Lyophilization Made Easy - Lyophilization Articles & Reports

Lyophilization Made Easy
March 2003
By
Thomas A. Jennings, Ph.D.
INSIGHT
Vol. 6 No. 3
It was during a planning session for the forthcoming Lyophilization Conference 2003 that will be held in Chicago, IL USA, that my colleague Dr. Irina Bakaltcheva suggested I present a paper. Based on the fact that I am President of the organization I had to protest to the idea for fear it would appear to be self-serving. However, Dr. Bakaltcheva can be very persuasive and I soon found myself agreeing to summit an abstract provided it was acceptable to the Session Chairperson - Professor Louis Rey. I did give her a possible title for such a paper but she would hear nothing of it and had one of her own in mind. The title paper was the same as the title of this INSIGHT. Now I really had to resist for fear that such a paper could never be well received from such a renowned audience. Having seen my firm stand on such a topic, Dr. Bakaltcheva relented and agreed that another paper might be more suitable.
Little did I let Dr. Bakaltcheva know that her suggested title had a far greater impact on me than she realized. For although I was well aware that she was jesting with me, still there was a strong element of truth in what she was saying. Dr. Bakaltcheva in her wisdom knew that a vast number of people working in the field of lyophilization or freeze drying would welcome such a paper. Far too often they have heard, and certainly from me in previous INSIGHTs too many to list, that lyophilization is indeed a very complex process. So how refreshing it would be to hear someone give a paper on ?Lyophilization Made Easy?. So I have elected, instead of presenting such a paper to a limited audience that will attend the conference, to present it in terms of an INSIGHT. For the main objective of the INSIGHT is to present the reader with my view point towards a given topic that is generally generic to the whole field of Lyophilization or freeze drying. So to Dr. Irina Bakaltcheva I dedicate the following INSIGHT on ?Lyophilization Made Easy?.
The first question that any reader must ask is do I really believe that lyophilization can indeed be made easy. I would have to say without any hesitation that the answer would be a firm yes. Lyophilization of a product can indeed made easy and to use an American colloquialism ?a snap?. No doubt there are many who are doubting me at this point or even perhaps questioning my sanity, but what better way to make my point than give an example. So to all you doubting ?Thomas?s? consider the following:
Formulation: In order to make lyophilization easy let us first start off with the formulation. An easy lyophilization process should also have an easy formulation. It should consist of just the active ingredient and the process water. Let the concentration of active ingredient be between 50 mg/ml to 100 mg/ml. At this range of concentrations we will tend to get a cake that will have a good self-supporting structure and not require the need of a bulking agent like mannitol that could perhaps only serve to reduce the yield from the batch by causing the breakage of the glass vials or bottles. In addition, our active ingredient does not require a buffer system, cryroprotectant, lyoprotectant or a dilute sodium chloride solution to make it isotonic [1] (see INSIGHT Vol. 2 No. 1). The addition of these other constituents will tend to make our formulation more complex and our objective in this INSIGHT is to make lyophilization easy. So it is only logical that we start off with an easy formulation that is stable at ambient temperature for a period of two weeks.
Thermal Properties: Since we have such a simple formulation, there would be no reason why we could not also expect that the resulting formation also to have good thermal properties [1] like the following:
Degree of supercooling is 10 oC. Such a degree of supercooling of the formulation (INSIGHT Vol. 2 No. 1) will prove to provide a uniform frozen matrix. Too high a degree of supercooling could form small ice crystals that would produce a dense matrix that would impede the flow of gas from the product and prolong the drying process. A uniform matrix would also be free of any crust or glaze that may not only impede the flow of water vapor but also provide a system where there may be some denaturing of the product or the formation of some covalent bonding [1]. In order to obtain such a degree of supercooling, our source of process water must have similar thermal properties. Finally, since we are making lyophilization easy, there is no frequency distribution to the degree of supercooling so all resulting matrices will have exactly the same configuration.
