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The ICH M7 Option 4 control of (potentially) mutagenic impurities is based on the use of scientific principles in lieu of routine analytical testing. This approach can reduce the burden of analytical testing without compromising patient safety, provided a scientifically rigorous approach is taken which is backed up by sufficient theoretical and/or analytical data. This paper introduces a consortium-led initiative and offers a proposal on the supporting evidence that could be presented in regulatory submissions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A simple and safe prototype apparatus was designed and adapted for the in situ determination of the moisture content of a cytotoxic compound (9-fluorenylmethyl-protected doxorubicin-peptide conjugate, or Fm-DPC) by near-infrared absorbance spectroscopy during optimization of the chemical isolation procedure. The cytotoxic nature of the compound restricts one's ability to safely sample such drying processes for more traditional means of moisture determination for fear of hazardous solids dusting, hence in situ sampling approaches are of great importance. These concerns also exist for the process development laboratory, where despite the smaller scale of operations, the volume of experiments (hence cytotoxic samples) required to define a chemical process is often more significant. In this application, partial least squares regression was used with Karl Fischer volumetric titration analysis to generate a calibration model. Although pronounced differences in cake density were observed as a function of the buffer selected for the isolation process, the model still achieved a standard error of calibration of 0.63% w/w and a standard error of prediction of 0.99% (w/w). These results demonstrated the versatility of the prototype apparatus/data processing approach to model Fm-DPC drying under extremely variable conditions, as inherently expected during the investigational laboratory development of a chemical process., (Copyright 2003 Wiley-Liss Inc. and the American Pharmaeceutical Association)

Thermodynamic analysis of the reversed-phase retention behavior of a doxorubicin-peptide conjugate demonstrated that the degree of non-linearity observed in Van't Hoff plots was impacted by mobile phase acetonitrile content over the 25-38% acetonitrile (v/v) range tested. Small decreases in the non-polar surface area of the doxorubicin-peptide conjugate as a function of temperature were estimated from these data using linear solvent strength relationships, suggesting that the retention behavior may be the result of minor analyte conformational changes during the chromatographic experiment. This hypothesis was supported via circular dichroism (CD), Raman and 1H NMR spectroscopic studies of the doxorubicin-peptide conjugate in selected chromatographic mobile phase compositions. The CD and Raman data indicated small changes to the apparent analyte microenvironment as a function of temperature and bulk solvent environment, while 1H NMR studies specifically demonstrated the environmental sensitivity of protons on three non-polar peptide residues and the proximal aromatic region of the analyte. Together, these data suggest that minor changes to the conformational order of the essentially random structure of the doxorubicin-peptide conjugate are sufficient to impact chromatographic performance.

A sensitive gas chromatographic method was developed to monitor the reaction of lithium diisopropylamide (LDA) with dimethyl methylphosphonate (DMMP) to generate the phosphonate carbanion (DMMPA). Analysis of the DMMPA was complicated due to its thermal instability and lack of a chromophore. To overcome these problems, samples were derivatized with trimethylsilylchloride (TMSCI) to form DMMPA-TMS which was sufficiently volatile and thermally stable for GC analysis. Work-up of the derivatized solution with 10 vol.% 2-propanol in hexanes was necessary to quench residual TMSCI prior to GC analysis. The presence of DMMPA-TMS and other sample components was confirmed by GC-MS analysis. This method was utilized to profile the synthesis of DMMPA as DMMP was added to LDA and then aged at -78 degrees C. Method precision for DMMPA-TMS of less than 0.2% RSD was achieved for repeat injections after normalization of the response with n-dodecane contained in the sample. Due to the thermal instability of the DMMPA, subambient derivatization temperatures were essential to the stability, and consequently, accurate quantification. Under optimized conditions, this derivatization was successfully utilized as a process monitoring tool.

The benzenesulfonate salt of an anti-methicillin-resistant Staphylococcus aureus carbapenem antibiotic studied is a crystalline, nonhygroscopic powder which is stable at room temperature, making it an ideal compound for long-term storage. However, the limited aqueous solubility of this salt prohibits parenteral administration. Conversely, the chloride salt of this carbapenem demonstrates opposing characteristics; it is quantitatively soluble in water, however is amorphous and subject to significant hydrolytic degradation in the solid state. Given two such extreme alternatives for pharmaceutical salt selection, a common approach taken is to develop the bioavailable salt and devise manufacturing and storage conditions that minimize degradation. This report describes a different approach to this manufacturing dilemma via the application of a simple and efficient nanofiltration process to convert the benzenesulfonate salt (storage entity) to the chloride salt (formulated drug product). Such an approach combines the positive attributes of these two salt forms into a single scalable process that reduces processing cycle times via elimination of redundant unit operations, increases the flexibility in manufacturing schedule, and improves overall product quality., (Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91: 923-932, 2002)