An amusing story (only in hindsight!) from the annals of Organic Process Research and Development :
Scale-up is a minefield! Impurities from somewhere contaminated the product. In GMP philosophy, impurities on an industrial scale must be lower than at the laboratory level. The reason is that raw materials, solvents, and reagent qualities are checked, and reactor vessels, pipelines and centrifuges are cleaned with great care prior to the GMP production. The contamination from the facilities, consequently, might be slight. However, we found unexpected impurities in the case of scale-up. They could not be completely anticipated in the laboratory....The authors describe noting turbidity in typically clear product solutions and unknown peaks in their HPLCs. An investigation ensued:
From these results (the wet cake showed turbidity), the product did not become contaminated with turbidity compounds before the activated carbon treatment or after drying. Therefore, all of the equipment, crystallizer, feed pipe, pressure filter, pumps, clothes, gloves, and storage bags were checked. That is, those components were rinsed with MeOH, and the MeOH was analyzed by HPLC. After that, no equipment, except for the natural rubber gloves, contained the peak B material, and the polyethylene bags used in this process contained peak C and peak D material! [snip]They found the impurities to be BHT, dioctylphthalate and other polymer stabilizers:
...During runs 2 and 3 in Table 1, the turbidity was caused by the 200-L polyethylene bag. It was caused by natural rubber gloves during run 4 (Tables 1 and 3). To prevent the turbidity, the process has been changed as follows: the material of the gloves was returned to polyethylene. In this case, the contact time with the wet cake is very short; therefore, there is no worry about turbidity. The containers for the wet cake storage were changed from polyethylene bags to stainless steel buckets. After these modifications, no turbidity was observed on the plant scale (Table 5).
Murphy is a jerk, let me tell ya.
1. Sano, T.; Senzaki, H.; Sugaya, T.; Kasai, M. "Contamination of Dipeptide by Polymer Stabilizers Leached from Gloves and Packaging during Scale-up." Organic Process Research & Development 2000, 4, 349−352.