The biopharmaceutical certificate of analysis (COA) has been prepared listing the test methods for the seven major CQA categories to be included in a biopharmaceutical certificate of analysis (COA), as discussed in the previous chapter: (1) appearance/description, (2) identity, (3) purity/impurities, (4) potency, (5) quantity, (6) safety, and (7) general. Now comes the challenge of assigning meaningful specifications to each of the test methods listed in each of the categories. Each test method listed needs an assigned descriptor, limit, or range—referred to as a specification. Specifications are required for release and shelf-life testing of the biopharmaceutical drug substance and drug product. In this chapter, the challenge of setting these specifications for the different types of biopharmaceuticals (protein-based, viral vectors, non-viral vectors, and genetically modified patient cells) will be discussed—a challenge that should not be underestimated. The need to apply the minimum CMC regulatory compliance continuum risk-based approach to specification assignments, from the start of clinical development through market approval, will be stressed. Regulatory guidance and industry practice on setting release and shelf-life specifications will be examined. In addition, the testing of limits (‘in-use’ testing) to guide the use of the biopharmaceutical at the patient administration site will also be discussed.