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34 Pharmaceutical Technology ® Quality and Regulatory Sourcebook March eBook 2023 PharmTech.com K nowledge ManageMent ISPE guide on the one hand, and address the subjec- tivity-, formality-, and clarity-related enhancements of ICH Q 9 (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 own- ership strategy, the qualification of a quality quartet relies on the sub-qualification 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 quartet itself is qualified at DQ. ICH Q8 control strat- egy (CS) and ICH Q12 established conditions (ECs) are interpreted as the integral of quality quartets for a process, along similar lines to an array or circuit di- agram. In most cases, quartets will not involve 1:1:1:1 combinations in isolation, given that many CQAs are supported by more than one CPP, at the same or dif ferent stages of a process. There is an oppor tu- nity for KM to enable such groupings to be extracted a nd a n a ly zed, ba sed on a n i nter rogat ion of t he overall process definition. By the same token, prior k nowledge ca n be u sed to popu l ate a nd a ssig n ow nersh ip of a four-pa r t "assembler" i n suppor t of the qua lit y quar tet process. To illustrate, here is an example of the contents of a t y pical qualit y quar tet placeholder: [CQA: % moisture; CPP: dr y- i ng temperat ure; CA: temperat ure cont rol; CDE: heat source]. Its unique KM identifier is of the form "x x.x x.x x.x x" or equivalent, ma ximizing both its findability and its inspectability. Quartet benchmarks Quartets are very well established, and successfully deployed in a number of domains, both technical and non-technical, as illustrated in Table I. What these diverse foursomes have in common, in addition to their universality, is seamlessness, conti- nuity, and a shared "corporate" identity. Their mem- bers are in complementary self-regulating relation- ships with each other and with the quartet as a whole and cannot exist or be expressed in isolation. Closer to the biopharmaceutical industry, the AGCT-based structure and symmetry of DNA is another example. The quality quartets proposed here are not theoretical or obscure, but every bit as real and as powerful as the above benchmarks. Take the relationship between CQA and CPP moni- toring, activities which are usually performed by sep- arate groups. With a quality quartet in play, there is a mechanism to provide technical and/or procedural line-of-sight between the two (ref lected in their re- spective specifications and SOPs) so that deteriora- tion (and improvement) of CQA performance can be assessed vis-à-vis that of its related CPPs, and vice versa. By the same token, CPPs are reliant on the availability and authenticity of the related CAs and CDEs, requiring the same degree of connectivity. Strings Quality quartets can be symbolized as strings, with each qualified part assigned a validity status in ad- dition to its dataset within the string. Working from right to left in conjunction with the lifecycle, each qualified part contributes 0.25 to an overall score of one for the "string quartet." This can also be done for parallel and subsequent quartets, and at a higher level, for entire manufacturing systems and process trains. At a more granular level, related test script re- sults (0,1) also contribute to the quartet status, result- ing in an evidence pyramid to accompany the preci- sion pyramid. Given that validity status is a function of lifecycle stage, the previously mentioned unique identifier also contains a time stamp, indicating that this is the validity at time t. Its compliance history can then be assessed if required by selecting previous times for the same quartet. In the case of a metrology CDE for example, if its calibration date has expired, then its validity status switches to 0, and the data integrit y of its qualit y quartet and connections can no longer be guaranteed. This should be a minimum KM requirement of bio- pharmaceutical factories of the present as well as the future. The interpretation of asset management as an activity that is applied to physical components only (i.e., CDEs) may also need to be reconsidered, given that four-part quality quartets are the ultimate asset. Syntax The concept of strings also aligns with syntax, typ- ically defined as "the grammatical arrangement of words in a sentence" (13). This is exactly what a qual- ity quartet does (i.e., four-part combinations form- ing a coherent string). What happens currently by comparison, via the traditional depar tmental org TABLE I. Quartet benchmarks. Members of a Quartet M1, M2l M3, M4 Kinds of Knowledge Factual, conceptual, procedural, metacognitive Quadrants of a Graph Q1, Q2, Q3, Q4 Facets of Communication Transmitter, receiver, signal, noise Dimensions of Spacetime x, y, z, t Lifecycle of a Butterfly egg, larva, pupa, adult Seasons of the Year Spring, Summer, Autumn, Winter Process of Homeostasis Change, receptor, control center, effector Properties of a Paradigm Precision, simplicity, utility, resilience Contents of Gene Ontology Gene products, cellular components, molecular functions, biological processes