Kiyoshi Fujimori

Glass prefilled syringes (PFS) are a container and delivery device of choice for storing and administering therapeutic protein products to patients. Addressing concerns and regulatory expectations related to the risk to biologic drug product quality and patient safety from PFS requires implementation of an extractable and leachable program based on understanding of materials, risk assessment, review of existing literature and testing based on a sound scientific foundation. Extractables and leachables data generated as part of thorough and holistic program are presented for 5 PFS systems, including glass and plastic syringes, and 12 biologic drug products encompassing the implementation of traditional and single-use biotechnology manufacturing processes. The comprehensive extractables and leachables data presented demonstrate and substantiate a holistic extractable and leachable program designed to ensure product quality and patient safety.

The European Pharmacopeia (Ph. Eur.) surface test to analyze the hydrolytic resistance is a common industrial method to understand and ensure the quality of produced glass vials. Hydrolytic resistance is evaluated by calculating the alkalinity of water extract from autoclaved vials by titration. As an alternative to this titration technique, a conductivity technique was assessed, which directly measures the ions in the water extract. A conductivity meter with 12 mm diameter electrode was calibrated with 100 μS/cm conductivity standard and carryover minimized by rinsing the probe in a water beaker per analysis. Limit of quantification at 1 μS/cm was determined as having a signal to noise ratio of 3 compared with the water blank. The conductivity method was selective for glass composing elements (boron, sodium, aluminum, silicon, potassium, and calcium) within the vial extract. Accuracies of spiked conductivity standard within the range of 1 to 100 μS/cm were ± 7% and had linearity with coefficient of determination (R2) of ≥ 0.9999. Intraday precision had RSD (n=5) of ≤ 6% for spiked conductivity standard within the range of 1 to 100 μS/cm. Interday precision had RSD (n=4) of ≤ 6% for ten vials from three glass vial lots. Conductivity of water extracts from nine sets of seven lots of glass vials had a precise linear relationship [R2 = 0.9876, RSD = 1% (n=9)] with titration volumes of the same lots. Conductivity results in μS/cm could be converted to titration values in mL by conversion factor of 0.0275. The simplicity, sample stability, and individual vial analysis of the conductivity technique were advantageous than the current titration technique.

Certain types of glass vials used as primary containers for liquid formulations of biopharmaceutical drug products have been observed with glass flake like delamination or 'lamellae' under certain conditions during storage. The cause of this delamination is in part related to the glass surface defects, which renders the vials susceptible to flaking, and are formed during the high temperature melting and annealing used for vial fabrication and shaping. Current European Pharmacopoeia (Ph. Eur.) method to assess glass vial quality utilizes acid titration of vial extract pools to determine hydrolytic resistance or alkalinity. Four alternative techniques with improved throughput, convenience, and/or comprehension were examined by subjecting seven lots of vials to analysis by all techniques. The first three new techniques of conductivity, flame photometry, and inductively coupled plasma mass spectrometry (ICP-MS) measured the same sample pools as acid titration. All three showed good correlation with alkalinity; conductivity (R2=0.9951), flame photometry sodium (R2=0.9895), and several elements by ICP-MS [(sodium (R2=0.9869), boron (R2=0.9796), silicon (R2=0.9426), total (R2=0.9639)]. The fourth technique processed the vials under conditions that promote delamination, termed the Accelerated Lamellae Formation (ALF), and then inspected those vials visually for lamellae. The visual inspection results without the lot with different processing condition correlated well with alkalinity (R2=0.9474). Due to vial processing differences affecting alkalinity measurements and delamination propensity differently, ratio of silicon and sodium measurements from ICP-MS was the most informative technique to assess overall vial quality and vial propensity for lamellae formation. The other techniques of conductivity, flame photometry, and ALF condition may still be suitable for routine screening of vial lots produced under consistent processes.

An unexpected, black particle (∼300 microns) was visually observed adhering to the interior shoulder of a prefilled glass syringe containing a biological drug product. The goal of this study was to determine the source, identity, and leachables of the black particle. The particle originated from a polymeric pin used during the syringe manufacturing process. Fourier transform infrared (FTIR) spectra comparison of the black particle and polymeric pin correlated to a database match of Nylon-MXD6 with glass fibers. Liquid chromatography/mass spectroscopy analyses identified Nylon-MXD6 and Nylon-6 photo-oxidized-related compounds in both the pin extract and syringe solution. The black particle originated from the pin and contained glass fibers, Nylon-MXD6, and Nylon-6. All nylon-related compounds were observed at <260 ng/mL (ppb) in the syringe solution. Syringes without black particles contained no detectable levels of nylon-related compounds, suggesting that routine contact between a pin and syringe barrel may not lead to syringe contamination or leachables originating from the pin. Abnormal heat exposure and/or extensive pin usage may have led to pin wear and tear.