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Most appellate judges and attorneys are familiar with at least some of the ways in which the Internet has affected legal practice in the last several years. Many appellate courts, [...]

The concept and application of quality by design (QbD) principles has been and will undoubtedly continue to be an evolving topic in the pharmaceutical industry. However, there are few and limited examples that demonstrate the actual practice of incorporating QbD assessments, especially for active pharmaceutical ingredients (API) manufacturing processes described in regulatory submissions. We recognize there are some inherent and fundamental differences in developing QbD approaches for drug substance (or API) vs drug product manufacturing processes. In particular, the development of relevant process understanding for API manufacturing is somewhat challenging relative to criteria outlined in ICH Q8 () guidelines, which are primarily oriented toward application of QbD for drug product manufacturing. This position paper provides a perspective of QbD application for API manufacture using an example from the torcetrapib API manufacturing process. The work includes a risk assessment, examples of multivariate design, and a proposed criticality assessment, all of which coalesce into an example of design space. Torcetrapib was a project in phase III development as a potent and selective inhibitor of cholesteryl ester transfer protein before being terminated in late 2006. The intent of Pfizer was to submit torcetrapib under the QbD paradigm (route selection, robustness, and reagent/solvent selection during phases I to III are significantly important in establishing a manufacturing process that would have the most flexibility in the final design space. For more information on this development phase for torcetrapib see Damon et al., Org Process Res Dev, 10(3):464–71, 2006, Org Process Res Dev, 10(3):472–80, 2006). [ABSTRACT FROM AUTHOR]

The breccia-hosted epithermal Au-Ag deposit of Roşa Montană is located 7 km northeast of Abrud, in the northern part of the South Apuseni Mountains, Romania. Estimated total reserves of 214.91 million metric tons (Mt) of ore at 1.46 g/t Au and 6.9 g/t Ag (10.1 Moz of An mid 47.6 Moz of Ag) make Roşia Montană one of the largest gold deposits in Europe. At this location, Miocene calc-alkaline magmatic and hydrothermal activity was associated with local extensional tectonics within a strike-slip regime related to the indentation of the Adriatic microplate into the European plate during the Carpathian orogenesis. The host rocks of the magmatic complex consist of pre-Mesozoic metamorphosed continental crest covered by Cretaceous turbiditic sediment (flysch), Magmatic activity at Roşia Montană and its surroundings occurred in several pulses and lasted about 7 m.y. Roşia Montană is a breccia-hosted epithermal system related to strong phreatomagmatic activity due to the shallow emplacement of the Montana dacite. The Montana dacite intruded Miocene volcaniclastic material (volcaniclastic breccias) and crops out at Cetate and Carnie Hills. Current mining is focused primarily on the Cetate open pit, which was mapped in detail, leading to the recognition of three distinct brecia bodies: the dacite breccia with a dominantly hydrothermal matrix, the gray polymict breccia with a greater proportion of sand-sized matrix support, and the black polymict breccia, which reached to the surface, contains carbonized tree trunks and has a dominantly barren elastic matrix. The hydrothermal alteration is pervasive. Adularia alteration with a phyllic overprint is ubiquitous; silicification and argillic alteration occur locally. Mineralization consists of quartz, adularia, carbonates (commonly Mn-rich), pyrite, Fe-poor sphalerite, galena, chalcopyrite, tetrahedrite, and native gold and occurs as disseminations, as well as in veins and fillings vugs within the Montana dacite and the different breccias. The age of mineralization (12.85 ± 0.07 Ma) was determined by 4th Ar39Ar dating on hydrothermal adularia crystals from vugs in the dacite breccia in the Cetate open pit. Microthermometric measurements of fluid inclusions in quartz phenocrysts from the Montana dacite revealed two fluid types that are absent from the hydrothermal breccia and must have leech trapped at depth prior to dacite dome emplacement: brine inclusions (32-5 wt % NaCl equiv, homogenizing at Th > 460°C) and intermediate density fluids (4.9-15.6 wt % NaCl equiv. Th between 345°--430°C). Secondary aqueous fluid inclusion assemblages in the phenocrysts have salinities of 0.2 to 2.2 wt percent NaCl equiv and Th, of 200° to 280°C, Fluid inclusion assemblages es in hydrothermal quartz from breccias and veins have salinities of 0.2 to 3.4 wt percent NaCl equiv and Th, from 200° to 270°C. The oxygen isotope composition of several zones ot an orerelated epithermal quartz crystal indicate a very constant δ18O of 4.5 to 5.0 per mil for the mineralizing fluid, despite significant salinity and temperature variation over time. Following microthermometry, selected fluid inclusion assemblages were analyzed by laser ablation-inductively coupled-plasma mass spectrometry (LAICPMS). Despite systematic differences in salinity between phenocryst-hosted fluids trapped at depth and fluids from quartz in the epithermal breccias, all fluids have overlapping major and trace cation ratios, including identical Na/K/Rb/Sr/Cs/Ba. Consistent with the constant near-magmatic oxygen isotope composition of the hydrothermal fluids, these data strongly indicate a common magmatic component of these chemically conservative solutes in all fluids.… [ABSTRACT FROM AUTHOR]