INSIGHT - Comments
Vol. 2 No. 1 Glossary of Terms for Lyophilization
I have some comments on the glossary to Insight:
1. What you described as "crust" is sometimes also called the "lid". Have you come across this term and do you think that it matches?
2. "Meltback":
This would not be as strong as collapse, but still a serious deformation to the cake.
3. "Shrinkage":
This is to describe the phenomenon that makes the cake look as if the fill volume was not big enough, so to say a horizontal shrinkage.
4. "Tailing":
A bit like shrinkage, but vertically. The cake has not only become separated from the glass, but also has holes. This sometimes looks like Swiss cheese.
What do you think?
Does this match your description of cakes?
It is sometimes difficult for non-native speakers to pick up on the nuances.
J.Z. of Germany - January 1999
Response by T.A. Jennings, Ph.D.
Thank you for commenting on the glossary of terms for lyophilization.
Lid: I have not seen the term lid used in the literature but that does not mean it is not a descriptive word for a cake property. Certainly, lid would be just as applicable as crust in that both would describe a system that could impede the flow of water vapor during the drying process.
Meltback: This term refers to a condition where there is a liquid state in the interstitial region. Thus during the primary drying one would form either a mass at the bottom of the container or web-like glassy system. One can have collapse without meltback but must have collapse when meltback is present. In other words, meltback is a severe form of collapse.
Shrinkage: Shrinkage appears to be another term for collapse.
Tailing: I have seen cakes with holes only once and have never seen any reference to them in the literature. Where does the term “tailing” come from? Perhaps it should be called the “Swiss Cheese Effect.” In any case, I am pleased that you brought the term to my attention.
-------------------------------------------------------------------------------------------------
In response to your request for further input, one definition in the glossary had drawn my attention, Collapse Temperature. I would like to raise the question of why water alone was chosen as the mobile constituent in defining collapse temperature (without introducing the term glass transition). Collapse temperature, as I understand it, is a function of all constituents (present in a glassy or amorphous state) and therefore unique across various formulations. Additionally, it may be stated that within a given system or formulation as water content is reduced via sublimation, the collapse temperature will increase. Although this highlights the importance of water in defining collapse, I am not certain that water alone is the mobile constituent. The glassy or amorphous state is referred to here since a crystalline constituent would have less of a propensity to be mobile (from the perspective of viscous flow) unless it is undergoing a phase transition.
Joseph Mertz
Pfizer Inc., Central Research Division January 1999
Response by T.A. Jennings, Ph.D.
I defined the collapse temperature as that temperature at which the mobility of water in the interstitial region becomes significant. This definition does not state or imply that the only mobile constituent would be water. However, other constituents can not be mobile without having mobile water. For example, the movement of Na+ ions in an electric field require mobile water to be present.
You stated that “Collapse temperature, as I understand it, is a function of all constituents (present in a glassy or amorphous state) and therefore unique across various formulations”. I am in full agreement with your statement, however, you are referring to the collapse temperature for a given system where the definition that I offered describes a general state for all aqueous glassy systems.
You further state that “Additionally, it may be stated that within a given system or formulation as water content is reduced via sublimation, the collapse temperature will increase”. I also agree with this statement. But by reducing the water content, one is also changing the composition of the formulation that existed in the interstitial region. However, I must point out to you that the collapse temperature in the frozen matrix below the gas-ice interface will still retain the collapse temperature of the original formulation.
________________________________________________________________________
I have been reading the Guide for Inspections of Lyophilized Products that it appears in the Web that already you know (www.fda.gov/ora/inspect_ref/igs/lyophi.html). There is one of the paragraphs that I have not been able to understand sufficiently well and you help me a lot if you can aclarme the point. It says... "There are some manufacturers that market multiple strengths, vial sizes and have different batch sizes. It is conceivable and probable that each will have its own cycle parameters. A manufacturer that has one cycle for multiple strengths of the same product probably has done a poor job of developing the cycle and probably has not adequately validated their process. Investigators should review the reports and data that support the filed lyophilization cycle". In particular to that refers with "multiple strengths", since I am not able to understand the meaning of the term. Once again I thank you for your cooperation and interested. I like to make a comment on the Glossary of the Guide, if due to your publication they (FDA) have modified the content of the Glossary, but at the present time it contains a definition for the Eutectic Point. If this was as a consequence of your intervention, my congratulations go for you.
Dr. Enrique Mella July 1999
Email address: e_mella@ciudad.com.ar - Republica Argentina
Response by T.A. Jennings, Ph.D.
I think, and I use the word "think" because I cannot be certain just what the FDA may really have in mind, that the term multiple dose refers to a drug made at different dosage forms. For example, there may be a single dosage form that has a fill-volume of just 5 mL while a multi-dosage form would be in a larger container with 50 mL.
Perhaps the FDA is objecting to companies having the same lyophilization process for both dosage forms. They may base their objection on the fact that the lower dosage form is just sitting for periods of time without any processing. It is my opinion that so long as the final product meets the drug specifications, efficiency should not be the concern of the regularly agency.
I have have not visited the FDA web site lately but if my INSIGHTs have done some small good then it has been worth the effort. I believe that the free exchange of information by the internet will make this a better world to live in.
