Process validation of commercial batches from development batch


We all know that we usually make development batches (eg 5 kg batch) in small scales but when we make large commercial batches then the process parameters may not be same like development batches. Bigger equipment may be required for commercial production so how we can do process validation utilising the critical process parameter specification that gained from development stage? Would be wondering if anybody helps me in this regard.

Kind regards, Mohammad Masum

Normally all the batches manufactured in R&D scale will have a batch manufacturing sheet and specific information and process parameters to control that batch. During the pilot scle the BMR is revised and specific input will be added based on the size of equipment and automation at the pilot level. There will be 4 to 5 pilot scale batches and the parameters are slightly varied and looked. This will give a basic guidance on the ranges to operate a praticular parameter.

During the late pilot batch i.e a batch which is submitted to the Regulatory approvals and also batch used for stability studies most of the parameters are validated and controlled.The final validated batch is taken as a late pilot batch.

Secondly this particular question tells us how a BMR is evolved from the R&D to production by controlling all parameters. All BMR’s from earlier stages are scrutinized properly and controlls are properly monitored during validation.Most of the comments from R&D, pre pilot & pilot batches are taken into consideration to carry a robust validation process with all controls in place.

Thanks Durga Prasad for your time to reply.

I understand what your getting at but still I have few confusions….as the pilot batches are usually 10% (or 100,000 units or which is greater according to CHMP & CVMP) of a commercial batch size, so the critical process parameters (CPP) may be required to change again during the manufacture of big commercial batches. Not a surprise if more than one commercial batch need to be trialed to finalise the acceptance criteria for CPP due to the increased batch size or introduction of higher capacity machines.

What should be the fate of the pilot batches and the first few (one or more) commercial batches which were under scrutiny but finally achieved the results and comply with USP/BP and have the good stability results? Do we throw them away or they are still saleable to market? What does regulatory body MHRA/PICS/FDA say? Have you any idea? Definitely I believe that we can’t play with drug.

Much appreciated again.

Every R&D has a stability department and also they are connected with QC to get exact results. Normally all the pilot batches which are 10% representatives of the commercial batches would return to R&D. At various intervals of time they are picked up and tested. They keep the record of all batches and the destruction and dsiposal records. These records are maintained for internal audit asssesment by finance and Quality purposes and also to show the respective regulatory bodies.

The Critical Control Parameters are evolved between the R&D phase and Pilot phase. But the exact and more detailed information is gathered from the Late pilot batches and also few pre commercial bathces that are run on the actual scale on commercial scale machinary. For this operation Both R&D and production will participate. R&D supervises the process and monitors controls and Production chemists actually take the batch.

I was involved from R&D side in such a situation once where we made a multivitamin drops for infants up to 6 months.We had to change a little on CCP’s and added few more too as its a bigger batch size.

The more details we get from R&D’s regarding the process problems and incompatabilities at this stage the more easier to control batch becomes at Pre-commercial runs with proper controls.