Improvement of arginine hydrochloride based antibody lyophilisates

Arginine hydrochloride (ArgHCl) can be used as stabiliser of protein drugs in both liquid and freeze dried formulations reducing aggregation. But ArgHCl exhibits a low T_g' value which can lead to cake collapse during lyophilisation. We analysed arginine (Arg) citrate hydrochloride and lactobionate based lyophilisates aiming for elegant cake appearance in combination with minimal protein aggregation using 2 mg/ml monoclonal antibody (mAb) without additional excipients and in combination with sucrose (Suc) as amorphous stabiliser as well as mannitol (Man) and phenylalanine (Phe) as crystalline bulking agents. Furthermore 50 mg/ml mAb was also used. Based on a process which resulted in poor cake appearance for the ArgHCl based cake with 2 mg/ml mAb the combination with sucrose mannitol (Man:Arg 4:1) and phenylalanine (Phe:Arg1:4 1.5:3.5 and 2:3) as well as a high mAb concentration were able to improve cake appearance. Overall the crystalline bulking agent Phe in combination with ArgHCl renders elegant cakes with minimal protein aggregation. The alternative Arg salts did not require cake quality enhancement but mAb stability was inferior to ArgHCl. The combination with mannitol showed reduced stability due to a substantially lower amount of amorphous matrix. Thus the combination of ArgHCl with phenylalanine was superior to any other formulation tested including the sucrose based and may allow for substantial process time reduction due to the crystalline scaffold delivering pharmaceutically elegant cakes.