In terms of enumerating particulate matter in parenteral biotherapeutics, the regulatory position is covered in USP general chapters <787> and <788>1. These chapters accept that some particulate matter may be present in the product, and limits are set based on the size and number of particles. However, not all particulate matter is ‘made equal’ and particles originate from a variety of sources. USP <1787> describes three different categories of particulate matter2:
- Inherent: particles derived from the product itself, such as protein or excipient agglomerations
- Intrinsic: particles derived from the process, such as silicone oil, rubber or glass
- Extrinsic: particles derived from unknown sources
As USP <1787> informational chapter states:
“Because multiple potential sources of particles exist, it is important to identify the particles and determine whether they are extrinsic, intrinsic, or inherent. Once this has been accomplished, it is possible to develop and apply appropriate control strategies. If deviations occur, particle identity will guide the root cause analysis, risk assessment, corrective actions, and control strategy.”
One of the techniques for particle identification described in this chapter is Raman Microspectroscopy, which involves using a light microscope to target individual particles for Raman spectroscopy. The identification can be rapid and can take place in the native suspension or when filtered. However, locating these particles requires both a substantial amount of time and a highly-skilled operative.
In this application note, we describe an automated method of Raman Microspectroscopy whereby the sample is scanned, and particles are located by image analysis. The particles are then targeted for Raman analysis, according to their morphological descriptors. This technique is known as Morphologically-Directed Raman Spectroscopy (MDRS®), is performed using Malvern Panalytical’s Morphologi 4-ID, and is increasingly used to determine component-specific particle size and shape3-6. In contrast to manual Raman microscopy, not only does the use of MDRS decrease the time and burden on the analyst, but it also enables enumeration of the particles and stores particle images with their spectral information. Thus, both the robustness of the test and the ability to audit the data are improved. Here we describe the use of MDRS for automatic identification and enumeration of particulate matter in a biotherapeutic product.
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