Using A Streamlined Workflow to Identify Particulates in Biologic Drugs

A case study presented at AAPS PharmSci 360, which is being held from Nov. 9–12 in San Antonio, outlined a streamlined approach to identifying and mitigating the presence of visible particles in biologics. Eda Fenercioglu, Scientist, Formulations at Pfizer, explains how the workflow was applied to biologic formulations (1). The process was developed to reduce time and resources and maintain quality and data generation relevance. The approach used aligns with Six Sigma methodology, Define, Measure, Analyze, Improve, Control (DMAIC). A structured path offered particulate detection through root cause resolution. For this study, particulates were observed after manufacturing steps and in drug product that had been frozen and was then thawed.

How does the workflow help with assessment of particulates in product?

Visual inspection and microscopy imaging was first used to assess particulate morphology so that reason for the particulates could be determined. After this step, the isolated particulates were re-imaged and measured. Spectroscopic analysis, such as Fourier-transform infrared (FT-IR) spectroscopy, was used to ascertain the biochemical composition of the particulates. This allowed the particulates to be classified as either inherent, intrinsic, or extrinsic for targeted follow-up studies to determine the origin particulates and prevent recurrence. While FT-IR spectroscopy was used in this study, the workflow developed allows for the primary identification tool to be adapted, as necessary.

For non-polar or symmetric molecules, Raman spectroscopy is recommended, while scanning electron microscopy with energy dispersive X-ray spectroscopy is suggested for identifying trace metals or inclusions not visible under optical microscopy (1). More detailed characterization of fiber types is achieved with polarized light microscopy. This tool also helps differentiate between protein and nylon when it is used with FT-IR spectroscopy.

During mixing and settling studies, particulate count, size distribution, and morphology were assessed by high-accuracy light obscuration (HIAC-LO) and microflow imaging (MFI) to determine particulate formulation and possible process changes that would eliminate particulate formulation in future batches.

What did the workflow find?

The study showed that particulates were inherent and their morphology and spectra were consistent with the components of the drug product. HIAC-LO and MFI were then used to identify that shear stress from mixing was the cause of the particulate formulation in the product. HIAC-LO was used to conduct a settling study that showed that turning off the mixer at a certain stage of manufacturing preserved solution homogeneity, therefore preventing the particulates from generating. The settling study also found that the drug product remained homogeneous over the hold time without continuous mixing; therefore, a process change could be made.

What does this mean for product inspection?

The study showed that an integrated approach to the identification and classification of particulates can assist in timely process improvements and process control. The use of analytical tools within the DMAIC framework provides efficient root cause analysis that can enhance the quality of the product. Robust control strategies can be established by defining and measuring particulate characteristics followed by analyzation of their composition that leads to the implementation of process improvements.

Reference

1. Fenercioglu, E. A Streamlined Workflow for Visible Particulate Indentification and Root Cause Mitigation in Biologic Drug Products. AAPS PharmSci 360 Poster Presentation. Nov. 11, 2025. https://aaps2025.eventscribe.net/fsPopup.asp?PosterID=764134&mode=posterInfo.