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50 Pharmaceutical Technology ® Regulating Innovation, Quality, and Risk eBook January 2024 PharmTech.com Qualit y applied, and the greater the need to reduce the level of uncertaint y associated with it. • Complexity: T he more complex a process or subjec t a rea is to a QR M ac t iv it y, t he h igher t he level of forma lit y t hat may be applied to a ssu re produc t qua l it y. Complex it y is a n at- tribute t hat can be expressed in many dif fer- ent ways. With regard to manufacturing pro- cesses, for example, it may be characterized by the number of unit operations and steps that ma ke up t he process, t he number of star ting m a t e r i a l s a nd i s ol a t e d i nt e r me d i a t e s t h a t m ay be i nvolved , or t he e x tent of out sou rc- ing t hat is used (7). But complex it y may a lso be cha rac ter ised by t he t y pe of process t hat is under consideration; aseptic processes, for e x a mple, a re of ten rega rded a s bei ng more complex when compa red to m a nu fac t u r i ng processes that generate non-sterile products, a nd wh i le t h is may be t r ue in ma ny cases, it may be something of an oversimplification in other cases. These three factors are useful to consider during QRM work, because, as ICH Q 9(R1) indicates, an un- derstanding of formality can support risk-based de- cision-making, "where the level of formality that is appl ied may ref lec t t he deg ree of i mpor t a nce of t he deci sion , a s wel l a s t he level of u ncer t a i nt y a nd comple x it y wh ic h m ay be present." T he re- v i sed g u idel i ne st ates t h at "h ig her level s of u n- cer taint y, impor tance or complexit y may require more formal quality risk management approaches to manage potential risks and to support effective risk-based decision making" (3). All of this is relevant when applying QRM prin- ciples to deter m i n i ng t he extent of com m ission- ing and qualification testing that may be required for facilities, systems, and equipment in line with the ISPE's 2019 Baseline Guide. Fur thermore, the Qua lit y Quar tet concept is a lso direct ly relevant, as illustrated by the following scenarios: • Scenario A: Certain equipment components or instruments used in a manufacturing process have been classif ied as CDEs in line with the ISPE's 2019 Baseline Guide. These components or instr uments are considered impor tant by virtue of their criticality designation, but their relationship to CPPs and their role in support- i ng t he ach ievement of produc t CQAs is not wel l understood. T here is relatively high un- certainty in this area, and there are no Quality Quartets documented that include these CDEs. • Scenario B: O t her equ ipment component s or instr uments have been classif ied as CDEs, a nd t hei r rel at ion sh ip to CPPs a nd produc t CQAs is known and firmly established. Thus, t he r e i s lo we r u nc e r t a i n t y w it h r e g a r d t o t hei r rel at ion sh ip to CPPs a nd t hei r role i n supporting the achievement of product CQAs. These components or instruments are consid- ered important. • Scenario C: Certain process parameters have been classified as critical by virtue of the pro- cess k nowledge t h at i s i n pl ace i n ter m s of their relationship to one or more CQAs. These process parameters have been designated as CPPs, a nd t hey a re con sidered i mpor t a nt to control. These CPPs have been listed in a num- ber of Quality Quartets, as in the pH and MeOH charge examples discussed previously, and the equipment components or i nst r uments t hat support those CPPs are known. Thus, there is low uncertaint y here. • Scenario D: For certain other process parame- ters, their relationship to any CQAs is not well understood; t here is signif icant uncer taint y in this area. The relative impor tance of such process pa ra meter s i s a l so not u nder s tood , and these parameters have not been included in any Qualit y Quartets to date. I n Scen a r io A—i mpor t a nt equ ipment compo - nents or instruments, but significant uncertaint y i n t he i r r e l a t ion s h ip t o CQA s , a n d no Q u a l it y Quartets documented—it may be usef ul to apply a higher degree of formality to any risk assessments t hat w i l l be used to help determ ine t he extent of commissioning and qualification testing that is re- quired. Doing this can be beneficial because, given the level of uncer taint y that is present, higher ef- for ts can be made when assessing risks to ensure that appropriate risk controls are identified which mitigate those risks. In Scenario D—process parameters of unknown i mpor ta nce, where t hei r relat ionsh ip to CQAs is uncertain and no Qualit y Quartets have been doc- umented—more effort will likely be needed when applying QRM principles to determine the extent of com m ission i ng a nd qua l i f icat ion test i ng t hat m ay be requ i red. T hus, a h ig her level of for m a l- ity may be needed in any risk assessments that are performed to help determine the extent of commis- sioning and qualification testing that is required. The extra effort may yield increased process under- standing in relation to the role that those process parameters have in risk control, if any. This should ser ve to reduce the level of uncertainty that is pres- ent a nd, t hus, it shou ld lead to r isk reduc t ion as knowledge increases. In Scenarios B and C, there are important equip- ment components/instruments and process param- eters i n place, t here is a low level of uncer ta i nt y about their relationship to CQAs, and documented