Host cell proteins (HCP) are process-related impurities that can co-purify with therapeutic proteins. Some HCP impurities potentially can have an impact on patient safety (immunogenicity or toxicity), efficacy, and/or product quality. It is important to reduce the levels of HCP impurities with a well-controlled manufacturing process and to monitor levels with a suitable analytical assay. Biopharmaceutical companies are now routinely using mass spectrometry (MS) to identify HCPs which are present in process intermediates and potentially in bulk drug substances and using the data to make decisions to continuously improve their processes and mitigate the potential risk to patients. The timing for the identification varies from one company to another. Some companies perform identification of HCPs starting from the nonclinical stage of development, while others perform HCP identification at later stages or as a part of root cause analysis for identified HCP ELISA-related issues, process, and product quality or safety concerns. No matter the approach, a comprehensive risk assessment framework for identified HCPs is needed to support decision-making during development and is expected by regulators to ensure a safe and efficacious drug product. In this paper the BioPhorum Development Group HCP Workstream has brought together a team of industry experts to build upon existing risk assessment frameworks (e.g., de Zafra et al., 2015) and develop recommendations for assessment of clinical safety risks upon identification of individual HCPs, incorporating regulatory considerations and industry experience and using a real-world case study to illustrate the use of the updated frameworks.