title: Root cause evaluation of particulates in the lyophilized indomethacin sodium trihydrate plug for parenteral administration.
abstract: Particulate growth in parenteral product frequently results in product recalls causing drug shortages. While this is mostly attributed to quality issues in a firm, particulates growth could also be due to inadequate product, process, or environmental understanding. Therefore, the objective of this study was to use indomethacin sodium trihydrate (drug) as a model drug for lyophilization and evaluates short-term stability with respect to particulate growth at different storage temperatures. Under aseptic condition, each vial filled with filtered drug solution was lyophilized, and stoppered in LyoStar3. Crimped vials were kept at 5°C, 15°C, 25°C, 25°C/60%RH, and 40°C/75%RH. At predefined time interval, samples were characterized using X-ray powder diffraction (XRPD), thermal, and spectroscopic method. Lyophilized formulation showed four thermal events: 60-90°C demonstrating glass transition, 110-160°C showing recrystallization exotherm,170-220°C exhibiting endotherm of potential polymorph, and 250°C showing melting endotherm. XRPD of the lyophilized powder demonstrated peak at 2 θ 11.10. Spectroscopic studies of lyophilized powder indicated alteration in symmetric and asymmetric carboxylate peaks over time indicating initiation of crystallization and crystal growth. Reconstitution studies indicated higher reconstitution time after six weeks for sample stored at 40°C/75%RH. Furthermore, reconstituted solution showed presence of particulates after 8 weeks storage. These studies suggest that particulate growth can stem from poorly developed formulation and not necessarily due to frequently ascribed filtration issues.
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, FDA, United States.
authors.forename: Akhtar
authors.initials: A
authors.lastname: Siddiqui
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, FDA, United States.
authors.forename: Ziyaur
authors.initials: Z
authors.lastname: Rahman
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, FDA, United States.
authors.forename: Saeed R
authors.initials: SR
authors.lastname: Khan
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, FDA, United States.
authors.forename: David
authors.initials: D
authors.lastname: Awotwe-Otoo
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, OPS, CDER, FDA, United States. Electronic address: Mansoor.Khan@fda.hhs.gov.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D005612:Freeze Drying; D007213:Indomethacin / Q000737:chemistry*; D033362:Powder Diffraction; D017550:Spectroscopy, Fourier Transform Infrared; D019265:Spectroscopy, Near-Infrared; D014961:X-Ray Diffraction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007213:Indomethacin
keywords: Indomethacin; Lyophilization; NIR; Spectroscopy; Stability