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www.biopharminternational.com Quality and Regulatory Sourcebook March eBook 2023 BioPharm International ® 33 K nowledge ManageMent ISPE guide ISPE issued a revised C&Q Baseline Guide in 2019 (5), in response to the changing regulatory guidelines just described. The ISPE document runs to 200 pages and defines a lifecycle with these five stages: define require- ments; design and specify; build and verify; accept and release; and periodic review. A precondition of stage one is the availability of target process criteria (CQAs and CPPs), and an itemization of regulatory 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 functionality/sequences and CDEs to componentry/metrology. This results in a strategy that can be described as "Big C and Little Q." The guide em- phasizes the role and legitimacy of subject matter experts (SMEs) and good engineering practice (GEP), and the ac- ceptability of evidence acquired in the course of factory acceptance tests (FATs) from qualified vendors. Although this is not stated by ISPE, the formal use of such evidence would require QA approval 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 workflow, but does not address product urgency or fast- track projects (the new normal), other than suggesting that activities can be simplified or excluded based on their relative complexity. Finally, the ISPE guide makes provision for the qualification of systems in advance of a nominated process being specified 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 regulatory authorities and the pharmaceutical industry to discuss technical and scientific aspects of pharma- ceuticals 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 re- sult of a number of issues being identified as incomplete in the original (i.e., high levels of subjectivity in risk as- sessments 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 ad- equately 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 flow dia- gram, 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 revisited, shortly after the publication of FDA's revised validation guid- ance in 2011 (11, 12); the current monograph reflects his experience gleaned in the interim period. The essential lesson learned is that many of the issues that arise within projects and at inspections can be alleviated by the appli- cation of a previously unrecognized fundamental object comprising CQA:CPP:CA:CDE parts. These are quality quartets, to be specified and managed in toto rather than piecemeal. From an engineering perspective, they are equivalent to shock absorbers, operating in support of an integrated and stable C&Q/QRM process. Default safety factors can be readily applied to each member of a quartet, resulting in a predictable and self-organizing precision pyramid (and a pyramid of pyramids for the process in its entirety). For standard platforms in particular, most quality quartets are pre- dictable and reusable, and amenable to standardiza- tion. Note that allowance must be made for the inclu- sion of product-specific target values when deploying such standards. For example, while temperature is a typical CPP within biopharma, its operating range and alarm settings will vary from instance to instance, both within and across processes. Whereas, units of measurement is an example of a requirement that should be specified universally. A recommendation in support of quality quartet visu- alization is the use of a one-page x four-box data sheet (or a digital equivalent) for each quartet. In terms of the re- lationship between quality and risk, these are antonyms and "mutually exclusive," to be managed in parallel; for example, if accuracy is the desired quality, inaccuracy is the related risk. Similarly for stability and instability; purity and impurity, and so on. Ownership Whether the quartets are assigned individual or distrib- uted ownership, they are a powerful enabler of the ISPE guide on the one hand, and address the subjectivity-, formality-, and clarity-related enhancements of ICH Q9 (R1) on the other hand. Note that in the event of shared responsibility, each link in a quartet is an ownership handshake. And regardless of ownership strategy, the qualification of a quality quartet relies on the sub-qual- ification of its members, always in the context of the overall quartet, as in: [CQA ---> PV; CPP ---> PPQ; CA ---> OQ; CDE ---> IQ]. On that basis, it seems logical to suggest that the quar- tet itself is qualified at DQ. ICH Q8 control strategy (CS)