USFDA 483 to Laurus cites deficiency in sampling, uniformity not assessed.

Observation 2:

Sampling plan for intermediates fail to ensure representative sample is obtained for assay and impurities. No assessment to ensure critical quality attributes like assay and impurities are uniform across a batch. 

Observation 2:

Sampling plan for intermediates fail to ensure representative sample is obtained for assay and impurities. No assessment to ensure critical quality attributes like assay and impurities are uniform across a batch. 

Manufacture of APIs and Intermediates (chemical synthesis) typically involve crystallisation / precipitation of product from a homogenous reaction mass, isolation by filtration (Centrifuge / Nutsche filter etc) and drying. For APIs and Intermediates, scope of non uniformity for parameters like assay and impurities within a batch are limited (unlike finished dosage forms). However, in the workup process (isolation, drying) there are few areas which can cause variability. 

During isolation (filtration) process the distribution of an impurity across the isolated wet cake may not be uniform due to insufficient washing, channelling in the wetcake during washings etc. Ensuring proper slurry wash of the wet cake (by stirring the material with washing solvent in a vessel/reactor or within the filter equipment followed by filtration, spinning/ pressing the cake) can address the non uniformity. During process validation, establish the parameters for washing the wet cake – quantity of solvent, duration for stirring, number of washing cycles etc. Develop a sampling plan to sample and test impurities at different stages – from the reaction mass, wet cake after each. Sample the wet cake at multiple locations and also at different depths (rather than only top surface of the wet cake). 

Another area of variability in APIs / Intermediates is the drying process for parameters like loss on drying (LOD)/ solvent content (residual solvents) or water content. Scope for variability is more in tray driers while in a rotary drier (like an RCVD) the concern is low.  Having a process step of a milling (to crush the lumps) and mixing at the end of the drying process helps to homogenise the material. Even better is to have in a rotary drier for drying. Establish duration of drying by collecting samples from the drier at different time points during drying and evaluating for parameters like LOD / solvent content. Also establish the uniformity of the batch by assessing samples from different locations in the drier / blender  – Drying validation. When Tray driers are used for drying establish uniformly of drying across material by collecting samples from multiple trays. Follow a ZigZag pattern of sampling from Tray Driers, ensuring sampling from each row of trays to ensure representativeness of whole batch. 

Establishing the parameters for isolation / drying processes with a scientifically designed sampling plan ensure consistent process and product quality with a Validated process and allays concerns of intrabath variability in an API / Intermediate.