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www.biopharminternational.com Quality and Regulatory Sourcebook March eBook 2023 BioPharm International ® 35 K nowledge ManageMent Note that each department can and should retain ownership of its specialist word vocabulary, in sup- port of the fine detail for which it is responsible, but with sentences now elevated to a shared interdisci- plinary level of ownership. To demonstrate that all of this is relevant, "[CQA:CPP:CA:CDE]" translates to "this quality quartet relates to this CQA, which re- quires this CPP, this CA, and this CDE, to ensure its validity," and vice versa. Using the earlier CQA vs CPP monitoring example by way of illustration, this has the following user requirement specification (URS) implication, which readers may wish to self-assess: "your monitoring system and my monitoring system must be interconnected." Discontinuity Evolutionary biologist Richard Dawkins has bemoaned what he calls the "tyranny of the discontinuous mind," and its pervasiveness across sectors and disciplines (14); in engineering, this is reflected in the conversion from analog to digital technology, both domestically and commercially (i.e., always specifying the most modern available option). Our senses and cognitive systems are analog (i.e., continuous) but our measurements are dig- ital, which is counterintuitive. Where such devices are utilized as part of a quality quartet, it is important to specify their polling frequency as well as their accu- racy, and to ensure that what is on display is in fact the actual value, and not the setpoint. The superiority of today's metrology is not in ques- tion, but there is a lesson to be learned by human machine interface designers and end-users within quality quartets. One counterexample to this is the car speedometer, which still relies on an analog rep- resentation of speed (and acceleration), in spite of the availability of a digital equivalent. While speed values are based on digital increments (e.g., a 200 step/rev stepper motor = 1.8° per step on a round dial; the dial being round because wheels are round) the overall dis- play is analog, in line with long-standing driver (and passenger) preference. Readers may wish to position the speedometer, and specify its three associates, in this "happy motoring" quartet. By the same token, there is an occupational haz- ard for risk assessors here, particularly when ago- nising over, and sometimes hiding behind, relative positions on an arbitrary high medium low scale. A compounding factor is the fact that we are dealing primarily with batch manufacturing processes. These are inherently discontinuous, and this has affected our industry's overall mindset and view of the world. A f ina l example of this mindset is the industr y's current interpretation of C&Q stage gates as being "normally closed," and obstacles to progress. The new paradigm turns this on its head, and uses validity statuses to enable sequential review and approval of quality quartet parts. On this view, quality quartets and their parts can be viewed as members of a sprint team in a relay race. Definition—quality quartet A quality quartet is knowledge management output, also known as Justified True Belief (15), that provides a contin- uous and testable expression of the understanding that a firm possesses about the relationship between CQAs and CPPs and their associated CAs and CDEs. Figuratively speaking, quality quartets have a valency of four. Recommendations The recommendations included in the preceding sec- tions are repeated here for reference: • Assign unique IDs and time stamps to the quality quartets. • Manage these objects as fundamental super-assets. • Create a one-page x four-box datasheet for each quartet. • Create a precision pyramid for each quartet. • Create an evidence pyramid for each quartet. • Qua l i f y qua r tet pa r ts v ia IQ(CDE), OQ(CA), PQ(CPP), PV(CQA). • Pre-qualify the quartets in toto in the course of DQ. • Create a four-part quartet "assembler" based on prior knowledge. • Use the totality of quartets as your control strategy deliverable. • Define quality as the flipside of risk, to be assessed simultaneously. • Don't multiply risk assessments beyond necessity. • Don't be dismissive of analog data. Conclusion All of the ingredients required for C&Q and QRM optimization are already available within the indus- try. This monograph is an engineer's positive contri- bution to pulling these disparate strands together, via the introduction of pivotal but previously elusive quality quartets as building blocks, and the applica- tion of an innovative and practical KM framework. It was written with a tangible sense of breakthrough, and readers are encouraged to reassess their status quo and consider its recommendations. Compared to t he comple x it y a nd s e l f-a s s o c i at ion of t y pi- cal biopharmaceutical products (e.g., inf li ximab: C6428H9912 N1694O1987S46; 149.1 k Da; >20,000 "par ts") implementation and extrapolation of the proposed paradigm within manufacturing (CQA- 1CPP1CA1CDE1) is a logical and achievable objective. References 1. ICH, Q9(R1) Quality Risk Management (2023) 2. FDA, Guidance for Industry, Process Validation: General Principles and Practices (CDER, Jan. 2011)