Thread by @SafeChem79

Here’s a few reasons why process chem tries to avoid chrom in early development, ESPECIALLY for the API. Yes there will be exceptions, but for the most part these points hold true …1/n

The first relatively large batch made by process chemists has different names depending on the company. At PFE we called it the regulatory tox batch, at VRTX it’s the GLP tox batch. This is the first time your chemistry will be done on multikilo scale 2/n

A typical batch size can range from 500g up to 4+ kg. When I was making material for ADCs the batch size was <5g. Again, it’s all about the projected dose before tox findings. So why do we avoid chrom like the plague (well like the bubonic plague anyway)? 3/n

It’s all about impurities! Your impurity profile in the GLP tox batch sets the profile for your First in Human batch. Therefore, if you chrom your 4kg API batch to 100% purity, your GMP batch must meet or exceed this spec (hard to exceed 100% purity right?) 4/

What is an acceptable spec for a GLP tox batch? Again, depends on the company and even project sometimes. Generally, folks strive for at least 95% purity with no single impurity above 0.5%. Some say NMT 1% is okay, again it depends. Also why analytical chemists are awesome 5/

What is an impurity? Enantiomers, diastereomers, residual SMs, byproducts from previous steps to names few. Solvents are allowed up to certain levels depending on Class and dose. “Potency” is used a lot in process and is not the same as purity 6/

So a good crystallization in your GLP tox process that meets this minimum spec not only saves you time versus chrom but also there is a good chance your FIH batch will meet or exceed this purity result. If your impurities are genotoxic, well that’s another thread 7/n

And yes, I’m the 🤡 who made this meme. This was for a key raw material that was still several steps from API. We didn’t have (and still don’t have) an enantioselective synthesis. So occasionally chrom does save your butt 8/8 #chemtwitter