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Pharmaceutical Technology Regulatory Sourcebook October 2020 9 'one-factor-at-a-time' approach, design of experi- ments is most typically deployed in this stage, al- lowing the identification of interaction effects be- tween variables. Table II summarizes the quality attributes of a parenteral product (solution and freeze-dried). This table has been adapted to a sterile prod- uct starting from what is reported in the FDA document on quality-by-design for ANDAs (5). It indicates which attributes are classif ied as drug product CQAs in the process design stage. The cause-and-effect diagram of Figure 2, which is referred to a freeze-dried process, is a simple and useful tool to identify the input variables that can impact the desired quality attributes. This information represents the basis for the initial risk assessment of the impact of each operation on t he ident i f ied CQAs (i.e., to def i ne t he high-risk steps that may affect the CQAs of the f ina l drug product) as illustrated in Table III. This is just an example, based on the following assumptions: • The API is very stable in the solid state but extremely unstable in aqueous solution. • A certain amount of a volatile organic solvent is to be added and the manufacture of the so- lution to be freeze-dried requires refrigera- tion to minimize API degradation during compounding and filling. • A buffer is present to keep solution pH at a constant value. Clearly, the experimental activities should be primarily conducted to address the identified areas of focus. Table IV suggests a series of studies to investigate and acquire experimental knowledge on a freeze- dried product in the different unit operations of the manufacturing process. Freezing Secondary drying Product temperature < temperature of complete solidification Holding time at the freezing temperature Freezing rate Annealing Ramp rate to secondary drying temperature Secondary drying temperature and time Chamber pressure Target product temperature Chamber pressure Sublimation rate Chamber geometry Efficiency of energy transfer Primary drying Ramp rate to primary drying temperature Primary drying time CQAs achievement Figure 2. Cause and effect diagram for freeze-drying process. The diagram shows the high dependency between process and formulation: formulation determines the process (e.g., glass transition temperature of the maximally freeze concentrated solution and collapse, product resistance to mass transfer) and process may determine formulation properties (e.g., crystallization may depend on freezing process and this can influence glass transition temperature of the maximally freeze concentrated solution). CQAs are critical quality attributes.