title: Stability characterization and appearance of particulates in a lyophilized formulation of a model peptide hormone-human secretin.
abstract: Drug shortages and recalls are often caused due to particulate growth in parenteral products and can have serious clinical implications. Root cause analysis of such recalls and shortages may arise due to insufficient understanding of process, formulations issues and environmental effects than often reported filtration and inadequate personnel training. Therefore, the goal of this study was to use a model peptide hormone, secretin that is currently under drug shortage, and investigate the effect of excipients on the lyophilized secretin formulation and evaluate the effect of storage and excursion temperatures. Lyophilized formulation was assayed for secretin by reverse phase HPLC. Solid state characteristics of lyophilized formulation were determined by X-ray powder diffraction (XRPD), thermal and spectroscopic methods. Dynamic light scattering (DLS) was used to detect particulates in the formulation after reconstitution. To assess the environmental impact, the lyophilized samples were stored at -20°C, 4°C, 25°C and 25°C/60%RH and analyzed at time 0, 1, 4, and 8 weeks. HPLC analyses exhibited a decrease in secretin concentration by 8 week (20-27% fold decrease). Visual observation and DLS showed particulates and increased reconstitution time (e.g., at 25°C/60%RH, particle size of ∼390 nm at day 0 to >2 μm as early as week 1; reconstitution time of ∼20s at day 0 to ∼67s at week 8). XRPD, thermal and spectroscopic methods demonstrated polymorphic transitions of mannitol and increased crystallinity in the lyophilized formulations with time. These studies potentially address the effect of product excursions outside the proposed label storage conditions which is -20°C for secretin formulation and this is the first time it has been investigated. These observations indicate that both environmental factor and excipient may have an impact on the stability of secretin formulation and appearance of particles in the product.
authors: Division of Product Quality Research, Office of Testing and Research, OPQ, CDER, FDA, United States.
authors: Charudharshini
authors: C
authors: Srinivasan
authors: Division of Product Quality Research, Office of Testing and Research, OPQ, CDER, FDA, United States.
authors: Akhtar
authors: A
authors: Siddiqui
authors: Division of Product Quality Research, Office of Testing and Research, OPQ, CDER, FDA, United States.
authors: Maxwell
authors: M
authors: Korang-Yeboah
authors: Division of Product Quality Research, Office of Testing and Research, OPQ, CDER, FDA, United States. Electronic address: Mansoor.Khan@fda.hhs.gov.
authors: Mansoor A
authors: MA
authors: Khan
mesh_terms: D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000737:chemistry; D004355:Drug Stability; D004356:Drug Storage; D005079:Excipients / Q000737:chemistry; D005612:Freeze Drying; D006801:Humans; D008353:Mannitol / Q000737:chemistry; D033362:Powder Diffraction; D012633:Secretin / Q000737:chemistry*; D012965:Sodium Chloride / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D019265:Spectroscopy, Near-Infrared; D013696:Temperature; D014961:X-Ray Diffraction
chemical_list: D005079:Excipients; D012633:Secretin; D008353:Mannitol; D012965:Sodium Chloride; D003545:Cysteine
keywords: Formulation; Lyophilization; Mannitol; Particulates; Peptide; Secretin; Stability