Scale-up - what does it mean? —from GP, co-founder and director of a biotech startup
NNVC, like any pharma/biotech, is almost certainly adhering to the distinction between R (Research) versus D (Development). Scale-up is the final stage of Development.
Development has a series of demands that push the process beyond the work that the Research people did. During Research, NNVC would have been trying to build a chemical structure that they believe will defeat the flu virus. Someone in Research has produced a tiny amount of material that passes the test (the assay) to show desired activity. Was this just being lucky once, or can more material be made that does the same thing each time? Was the success a fluke due to some undocumented variable? Think of a beginner basketball player’s incredible lucky goal from mid-court, but perhaps never being able to sink another basket again. That’s Research.
1. Development establishes repeatability and reliability. To use the basketball analogy, it is the ability to sink the shot every time.
2. Development reduces costs to make the product commercially viable. Development usually has to re-invent the entire process for making the drug in order to be commercially cost effective. Development receives an existence proof from Research : it is possible to somehow make a compound that will kill flu virus according to the assay. Researchers will use any method possible, with limited regard to how expensive it is or how many steps are involved, to generate a compound that works. The yields may be terrible. This by-hook-or-by-crook method may be so expensive that a single dose might cost hundreds of thousands of dollars. Example: Postulate a process with 20 steps to build the drug, and, to pick an easy number to work with, say that you lose 50% of the material in each step. At that rate, for NNVC to deliver 2.5kg to tox, they would be starting with over 1.25 Million Kilos of starting material. Clearly commercially impossible.
Development will invent a completely new method for building the drug that cuts the number of steps to the minimum, gets the yields on each step heading towards 98-99%, and redesigns the synthesis to attempt to eliminate expensive ingredients or costly processes.
3. Once this has been achieved, Development figures out how to make ever larger batches: scale-up. Scale-up is done in stages so that the effects of working with larger volumes are clearly revealed. Think of going from making a single cake from an established recipe, and trying to scale up. If 4 batches went into a single large pan, the outer edges may be dry or burnt while the center is still uncooked. If the surface area is reduced and evaporative losses decreased, the recipe may contain too much liquid and has to be adjusted. The baking profile of time and temperature that worked with one cake fell apart when 4 pans simultaneously went into the kitchen oven. With two tiers of pans, the ones closer to a heating element begin to burn. As the scale-up goes to making 100 cakes simultaneously and then 1,000 cakes, none of the kitchen equipment used for the single cake is useful any longer and the recipes all need adjusting again. You can easily envision how a larger volume of material might require more mixing time or prep time. With longer times, one of the ingredients is now exposed to air or room temperature and starts to oxidize or melt, etc.
