Issue link: https://www.e-digitaleditions.com/i/1300450
36 BioPharm International eBook October 2020 www.biopharminternational.com Regulatory Sourcebook Process Development the process design stage. The cause- and- effect diag ram of Figure 2, which is referred to a freeze-dried process, is a simple and usef ul tool to identify the input variables that can impact the desired qual- ity attributes. This information represents the basis for the initial risk assessment of the impact of each operation on the identified CQAs (i.e., to define the high-risk steps that may affect the CQAs of the final drug product) as illus- trated in Table III. This is just an example, based on the following assumptions: • The API is very stable in the solid state but extremely unsta- ble in aqueous solution. • A certain amount of a volatile organic solvent is to be added and the manufacture of the solut ion to be f reeze- d r ied requires refrigeration to min- imize API degradation during compounding and filling. • A buffer is present to keep solu- tion pH at a constant value. 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. 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 DP CQAs Manufacturing process steps Manufacture of the solution to be freeze-dried Sterilizing filtration Filling and pre-stoppering Freeze-dryer loading Lyo cycle - freezing Lyo cycle -primary drying Lyo cycle -secondary drying Stoppering and capping Assay Medium High High High Low Low Medium Low Degradation products High High High High Low Medium High Low Appearance of freeze-dried cake Low N/A N/A N/A Low Medium Low Low DP water content N/A N/A N/A N/A N/A Low Medium Low DP residual solvents N/A N/A N/A N/A N/A Low Medium N/A Sterility Low Medium Medium Medium Low Low Low Medium Reconstitution time Low N/A N/A N/A Low Low Low Low Appearance (pri- mary reconstituted solution) Low Low N/A N/A Low Low Low Low pH (primary reconsti- tuted solution) Low N/A N/A N/A N/A N/A N/A N/A Table III. Initial risk assessment of the manufacturing process of a lyophilized product for injection. DP is drug product and CQAs are critical quality attributes.