With the acquisition of Esperion by Pfizer in early 2004, the ETC216 project was transferred to Pfizer Global Biologics. ETC216 is an HDL-mimic complex of ApoA-1M and a phospholipid with demonstrated reversed cholesterol transport property. The Esperion process for ApoA-1M manufacture was rather complicated, especially the downstream purification, which consisted of a complex product recovery scheme from fermentation broth, 5 chromatography columns, several ultrafiltration/diafiltration steps, and one reaction step. In its first production campaign to produce additional protein materials at a CMO, the Pfizer Biologics team had to deal with the problem that the first few purified protein batches did not meet the HCP specification, which was also an issue experienced by Esperion in previous campaigns. Through process modification supported by analytical data of key in-process samples, the team was able to finally overcome the HCP hurdle and consistently made materials that met all product specifications. Post campaign development work led to the identification of the main difficult-to-remove host cell proteins. A combination of genetic modification and purification enhancement later resulted in a second generation manufacturing process that not only easily met a more stringent HCP specification but also achieved higher yield and better product quality.