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In achieving this goal, the guideline they produced describes the suggested contents for Section 32P2 of a regulatory submission in the ICH M4 common technical document (CTD) [59] and the FDA electronic common technical document (eCTD) [60] The pharmaceutical development and quality overall summary (QOS) sections of the CTD (Figure 10) provide pharmaceutical scientists with dedicated channels to present regulators with the relevant knowledge and process understanding gathered during the development of a new product (which can be updated to support new knowledge gained over the life cycle of the product following approval) The knowledge communicated within these sections are important considerations for justi cation of a lower site risk potential (ie, SRP, with regard to risk-based inspection) and for facilitation of ef cient, question-based review (QbR) [61].



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Questionbased review is another mechanism by which the agency intends to streamline the regulatory process as well as reward producers for adopting best practices in quality management In addition to facilitating risk-based oversight, the content of the pharmaceutical development and QOS sections of the CTD are critical to enabling continuous improvement and exible operation The information and knowledge communicated within these sections provide scienti c understanding to support the establishment of a manufacturing design space, in-process and release speci cations, and manufacturing controls As described within the Q8 guideline, a design space is the multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality So long as process control is maintained within the bounds of the design space, operating parameters can be adjusted to improve product quality or manufacturing ef ciency Based on the.





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trials for each experiment. For each con guration, there are ve bars representing total cost for Z-repart, M-repart, Z-re ne, Z-scratch, and M-scratch, from left to right, respectively. Total cost in each bar is normalized by the total cost of Z-repart in the respective con guration and consists of two components: communication (bottom) and migration (top) costs. The rst 10 gures (Figures 15.2 15.11) display comparisons of the ve methods in terms of total cost, for each one of the ve test cases, with perturbed data structure and weights. Figures 15.12 and 15.13 display the average quality results for those ve test data sets. The results indicate that our new hypergraph repartitioning method Z-repart performs better than M-repart in terms of minimizing the total cost in the majority of the test cases. This can be explained by the fact that migration cost minimization objective is completely integrated into the multilevel scheme rather than handled only in the re nement phase. Therefore, Z-repart provides a more accurate trade-off between communication and migration costs than M-repart to minimize the total cost.

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Anatomy Rules (P)a Imaging Feature Interpretation Rules (Q)a Low probability of AIH for candidates presenting calci cations or normal high-density structures Mid-sagittal plane, Vertically aligned, Falx calci cation supracranial fossa attenuation, eccentricity, long axis length, short axis length Mid-sagittal plane, Intermediate attenuation, Superior sagittal sinus supracranial fossa Intermediate eccentricity, Periphery convex hull Medial portion of basal Attenuation ( if area ), Basal ganglia ganglia calci cation area ( if symmetrical), Symmetrical Central portion of cerebellum Attenuation ( if area ), Dentate nuclei area ( if symmetrical), calci cation symmetrical Low probability of AIH for candidates presenting artifacts Posterior cranial fossa Eccentricity, Beam hardening artifact long axis length, short axis length Above anterior cranial fossa Attenuation Partial volume averaging Above temporal bone area beyond adjacent bone Periphery near vertex in contiguous section High probability of AIH for candidates presenting particular type of AIH Sylvian ssure Vertically aligned, Sylvian ssure intermediate attenuation, subarachnoid hemorrhage eccentricity, intermediate long axis length, short axis length Periphery Perpendicular to perimeter of Sulcal space brain, subarachnoid hemorrhage long axis length, short axis length

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