The Placebo Effect

We have all heard about the use of placebos in clinical trials and healthcare, but a placebo can also be useful when developing or scaling up manufacturing processes, such as lyophilization. Freeze drying is primarily used as a means of preservation, yielding a stable product that has a prolonged shelf life and can cope with ambient storage conditions (eliminating the need for an expensive and onerous cold chain). In my view, placebos are a vital tool in freeze-drying research and development projects – after all, why waste valuable amounts of active pharmaceutical ingredient (API) if you don’t need to? Often, developers find themselves faced with low availability of the API or restrictions due to high toxicity.

In development projects, the role of the placebo is not to act as a decoy, as with clinical trials, but to actually replicate, as closely as possible, the physiochemical properties of the API in terms of its freezing and freeze-drying behavior. Inappropriate use of placebo formulations is not uncommon in the industry; for example, the API may simply be removed from the formulation even though it exerts an influence on its freeze-drying behavior. I’ve also seen active protein being substituted with a common sugar, even though the sugar has very different thermal characteristics!

If the API is present in very low concentrations, it can sometimes be removed completely for freeze-drying studies with no ill effect. It is also possible to replace the API with a molecule that will simulate its presence in the formulation. Care must be taken, however, in choice of the simulant to ensure that it does not alter any significant behavior shown by the product. The simulant should be a match in terms of any critical frozen state or drying events inherent to the product such as collapse, glass transitions or eutectic melts.

If there is a higher quantity of API, this can make simulant selection even more difficult, as the API is more likely to exert a strong impact on the critical properties of the formulation and how it behaves during freeze drying. Here, careful consideration must be given to the selection of an appropriate placebo formulation and, indeed, whether the use of a placebo is a viable option at all. From my own experience, designing a placebo in this instance, although difficult, is not usually impossible. The trick is to create a placebo that acts as a suitable thermal simulant. For example, if the API is a protein, it may be possible to replace it with a routine protein, such as human serum albumin or bovine serum albumin, but it is essential to characterize both the placebo and the API to ensure equivalency.

It is also very important to match the overall weight/volume concentration of the placebo to the API to replicate product resistance during drying; a higher concentration formulation will give a denser structure of dried solute solution as drying progresses down from the top of the sample, giving a greater resistance to vapor flow. A placebo formulation that is less concentrated may dry quicker and give misleading results. It goes without saying that it is also important to ensure that the same materials (vials, trays, and so on) and fill depth are used for the placebo as for the actual product. You may be surprised at how many developmental scientists do not consider these parameters...

Placebos really are an essential part of developing and validating the freeze-drying process and we’ll no doubt be seeing more activity in terms of formulation and reformulation with placebos in the future. The big challenge, however, will be overcoming the industry’s common misconceptions. I would like to stress that simply removing the API, or substituting it with an unsuitable alternative will definitely not give you equivalent results of how the formulation will behave when using the API. And such mistakes are very expensive. It’s important to spend time ensuring that the properties of placebo you are using are equal to the API; it will ultimately streamline the performance and productivity of your development project.