* * * INSIGHT * * *
Yes, You have no Eutectic
By
Thomas A. Jennings, Ph.D.
ABSTRACT: Recently, I was browsing the web on a search engine and I came across the following web site.
65% GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS - Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).
http://www.fda.gov/ora/inspect_ref/igs/lyophi.html
Upon accessing the web site, I was at first impressed with the definition that was given regarding the lyophilization process. It was similar to the one that was expressed in the previous issue of INSIGHT (Vol. 1 No. 9). But my enthusiasm was soon dampened when I read the following statements.
Typically, the product is frozen at a temperature well below the eutectic point.
It is desirable after freezing and during primary drying to hold the drying temperature (in the product) at least 4-5 o below the eutectic point. Obviously, the manufacturer should know the eutectic point and have the necessary instrumentation to assure the uniformity of product temperatures. The lyophilizer should also have the necessary instrumentation to control and record the key process parameters. These include: shelf temperature, product temperature, condenser temperature, chamber pressure and condenser pressure. The manufacturing directions should provide for time, temperature and pressure limits necessary for a lyophilization cycle for a product. The monitoring of product temperature is particularly important for those cycles for which there are atypical operating procedures, such as power failures or equipment breakdown.
While not taking issue with all of the guidelines offered in the above, I must take exception with the premise that formulations obviously have eutectic points or temperatures and that manufacturers should have such information. The basis for my concern is that for more than 20 years, I determined the thermal properties of a wide range of lyophilized biological, diagnostic and pharmaceutical formulations using an instrument that performed both D2 and DTA measurements. While not knowing exactly how many thermal analyses were performed during this time period, my estimate would be that the number is close to 2,000. Of those formulations, there were no more than two or three that had, by definition, formed a eutectic during the freezing process. The remaining formulations had what is referred to as a collapse temperature and is defined as that temperature at which the mobility of the water in the interstitial region becomes significant [1]. The collapse temperatures were generally found not to be sharp and well defined because it represents a measure of the onset temperature for melting of a glassy state. In addition, the results of 17 thermal analysis of a 3 % lactose solution suggested that systems forming glassy interstitial regions had a frequency distribution of collapse temperatures [2,3].
Reading further on the web page, I came across a GLOSSARY section in which key terms of the lyophilization process were defined. Although the guideline stressed the importance of freezing and drying below the eutectic point, it provided the investigators and other FDA personnel with no definition of the term. It is the objective of this INSIGHT to provide a definition of the eutectic point and temperature and also discuss the possibility of its existence in a multi-constituent formulation.
Volume 1 No. 10 December 1998
4 Pages 3 References 1 Figure
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