Development of a Control Strategy for Benzene Impurity in HPMCAS-Stabilized Spray-Dried Dispersion Drug Products Using a Science-Based and Risk-Based Approach.

PURPOSE: To develop a strategy to control benzene, an ICH Q3C Class 1 impurity that may be present in spray solvents at ppm concentration, in amorphous polymer-stabilized spray-dried dispersion (SDD) products. METHODS: Risk assessments included determining the probability for benzene concentration in primary spray solvents, the physical properties of volatiles, and the potential enrichment of benzene from solution to solid. Mechanistic understanding of benzene removal was gained through a benzene-spiked fate and tolerance (F&T) study simulating worst-case spray-drying conditions and application of diffusion models for secondary drying. RESULTS: The mass ratio of spray solution to solid presented the highest risk of benzene enrichment. With slow spray-drying kinetics, benzene was reduced about 700-fold. Under standard secondary-drying conditions to remove residual solvents, residual benzene was further removed. Using diffusion models, the maximum benzene concentration was approximated for SDDs dried to the in-process control (IPC) limit of primary solvents. CONCLUSIONS: Two critical control points were established to eliminate any risk of residual benzene reaching patients: (1) upstream control of benzene in solvents (≤10 ppm) and (2) IPC of residual solvents in polymer-stabilized SDDs.

Minimally destructive sampling of type specimens of Pyropia (Bangiales, Rhodophyta) recovers complete plastid and mitochondrial genomes.

Plant species, including algae and fungi, are based on type specimens to which the name of a taxon is permanently attached. Applying a scientific name to any specimen therefore requires demonstrating correspondence between the type and that specimen. Traditionally, identifications are based on morpho-anatomical characters, but recently systematists are using DNA sequence data. These studies are flawed if the DNA is isolated from misidentified modern specimens. We propose a genome-based solution. Using 4 × 4 mm(2) of material from type specimens, we assembled 14 plastid and 15 mitochondrial genomes attributed to the red algae Pyropia perforata, Py. fucicola, and Py. kanakaensis. The chloroplast genomes were fairly conserved, but the mitochondrial genomes differed significantly among populations in content and length. Complete genomes are attainable from 19(th) and early 20(th) century type specimens; this validates the effort and cost of their curation as well as supports the practice of the type method.

Comprehensive determination of extractables from five different brands of stoppers used for injectable products.

Five commonly used stopper formulations were tested for extractables using three different vehicles (pH 3 citrate buffer with 20% w/v sulfobutylether-beta-cyclodextrin, pH 8 phosphate buffer and 50/50 v/v polyoxyethylated castor oil/dehydrated alcohol). The stoppers, made from butyl and halobutyl rubbers, coated and uncoated with proprietary films, were stored in contact with each vehicle for up to 6 months at 40 degrees C/75% relative humidity (RH) or for up to 24 months at 25 degrees C/60% RH. Samples were analyzed for the presence of extractables using inductively coupled plasma-atomic emission spectroscopy, ion chromatography, high-performance liquid chromatography, and gas chromatography. Extractables were observed at greater than 10 ppm for only one of the five stoppers that were tested. Based on these results, a standardized protocol for stopper extractable testing was developed. This protocol has been used to satisfy stopper extractable testing regulatory requirements for a number of different new injectable products.