Case Study: Identification of Particulate Contamination in Pharmaceutical Products

Pharmaceutical ingredients undergo stringent testing guidelines to meet tough quality standards. In rare occasions, passing USP compendial testing cannot guarantee the pharmaceutical ingredients are not tainted with foreign contaminants.

In this case study, we will focus on the identification of particulate contamination in pharmaceutical products. This is an example where several batches of pharmaceutical raw materials passed the USP compendial tests but received numerous customer complaints due to particulate contamination.

The particulate was first isolated from the raw material by dissolution of the product followed by filtration. In Figure 1, the two filters to the right are lab blanks and the two to the left are raw material samples. You can clearly see the filters on the left are tainted. Figure 2 shows a closer look of the filters by light microscopy; the filters are loaded with extraneous particles of various colors, shapes and sizes.

Figure 1 – Samples prepared by filtration

Figure 2 – Examination of a filter by light microscopy

After the initial documentation and examination of the filters by light microscopy, we begin to isolate representative particulate for identification. We will illustrate a few examples here. Black particles (Figure 3) were prevalent on the filters, so we isolated a couple and analyzed them by Raman spectroscopy. Raman spectroscopy is great for analyzing small particles (down to one micrometer). The technique is also non-destructive if you don’t burn the sample by ramping up the laser power. Figure 4 shows a Raman spectrum of a black particle; the spectrum is consistent with a charred carbon.

Figure 3 – Black particulate isolated from the filter

Figure 4 – Raman analysis of the black particulate

Figure 5 shows a filter with an extraneous fiber in addition to the small particles. Examination of the fiber by polarized microscopy determined it to be consistent with a human hair (Figure 6). Human hair is one of the most common particulate contaminants that occur in pharmaceutical raw material.

Figure 5 – Examination of a filter by light microscopy

Figure 6 – Polarized light microscopy image of a hair contaminant

Figure 7 shows a scanning electron microscopy (SEM) image of one of the black particles isolated from the filter. SEM analysis is great for looking at the surface morphology and texture of small particles. Energy dispersive x-ray analysis shows that this particle is consistent with an iron oxide (Figure 8). We suspect it is a corrosion product.

Figure 7- SEM imaging of a black particulate

Figure 8 – Elemental analysis of a black particulate

 

Figure 9 shows an SEM image of some polymeric material. Analysis by FTIR shows that it is consistent with a fluorocarbon polymer (Figure 10). FTIR is a great instrument for identifying organic materials. It is non-destructive and gives molecular information to help quickly identify unknown materials.

Figure 9 – SEM imaging of a polymeric particulate

Figure 10 – FTIR analysis of a polymer

Analysis of the contaminants in the raw materials by SEM, light microscopy, FTIR and Raman showed a large variety of materials including several different polymers, metals and metal corrosions, inorganic salts, combustion products, charcoal, textile fibers and hair. The investigation revealed that the particles originated from multiple sources.