The Remedy for Pharmaceutical Tank Cleanliness

As living standards rise, consumers are becoming more demanding when it comes to quality. One of those needs is that the product be clean; this is especially true for pharmaceuticals, which  are a vital product with a direct bearing on human health.

Solid (pills) and liquid (syrups, tinctures, etc.) form factors are the two main types of pharmaceuticals, and each has specific requirements for process cleanliness. Pill-pressing powders can leave solid residue in the molds, and the enormous surface areas of the processing tanks for liquids require thorough cleaning.

Broadband spectroscopy lets you do this on pharmaceutical molds and tanks to assess cleanliness before and after the CIP (Cleaningin-Place) process.

Measurements

Most common APIs (Active Pharmaceutical Ingredients) are optically active in the UV and provide strong absorbance in that region. This may not give the specificity of NIR bands to determine exactly which APIs are present but does give a much stronger general representation of the presence or absence of the ingredient at low concentration levels. Let’s take a look at an example of diphenhydramine powder (Benadryl®) on stainless steel going from an area of heavy API residue to an area of clean steel (Figure 1).

Figure 1. Broadband spectroscopy is an excellent tool for monitoring the presence of powder residues on stainless steel, comparable to what’s encountered during pharma tanking cleaning.

Note the steady reduction of UV absorbance as the probe moves to cleaner areas of the steel surface, eventually dropping to a nice zero-level at the sufficiently cleaned region. By taking a light reference on a known-clean sample of the tank surface, this UV absorbance can be used as a gauge for how much solid residue may be present across other areas of the tank. Liquids are the other common form factor for APIs. Most of us have taken cough syrup at some point in our lives, so let’s look at a liquid example using common dextromethorphan cough syrup in a standard 1 cm cuvette. For liquid tank cleaning the tanks typically go through cycles of both acid and alkaline washes, and these wash solutions and subsequent rinse water can be analyzed for the presence of API as an indication of cleanliness . But before we look at spectra for the various rinses we need to have some general correlation between absorbance and API concentration. Figure 2 shows three dilution levels of the cough syrup along with a rough calibration trend in the upper-right corner. By looking at the absorbance around 315 nm we get a nice linear relationship with syrup concentration.

Figure 2. UV-vis spectroscopy is ideal for monitoring the concentration of liquid pharma samples including this cough syrup example

The plot also includes an allusion to the first few rinses of the tank with each rinse giving a dramatic reduction in API concentration. But let’s zoom more closely into what’s happening across all seven rinses performed for this study. The plot in Figure 3 shows us that by the fourth rinse we are very close to zero API but still have low levels present. Even rinses five and six show some statistical non-zero level of API, but the seventh rinse eliminates traces beyond the limit of detection.

Plots are nice visual representations, but the actual absorbance numbers can be extracted from those trends and processed against our calibration correlation to give more precise figures on API residue level. Table I (see next page) shows the steady reduction in API concentration for each rinse, getting down to essentially 1 ppm after six washes and statistically undetectable after the seventh.

Additional Considerations

Both sampling approaches have considerations to ensure proper measurement and to potentially enhance the limits of detection. For the solid sample approach using the reflective probe, the repeatability of probe positioning with respect to distance and angle will determine the repeatability and accuracy of the concentration measurements. Generally, flimsy fixturing will lead to flimsy readings. That said, there are software techniques involving baselines and SNV normalization that can help correct for these variances in real world settings. For the liquid approach using a transmissive cell, an increased pathlength will proportionally improve the limit of detection.

Also, cell cleanliness is crucial for accurate readings, as the challenge of cleaning optical cell walls is similar to cleaning tank walls. The choice between a discrete cell (manually injected or removed) and a continuous flow cell linked to the wash process determines ease of cleaning and confidence in readings. The discrete option allows easier cleaning and potentially more confidence in readings, while the continuous option requires less human interaction but may involve more regular maintenance work.

Conclusion

Many pharmaceutical companies choose an over-cleaning approach, which involves them rinsing out vats with solvent for hours or days longer than necessary in an attempt to guarantee runoff doesn't contain unexpected reagents, due to the financial and reputational risk of producing contaminated products. Although runoff regulation is achieved in this way, a significant amount of time, energy, and resources are also lost in the process. Pharmaceutical companies can enhance their ability to monitor ongoing API reactions and expedite cleaning validation processes by integrating robust spectroscopy systems, such as Ocean Optics' HR6 spectrometer, into their operations.pharmaceutical firms will be better equipped to monitor ongoing API reactions and streamline cleaning validation processes.