The complex biologics such as gene therapy, cell therapy, multi-specific antibodies, oncolytic viruses, and fusion proteins are being pursued in clinical development to address various hard to treat diseases and conditions. The pipeline of these molecules is increasing significantly due to rapid understanding of underlying biology and new discovery tools. These therapies require efficient and cost-effective manufacturing processes to realize their benefits. There are many challenges that appear when scaling-up complex biologic products. The two most critical challenge includes (1) managing yield and quality and (2) addressing new impurities that are not seen during previous studies. The root cause of these includes limited understanding of the process, limitations of process steps due to properties of complex biologics and limited understanding of impact of raw material attributes on the process performance and product quality. Beyond attributes impacting the process, other impurities such nitrosamine, ethylene glycol, genotoxic impurities, and bioburden/adventitious agents, if not addressed in time, can delay the potential product entering into clinical/commercial phase. This presentation will discuss the critical quality attributes of various raw materials, impact of variability on the process and approaches to control variability and thereby improve complex biologic manufacturing processes. Specific case studies and lesson learned will be discussed by comparing and contrasting with traditional monoclonal antibody or recombinant protein manufacturing processes.