container rests in a valley and there is a valley on the bottom surface of the shelf above. So the message here is dont forget to specify the flatness of the shelf and also make it part of the acceptance testing of the dryer prior to shipment. In fact, a good factory acceptance test would be to ship to the equipment manufacturer a sufficient number of vials and closures for testing of the stoppering system and the flatness of the shelves.

References:
1. H.R. Powell, in International Symposium on freeze-drying of biological products, Washington DC, 1976 (S. Karger, Basel 1977) Develop. Biol. Standard., 36, p. 105. 2. T.W.G. Rowe, in International Symposium on freeze-drying of biological products, Washington DC, 1976 (S. Karger, Basel 1977) Develop. Biol. Standard., 36, p 117. 3. T. A. Jennings, Lyophilization - Introduction and Basic Principles, Interpharm Press, Buffalo Grove, IL 1999. 4. http://www.pinlaser.com/microCap.html

Volume 5 No. 12

December 2002