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PharmTech.com Quality and Regulatory Sourcebook March eBook 2023 Pharmaceutical Technology ® 33 K nowledge ManageMent practice (GMP) of medicinal products. It presently com- prises 54 participating authorities from Europe, Africa, America, Asia, and Australia. PIC/S publishes shared standards and guidances on behalf of its members. ISPE guide ISPE issued a revised C&Q Baseline Guide in 2019 (5), in response to the changing regulator y guidelines just described. The ISPE document runs to 200 pages and defines a lifecycle with these five stages: define requirements; design and specify; build and verify; accept and release; and periodic review. A precondi- tion of stage one is the availability of target process criteria (CQAs and CPPs), and an itemization of regu- latory and corporate health, safety, and environment (HSE) requirements. Three key aspects of the revised guide are: 1. direct vs non-direct system impact assessment 2. identification of CAs and CDEs via a system risk assessment (SRA) process 3. restriction of qualification activit y to these items only. CAs relate to f unctionality/sequences and CDEs to componentr y/metrolog y. This results in a strat- egy that can be described as "Big C and Little Q." The guide emphasizes the role and legitimacy of subject matter experts (SMEs) and good engineering practice (GEP), and the acceptability of evidence acquired in the course of factor y acceptance tests (FATs) from qualified vendors. Although this is not stated by ISPE, the formal use of such evidence would require QA ap- proval under GMP control. It should be noted that there was an eight-year delay between the publication of the FDA guidance and the ISPE document, which was itself issued prior to the COVID pandemic. It specifies a very comprehensive workf low, but does not address product urgency or fast-track projects (the new normal), other than sug- gesting that activities can be simplified or excluded based on their relative complexity. Finally, the ISPE guide makes provision for the qualification of sys- tems in advance of a nominated process being spec- ified for the facility. In such cases, prior knowledge can be used as the basis of the initial C&Q effort, as long as a gap analysis (and potential requalification) are performed prior to actual product introduction. ICH guidelines ICH's mission is to facilitate communication between regulator y authorities and the pharmaceutical in- dustr y to discuss technical and scientific aspects of pharmaceuticals and to issue guidelines. From a manufacturing perspective, these include but are not limited to: ICH Q8, ICH Q9, ICH Q10, ICH Q11, ICH Q12, and ICH Q13 (6, 1, 7, 8, 9, 10). The ICH Q9 guideline was recently revised as a result of a number of issues being identified as incomplete in the original (i.e., high lev- els of subjectivity in risk assessments and in QRM outputs; lack of understanding as to what constitutes formality in QRM work; a lack of clarity on risk-based decision-making; and failing to adequately manage supply and product availability risks). The second item has particular relevance to C&Q, as it opens the door for less formal risk assessment in many cases, as also alluded to in the ISPE guide. The revised version includes hazard as well as risk in its f low diagram, and hazard identification and risk-based decision making in its definition of terms. Quality quartets The author has previously co-published with FDA's Paula Katz on the topic of process validation revis- ited, shortly af ter the publication of FDA's revised validation guidance in 2011 (11, 12); the current mono- graph ref lects his experience gleaned in the interim period. The essential lesson learned is that many of the issues that arise within projects and at inspec- tions can be alleviated by the application of a previ- ously unrecognized fundamental object comprising CQA:CPP:CA:CDE parts. These are quality quartets, to be specified and managed in toto rather than piece- mea l. From an engineering perspective, they are equivalent to shock absorbers, operating in support of an integrated and stable C&Q/QRM process. Default safet y factors can be readi ly applied to each member of a qua r tet, resu lt i ng i n a pred ict- able a nd sel f-orga n izi ng precision py ra m id (a nd a py ra m id of py ra m id s for t he process i n it s en- tiret y). For standard platforms in particular, most qualit y quartets are predictable and reusable, and amenable to standardization. Note that allowance mu s t be m ade for t he i nc lu sion of produc t-s pe- cific target values when deploying such standards. For exa mple, wh i le temperat ure is a t y pica l CPP within biopharma, its operating range and alarm settings will var y from instance to instance, both within and across processes. Whereas, units of mea- surement is an example of a requirement that should be specified universally. A recommendation in support of quality quartet visualization is the use of a one-page x four-box data sheet (or a digital equivalent) for each quar tet. In terms of the relationship between quality and risk, t hese a re a ntony m s a nd mut u a l ly e xc lu sive, to be managed in parallel; for example, if accuracy is the desired qualit y, inaccuracy is the related risk. Similarly for stabilit y and instabilit y; purit y and impurity, and so on. Ownership Whether the quartets are assigned individual or dis- tributed ownership, they are a powerful enabler of the