Wednesday, June 13, 2012

Process Wednesday: step 1 of troubleshooting

Having problems in the plant? Low yield? Low purity? What should you be doing? If you're Neal Anderson, step 1 is:
1. Confirm there is a problem.  
It is often wise to check any calculations, especially those used for purity or mass balance determinations. Check the reproducibility and reliability of the assay method and calculations. Inconsistent sampling can product anomalous results. When monitoring scale-up batches, it may be wise to obtain another sample from the reaction; then prepare another sample for IPC analysis and reassay.  (from Practical Process Research and Development)
I can't tell you how many times that I've begun to feel that rising feeling of panic, only to get another sample or redo an assay and get a great big sigh of relief.

(Of course, if your second sample confirms your bad result, don't go check a 3rd time, or a 4th, or a 5th. Sometimes bad news is really bad news.)


  1. High five, CJ!
    Perfect timing of your post. I am just finishing up a root cause investigation of low yield.
    It pays to understand the capabilities and SOPs of the plant to avoid an investigation altogether. The uncertainty of weighing and dead volumes in process hoses, pumps, and filters add up quickly and conspire to consume your yields.

  2. You would maybe surprised at what can happen in the plant. This is where you should check first, assuming the lab development is solid.
    I've seen things that would make your hair stand on end, or fall out like mine. Adding a solvent to the reactor and wondering why the vessel was not filling up. The bottom valve was open! Holes in centrifuge sacks.
    Not installing a pH electrode properly and then wondering why we could not pressurize the reactor, the RM was spraying out.
    False weighing, adding things to fast, stirring too long . Damm I could go on for ever.
    Best thing to do is to stand by the reactor for the first two or three times and watch everything.

  3. OK, so what do you do if the "plant" - a CRO - is hundreds or thousands of miles away and the travel budget is good for one 2-day visit? No amount of feet-stomping or head-banging would change these financial facts on the ground.
    I get to see daily updates, and later the executed batch records, and have to wander what is the chance of actually producing 100.00 ± 0.01 kg of something nine times in a row in a complex process.
    This is only tangentially related to the original (good) post, so I think I need to stop now :).

    1. Quite simple, you do not give your chemistry to a CRO basta!
      The best person to do your chemistry is yourself.

  4. Well, this is not "my" chemistry, we don't have a plant anyway (or staff to run it), and the decision was not in my budget.
    I just manage risks :).
    In one of my previous lives when "my" chemistry went to the plant I was the operator. Nobody to blame for low yield :).