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34 BioPharm International ® Quality and Regulatory Sourcebook March eBook 2023 www.biopharminternational.com 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 diagram. 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 different stages of a process. There is an opportunity for KM to enable such groupings to be extracted and analyzed, based on an interrogation of the overall process definition. By the same token, prior knowledge can be used to populate and assign owner- ship of a four-part "assembler" in support of the quality quartet process. To illustrate, here is an example of the contents of a typical quality quartet placeholder: [CQA: % moisture; CPP: drying temperature; CA: temperature control; CDE: heat source]. Its unique KM identifier is of the form "xx.xx.xx.xx" or equivalent, maximizing 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 ad- dition to their universality, is seamlessness, continuity, and a shared "corporate" identity. Their members are in complementary self-regulating relationships with each other and with the quartet as a whole and cannot exist or be expressed in isolation. Closer to the biopharmaceuti- cal 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 (reflected in their respec- tive specifications and SOPs) so that deterioration (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 addition 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 subse- quent quartets, and at a higher level, for entire manu- facturing systems and process trains. At a more gran- ular level, related test script results (0,1) also contribute to the quartet status, resulting in an evidence pyramid to accompany the precision pyramid. Given that valid- ity 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 compli- ance 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 cali- bration date has expired, then its validity status switches to 0, and the data integrity of its quality quartet and con- nections can no longer be guaranteed. This should be a minimum KM requirement of biopharmaceutical facto- ries of the present as well as the future. The interpreta- tion 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, typically defined as "the grammatical arrangement of words in a sentence" (13). This is exactly what a quality quartet does (i.e., four-part combinations forming a coherent string). What happens currently by comparison, via the traditional departmental org chart, is that each of these parts is managed separately, at the risk of their inter- faces becoming "sins of omission." Such fragmentation is justified at the detailed technical level, given the com- plexity and multiplicity of the systems involved. What is at issue, however, is the mechanism whereby these departments and their related systems communicate. From a syntax perspective, each of the above parts is equivalent to a word, and their integration into a qualit y quar tet that of a sentence. By compari- son, attempting to communicate meaningf ully at the word level leads to incoherence and misunder- standing, both personally and technically. What this monograph is recommending therefore, is an exercise in biopharma sentence making, and stringing such sentences together to build processes. 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 K nowledge ManageMent