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48 Pharmaceutical Technology ® Regulating Innovation, Quality, and Risk eBook January 2024 PharmTech.com Qualit y ach iev ing more k nowledge-dr iven r isk-based ap- proaches to commissioning and qualification. The Inter nat iona l Counci l for Ha r mon isat ion's (ICH) Q 9(R1), which is a revised version of ICH's Qualit y Risk Management guideline (3), can be referred to in this regard. As outlined in the ICH Concept Paper for t h at rev i sion work (4), t here were fou r m a i n topic a rea s t h at t he re v i sion soug ht to add ress. These were: • High levels of subjectivity in risk assessments a nd i n qua l it y r i sk m a n agement (QR M) out- puts • A lack of understanding as to what constitutes formalit y in QRM work • A lack of clarity on risk-based decision-making • Failing to adequately manage supply and prod- uct availabilit y risks. Two of these four areas, subjectivit y and formal- it y i n QR M, a re pa r t ic u la rly releva nt to t he sub- ject mat ter of t h is paper—risk-based approaches t o c om m i s s i on i n g a n d q u a l i f i c a t i on , a n d t h e 2019 ISPE Baseline Guide—and t he g uidance pre- sented in ICH Q 9(R1) in t hose t wo areas is usef ul to consider. Subjectivity in QRM ICH Q 9(R1) h igh l ights t he i mpor ta nce of ma nag- ing and controlling subjectivit y when performing QRM activities, and it discusses how subjectivit y can impact every stage of a QRM process, including the identification of hazards and the estimation of probabilities of occurrence and severities of harm. It indicates t hat subject iv it y ca n a lso impact t he estimation of risk reduction and the effectiveness of the decisions made from QRM activities. The re- vised guideline places a heav y emphasis on the use of knowledge in supporting the application of QRM principles. For example, it states in t he Introduc- tion section t hat QRM "is par t of bui lding k nowl- edge and understanding risk scenarios" and that "k nowledge is used to ma ke i n for med r isk-based deci sion s, t r ig ger re-eva lu at ion s a nd st i mu late cont i nua l i mprovements." It h igh l ights how "a l l decision ma k ing relies on t he use of k nowledge," and it points the reader to ICH Q10 (5) for guidance on knowledge management. In relation to applying QRM principles when de- signing and executing commissioning and qua li- fication activities, it is important to minimize any subjectivit y that may be present in the risk assess- ments that support such activities. The authors pro- pose that applying the Qualit y Quartet concept as outlined in reference 1 is a practical means toward ach iev ing t h is. T h is is because t he Qua lit y Quar- tet concept essentially links process and product understanding with the technical knowledge that a site has in relation to its facilities, systems, and equipment. When risk assessments are performed to support commissioning and qualification activi- ties as per the 2019 Baseline Guide, that knowledge can be used to make those risk assessments more evidence-based and objective and, therefore, less subjective. To illustrate this, consider the following scenario in relation to Qualit y Quartets: • A n act ive substa nce ma nufact ur i ng site pro- duces an active substance for which there is a CQA associated with a particular impurity (X). • This is a five-stage manufacturing process in- volving a number of different unit operations, wh ich i nclude va r ious chem ica l react ions, a salt formation step, a phase separation, a pre- cipitation step, and isolation and dr ying steps. • T he pH of a par ticula r hydrolysis reaction at Stage 3 of t he process is k now n to a f fect t he generation of impurit y X. • There is pH control during this hydrolysis re- action—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. • The impurity X level is further reduced during the isolation step near the end of the process, wh ich occ u rs i n a f i lter d r yer, whereby t wo methanol (MeOH) additions to the filter dr yer remove the impurity from the product prior to the dr ying step. • The first MeOH addition is made when the batch is sti l l in slurr y form and under ag- it at ion at 10 R PM. T he MeOH cha rge vol- ume is considered a CPP. (The f i lter dr yer agitation rate is not considered a CPP—it is classified as a process parameter.) • T he batch is t hen f i ltered under pressure, resulting in a wet cake. • The agitator is then stopped, and a second MeOH c h a rge i s m ade —t h i s wa shes t he ca ke to remove a ny residua l I mpu r it y X. T h is second MeOH cha rge is a lso con sid- ered a CPP. (T he ca ke is inspected during t he MeOH wa sh for a ny crack s a nd cha n- ne l s wh ic h cou ld i mpac t t he ef f ic ac y of the wash.). • There are two in-process controls (IPCs) in the process which relate to this impurit y: • A pH measurement during the hydrolysis reaction at Stage 3 of the process—as indi- cated prev iously, t his is done using an in- line pH probe on the reactor. • An of f-line high-performance liquid chro- m a t o g r a p h y ( H P L C) i m p u r i t y t e s t p e r- for med on a sa mple ta ken f rom t he f i lter dr yer following the second MeOH charge.