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32 BioPharm International ® Quality and Regulatory Sourcebook March eBook 2023 www.biopharminternational.com K nowledge ManageMent stages of a process, along with their related CAs and CDEs. Recommended specification and visualization is via a one-page x four-box data sheet (or a digital equivalent) for each quality quartet, whereby con- text is transparent and both process understanding and knowledge gaps are immediately apparent. Ideal qualit y quartets are analogous to pyramids, with CQAs at the base and CDEs at the apex, with each layer protected by progressively tighter tolerances (i.e., in- creased precision) of the adjoining upper layers. From an engineering perspective, they are self-regulating, and equivalent to shock absorbers operating in sup- port of C&Q/QRM optimization. For standard platforms in particular, most quality quartets and their contents are predictable, reusable, and amenable to codification based on bidirectional 'pairing rules' between their parts. Quality and risk are viewed as two sides of a plus-minus coin, best man- aged as parallel rather than sequential activities. For example, if accuracy is a quality requirement, inaccu- racy is the related risk. Rather than being documented independently, ICH Q8 control strategy (CS) is inter- preted as the sum of quality quartets for a process and is a direct beneficiary of the paradigm. The ICH Q12 requirement for established conditions (ECs) to be doc- umented and reported is also satisfied. 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. This monograph defines quality quartets as "knowl- edge management outputs that provide a continuous and testable expression of the understanding that a firm possesses about the relationship between CQAs and CPPs and their associated CAs and CDEs. Figu- ratively speaking, quality quartets have a valency of four." They are introduced here as the missing KM link within C&Q and QRM, and the paradigm is intended to be used and shared by progressive manufacturers, regulators, and other stakeholders. Biopharma specifics Biopharmaceutical manufacturing systems fall into these five main categories: facilities and equipment; laborator y controls; raw materials; packaging and label i ng; a nd produc t ion. Depend i ng on projec t scope, product transportation is considered an ad- ditional manufacturing operation and system. The manufact uring process is div ided into dr ug sub- stance (DS) and drug product (DP) operations, and these can occur at shared or separate buildings or geographical locations. DS operations include upstream and downstream pro- cessing (USP and DSP), supported by ancillary operations such as media and buffer preparation, purified water gen- eration/distribution, and so on. USP operations include cell culture and clarification, and DSP involves product capture and purification. The overall process is a batch process, with some individual operations performed on an internally continuous basis. Material sampling, and transfers between operations are largely manual, while the process operations themselves are primarily auto- mated. Processes typically employ a combination of per- manent and single-use equipment and disposable bags (all of which are standard), with cleaning requirements eliminated in the case of single-use equipment. Biopharmaceutical facilities can operate in ded- icated or multi-purpose/campaign modes. Several are owned by contract manufacturing organizations (CMOs) engaged in the delivery of outsourced prod- ucts. The majority are designed for commercial oper- ation, with process development activities performed within pilot plant facilities on the same or at separate locations. There is a global drive to digitalization, as manifested by the utilization of electronic batch re- cords, paperless standard operating procedures (SOPs), training records, and qualification protocols. Regulations Requirements in relation to validation exist in all ju- risdictions, with FDA considered the historical leader in this space. FDA's revised validation guide outlines a three-stage lifecycle approach, as follows: process de- sign, process qualification, and continued process veri- fication (2). C&Q activity is positioned as the initiator of stage 2, on the proviso that CQAs and CPPs are known and specified as part of the completion of stage 1. In Eu- rope, the European Medicines Agency's (EMA) Annex 15 follows a similar approach to FDA, using slightly differ- ent terminology in certain cases (3). Within the valida- tion guides, there is a transition from a fragmented and one-off activity to an integrated and risk-based lifecycle, enabled by a combination of process understanding and engineering/supplier know-how. This equates to a direc- tive to stakeholders to define workflows and datasets, and deliver evidence, that "follow the molecule." Both FDA and EMA were proactive in the provision of regulatory relief to manufacturers in the course of the COVID pandemic. EMA in particular posted a formal notice to stakeholders on its website to this effect (4). In addition to FDA/EMA, the Pharmaceutical Inspection Co-operation Scheme (PIC/S) is a non-binding, informal co-operative arrangement between regulatory authori- ties in the field of good manufacturing practice (GMP) of medicinal products. It presently comprises 54 partic- ipating authorities from Europe, Africa, America, Asia, and Australia. PIC/S publishes shared standards and guidances on behalf of its members.