Degree of crystallization is 1. The degree of crystallization defines how much of the water in the formulation actually crystallized during the freezing process. It is surprising how little attention has been paid to this thermal property and yet it can greatly impact the drying process. For example if you found the degree of crystallization = or < 0.5 one would have to take steps to improve this thermal property or change the formulation prior to even starting a drying process. In making lyophilization easy, the degree of crystallization of our formulation will be 1 which will mean that all of the water is in the form of ice crystals and thus the product is in essence dried (except for any adsorbed moisture) prior to the start of the drying process.
Eutectic temperature of -5.00 oC. By only having just the active ingredient in the formulation, we can make lyophilization easy by having the active ingredient also a component by forming a true eutectic mixture during the freezing process. A well defined eutectic temperature will eliminate any concern over the effects of a frequency distribution for we are able to obtain reproducible eutectic temperatures to an accuracy of a tenth of a oC. Such an accuracy of the temperature when a phase change will occur in the interstitial region would not only make lyophilization easy but also its validation a breeze.
Now that we have knowledge of the thermal properties we can now proceed with the lyophilization process for a 1 ml fill volume in a 10 ml tubing vial.
Freezing: With a 1 ml fill volume in a 10 ml tubing vial and a formulation being stable for two weeks at ambient temperatures and having a degree of supercooling of 10 oC and a eutectic temperature of just -5 oC, we can load the product at a shelf temperature of 20 oC. Once the product is completely loaded in the dryer, the shelf surface temperature is reduced to -15 oC. To make our lyophilization process easy we have been fortunate enough to have purchased a freeze dryer where the temperature variation across a shelf and from shelf to shelf is 0.1 oC so that when the product temperature reaches and maintains - 15 oC for no less than 1 hour we are certain that all the product is frozen. We can now increase the shelf temperature to -10 oC. This will be the product temperature at which we plan to do our primary drying process.
Primary Drying: Just as soon as the shelf temperature reaches -10 oC, we begin to chill the condenser. Being that we will have a product temperature of just -10 oC, we know that a condenser temperature of only -40 oC is more than adequate. By the time the condenser temperature reaches -40 oC, all product temperatures have reached and maintained -10 oC. Since the formulation has a eutectic temperature of -5 oC we know that there is no mobile water present in the frozen matrix.
Since the vapor pressure of ice at -10 oC is 260 kilopascal (1,950 mTorr) [2], we have found that by maintaining a chamber pressure, by a nitrogen gas bleed, at 120 kilopascal (900 mTorr) and the shelf surface temperature of 20 oC, the product temperature will remain at -10 oC 0.1 oC throughout the entire primary drying process. The reason being is that the frequency distribution for the heat transfer coefficient Co of the vials [1, 3] is known to have a very narrow gaussian distribution such that there will be a high degree of confidence that the entire batch of product has completed the primary drying when all of the product temperatures indicate 20 oC 0.1 oC. In addition, the pressures that are required should not be a problem for any of the commercial freeze dryers.
Secondary Drying: Since the product temperature is already at the final product temperature of 20 oC 0.1 oC, the desired residual moisture is obtained by reducing and maintaining the pressure, by means of a nitrogen gas bleed, in the chamber to 35 kilopascal (265 mTorr) and maintaining this pressure for one hour. This pressure is sufficient to reduce the moisture to within the desired limits and at the same time is high enough to guarantee that there will be no backstreaming of hydrocarbon vapor from the vacuum pump. Once obtained, this pressure should not represent a problem for any freeze dryer in proper working order to maintain.
Summary: With the above example, one can expect, depending on the fill volume, that the entire lyophilization process will be less than 8 hours. This INSIGHT has shown that lyophilization can indeed be made easy. In fact, the lyophilization process is not the problem but will be dependent on the formulation if it (the process) is a dream or nightmare. What kind of formulation do you have?
References:
1. T. A. Jennings, Lyophilization - Introduction and Basic Principles, Interpharm Press, Buffalo Grove, IL 1999.
2. L. Ulfik, ?Standards Committee Report I - Recommendations for pressure measurement? ISL-FD, Inc.
3.T. A. Jennings and Henry Duan "Calorimetric Monitoring of Lyophilization", Journal of Parenteral Science and Technology, Vol. 49, No. 6 pp. 272-282 (1995).