* * * INSIGHT * * *
How to Evaluate a Publication on Lyophilization/Freeze Drying
For those of us who are experienced in this field, and perhaps already have a well established view on the subject, it may only require the looking at the author’s name to shape an opinion regarding the value of the publication. As with any other field of technology, we tend to develop a list of those authors whom we prefer and those whom we tend to disregard. However, in the case of a Novice to the field one name bears as much weigh as any other and so these individuals, having no experience to reply upon, must use some other criteria to determine the worth of a publication. While it might be said because the paper is published its contents must be factual and accurate, and I sincerely wish that were the case, that may not always be true and it has absolutely nothing to do with the honesty and the integrity of the author(s). Therefore, let us rule out any other possible motive on the part of the author(s) and just consider issues that one should be aware of when reading a reputable publication on lyophilization/freeze drying.
Title: The title is often the very first impression one obtains about the publication. The title should be very descriptive of the nature of the publication. The following are some key words to look for in a title. These words will often provide you with an overview of the intent of the publication.
Discussion The word Discussion would tend to mean that the article is considering a particular topic or issue. Be aware that while the author may try to remain completely objective when writing a discussion, but he or she may have a tendency to favor a particular view point. This is not to the discredit of the author(s) for having a preference but the key point is that you should be aware that such a bias may exist and can at times be difficult to detect.
Review The reader should keep the same caution in mind when the title indicates it is a review of a topic or subject. When the title bears the word review, then one expects that the author(s) has done an extensive literature search on the topic and has condensed the subject or topic down to provide the reader with a good fundamental overview of the topic from various points of view. A well prepared and written review to me is a very valuable publication for it will save the reader countless hours of searching the literature and attempting to put the pieces together so that some sort of comprehensive picture of the topic will emerge. It is my opinion that the author(s) who writes a truly objective review article makes a major contribution to our scientific knowledge of lyophilization just as much as those whom he cites in his references. Once again the reader should be careful that the review was performed without any bias. One simple test to detect if biases do exist is to examine the references that are cited. Given the often broad scope of the topic or subject, the reviewer cannot, nor can it be expected, cite every paper written on the subject as a reference. However, in going through the references, one should take notice of any dearth to references to the work of one or more authors or there appears to be a group of authors, including those of the author(s) of the review, whose works are repeatedly cited. In such cases, the review may be not be completely objective and the reader should take that into account in judging the worth of the publication.
Research A title bearing the word research should alert the reader that the publication contains new information on a particular topic. Research on a new technique for measuring a key parameter of the lyophilization process, e.g., new method for determining the thermal properties of a formulation or research a new rapid means for determining product stability would make welcome reading. Unfortunately, research papers involving the lyophilization process are not plentiful and when they do appear they are most welcome.
Key Words Sometimes authors will use key words like lyophilization, freeze drying and validation in the title of their paper to attract attention. That is not to say that these and perhaps other key words should not appear in a title but the reader should read such papers with some caution. For example, a paper titled Lyophilization and Validation of Surcure (see INSIGHTs Volume 2 No. 3, No. 5, No. 7, and No. 9) may have little or nothing to do with the actual product Surcure if that is the information the reader is really seeking.
So the title can be very revealing about the contents of publication but one still should reserve judgment as to the actual value of the paper until after all of the paper has been read and understood.
Introduction: This section really sets the tone for the rest of the paper. A good paper will provide the reader with general background information that may be necessary to understand the main objectives of the paper. These objectives should be clearly stated and if after reading the introduction you are not sure of the intent of the paper you may not understand the remaining portion of the paper. Clearly, a paper that uses the fundamental laws of nature, e.g., the phase diagram of water, is a good indicator of a well prepared publication. If the authors use some obscure function that may have been proposed in a previous publication and now treated as being a universally accepted law of nature, then one must either take the trouble to review the reference or exercise caution when reading further. Just as with people, first impressions are important and so too your first impression of the paper is equally important. I may sound a bit cynical to you but that is not really the case. When I read a paper I do have what can be called an open mind. I don’t pre-judge the value of the paper nor do I take the view that because the paper has been published its contents must be factual. Needless to say I am disappointed if I find parts of the paper are questionable but delighted when I read a paper that is well done.
Body: A well written publication will take the reader from the simple to complex in stages that are easily understood and constant with the format outlined in the introduction. In reading the main portion of the paper I would like to caution you of the following key points.
Terminology: The fact that one is writing a paper in the first place is a clear indication of the author(s) desire to share their knowledge of lyophilization or freeze drying with others. However, it is only human nature that an author, and I may well be guilty of this myself, to offer new terminology when accepted terminology already exists. If you find yourself confused by the fact that the reboforestate is a function of the rebodumbus during primary drying, when the author(s) simply means that the product temperature is dependent on the chamber pressure then understanding the paper becomes a major task. While I admit that my latter example is a bit far fetched, none the less the use on unfamiliar terms makes understanding of the paper rather difficult. If I cannot understand what the author is saying I tend to quickly stop reading for I feel it to be a waste of time.
