Quality Quartets in Risk-Based Qualification: ICH Q9(R1) Considerations

[...]it states in the Introduction section that QRM "is part of building knowledge and understanding risk scenarios" and that "knowledge is used to make informed risk-based decisions, trigger re-evaluations and stimulate continual improvements." To illustrate this, consider the following scenario in relation to Quality Quartets: o An active substance manufacturing site produces an active substance for which there is a CQA associated with a particular impurity (X). o This is a five-stage manufacturing process involving a number of different unit operations, which include various chemical reactions, a salt formation step, a phase separation, a precipitation step, and isolation and drying steps. o The pH of a particular hydrolysis reaction at Stage 3 of the process is known to affect the generation of impurity X. o There is pH control during this hydrolysis reaction-this is considered a CA of the process- the pH of the batch at this step is considered a CPP, and the in-line pH probe on the reactor is considered a CDE. o The impurity X level is further reduced during the isolation step near the end of the process, which occurs in a filter dryer, whereby two methanol (MeOH) additions to the filter dryer remove the impurity from the product prior to the drying step. o The first MeOH addition is made when the batch is still in slurry form and under agitation at 10 RPM. (The cake is inspected during the MeOH wash for any cracks and channels which could impact the efficacy of the wash.) There are two in-process controls (IPCs) in the process which relate to this impurity: o A pH measurement during the hydrolysis reaction at Stage 3 of the process-as indicated previously, this is done using an in-line pH probe on the reactor. o An off-line high-performance liquid chromatography (HPLC) impurity test performed on a sample taken from the filter dryer following the second MeOH charge. [...]any probability of occurrence or detection ratings related to failure