While it may be easy at times for the reader to spot when the author(s) have taken liberty to introduce new terminology, there are other conflicts in terminology which are not so obvious. Perhaps the one that troubles me the most is the shelf temperature (see INSIGHT Vol. 1 No. 7). In many papers this is not the actual shelf surface temperature that is in contact with the container but the fluid temperature that circulates through the shelves. Thus the actual shelf surface temperature will be dependent on the design of the shelves, the heat transfer fluid system and the nature of the heat transfer fluid itself. It is therefore difficult, unless the author(s) have been careful to specify fluid, or shelf surface, to know exactly which shelf temperature is being used in the paper.
Another term that often causes some confusion is that of the leak rate of a system. In some instances it may be reported in terms of change in pressure per unit time while others it may be pressure-volume (or mass) per unit time. So once again the reader must be careful to understand the exact meaning of the terminology being used.
Units: In the ideal world there would be a general acceptance for standards of the units of measurements. I have already considered this question in a previous issue (INSIGHT Vol. 6 No. 2.). While most scientific disciplines will have a given accepted set of units that is not quite the case for the field of lyophilization or freeze drying. No doubt the unit that generates the most confusion for us is that of pressure and it was gratifying to see the Standards Committee of ISL-FD, Inc. take the bold step of adopting Pascals as the standard pressure unit for this field. Perhaps the only generally accepted units is temperature given in oC. Until we can come together and agree on a standard set of units, reading of a paper on lyophilization or freeze drying will often remain a difficult and perhaps confusing task.
Calculations and Measurements: Unfortunately the computer programs today are not sophisticated enough to prevent us from making some really serious errors. Just because you get a number does not mean that it is correct or even accurate. Perhaps the one that bothers me the most is when an author will report the mean and standard deviation for a sample size of only three when one should have a minimum of 25 samples to make such calculations statistically significant.
Then there is the case of significant numbers in reporting data. In our world of computers we are often given more information than is needed. For example, the case of a digital display of pressure in a chamber. Let the accuracy of the gauge be 3% of the actual reading. The display gives a pressure reading of 50.2 mTorr. However the error in the reading is 1.5 mTorr. Therefore reporting pressure readings to a tenth of a mTorr has little or no meaning. Just because the numbers are there does not mean that the accuracy is also present.
Big Questions: The above are key issues a reader should keep in mind as they read a paper, however, I have saved what I think is the most important points for last. One “big question” that you should ask yourself after reading a paper is can I reproduce the findings or results of the paper? If the answer is “no”, then the paper has no value. Let me give you some examples to illustrate this point.
Let us say that the author(s) is describing the effect that helium pressure has on the drying rate. In the paper he provides the reader with accurate shelf surface and product temperatures for the lyophilization of a given concentration of lactose for a range of helium chamber pressures. He shows the effect of varying the helium pressure during both the primary and secondary drying processes. After reading the paper you may feel that the use of helium may well be beneficial to improving the lyophilization and resulting final product in your freeze dryer. But rather than risk losing your valuable product you would like to verify the results of the author(s). This is easily done for helium and lactose are readily available materials and if you have the same type of pressure and temperature transducers there is a reasonable chance you will be able to reproduce the results. So you are able to do a trial run and see if you obtain similar results. If you reproduce the results of the author(s), then you will be inclined to try the process on your product. Thus the fact that you can reproduce the results is a very important factor in considering the value of the paper. Of course this need not be limited just to the lyophilization but also to other areas like the IQ and OQ of a freeze dryer.
Now let us take the example of the author(s) describing the freeze drying process for a formulation that is only available to the author(s) using a 2 ml fill volume in their special 7 ml ultra thin walled tubing vial. In addition, the drying is done in a freeze dryer without any provision for measuring the product temperature and the authors only report the shelf fluid temperature during the freezing and drying process. There is no pressure control and the pressure is allowed to vary on its own. To make things worse the pressure is measured on the foreline of the system, the piping between the condenser and the vacuum pump. The authors report that with this drying process they were able to obtain low residual moisture values, excellent real time stability and reconstitution of the product is nearly instantaneous producing a homogeneous solution with no particulate matter. No doubt the results of the drying process are indeed remarkable but of what value are they to you with your product? I will let you be the judge of that but I do have my own opinion. The problem is that often non-reproducibility of the results of the paper may not be clearly apparent so one must be read carefully and be wary if there are any doubts.
But there is yet still another big question and that is how would such a paper, as just described, get past a peer review? Who are those reviewers and upon what basis were they selected? This is a serious issue for the reader often will assume that more than one expert in the field has examined the paper and has either suggested changes or recommended the paper not to be published. The failure of having an unbiased panel of reviewers examine papers regarding the lyophilization process and its associated equipment only hinders efforts to move this field from an art to a science.
Lyophilization or freeze drying is, in my opinion, for the most part 10% science and 90% uncommon sense [1]. The term uncommon sense seems more appropriate to this field for it appears that common sense more than often does not seem to prevail thus it must be those whose apply some sort of logically approach that are the ones who are uncommon.
Reference:
1. B.E. Jennings - private communications (July 2003)
Volume 6 No. 8 August 2003
