Ensuring Reliable Material Identification in Pharmaceutical Manufacturing

To ensure alignment with good manufacturing practice (GMP) in pharmaceutical production, it is crucial that pharmaceutical and biotechnology manufacturers can ensure the quality of their materials. This includes identifying incoming raw materials at the start of a process pipeline and those used throughout the process, right up until the finished product is produced.

Variability in the quality of raw materials can not only impact production yields, but can also affect the quality, efficacy and safety of the final pharmaceutical product.

In this interview, we spoke with Ana Fiadeiro, senior marketing manager, pharmaceutical vertical leader at Thermo Fisher Scientific, to learn about how the capabilities of two handheld products, the TruScan RM analyzer and the microPHAZIR RX analyzer, ensure reliable material identity verification.

Molly Campbell (MC): Why is raw material identification such a critical step in quality assurance, and what challenges exist in this space?

Ana Fiadeiro (AF): For good manufacturing practice (GMP) in pharmaceutical manufacturing, there's a requirement to test raw materials for identity, purity, assay and several other physical tasks. That requirement is handled by the local pharmacopoeias. You have the United States pharmacopoeia, the European pharmacopoeia, and the Japanese pharmacopoeia – these are the ones that are recognized globally. Every raw material must be correctly identified as it enters a facility for pharmaceutical manufacturing. It can be very time consuming to identify the various raw materials that are received.

The pharmacopeia tests are essentially like a "cookbook", where you must conduct X, Y or Z tests. Identity tests can include titrations, looking for precipitants, or using spectroscopy, typically Fourier-transform infrared spectroscopy (FTIR) which requires that we sample and bring the materials to a laboratory environment. If you think about receiving hundreds of different raw materials, sampling from hundreds of tons of raw material and then conducting laboratory tests on them, it's a time-consuming process. The challenges really are ensuring that you are in compliance with the GMP regulations and the amount of time that it takes to identify the materials.

MC: The TruScan RM Analyzer delivers reliable material identification in seconds. How exactly is this achieved?

AF: The TruScan analyzer is a handheld Raman instrument that uses a type of laser spectroscopy. This enables us to optically see-through a raw material’s primary packaging in most cases and compare the spectrum we get to a reference library. From this we can tell if it conforms to that spectral reference or “fingerprint”.

Raman spectroscopy is very similar to FTIR spectroscopy. In FTIR spectroscopy we use multiple wavelengths of light, and we look for absorption of that light to form a structural fingerprint. In Raman spectroscopy, we actually use one wavelength of light and we look for light that is scattered off at a different wavelength. It provides the same type of fundamental spectral fingerprint that is achieved with FTIR spectroscopy. One of the advantages of the TruScan RM analyzer is that we can analyze through the primary packaging which saves a tremendous amount of time. Additionally, this instrument is designed to use multivariate residual p values. Multivariate, in this case, refers to uncertainty characteristics of each measurement/scan by the TruScan RM, that is, factors influencing the measurement and the measurement uncertainty.

Uncertainty characteristics fall into three categories:

• Measurement settings (e.g. exposure time, number of scans)
  
  
• Environmental properties (e.g. temperature)
  
  
• Material being scanned (e.g. absorbance)

Simply put, the P-value TruScan RM calculates is the probability (given the uncertainties in a scan) that the scanned material is the same as the known reference material; in other words that the measurement spectrum belongs to the population of the reference spectrum given measurement uncertainties.

This is a technique in which we are looking at both the response of the material and some fundamental parameters of how the material is responding to the instrument.

We've really put the Ph.D spectroscopists within the instrument itself. We are constantly monitoring the environment for interferences and correcting them in real time and correcting for the amount of signal that we are getting back from the material.

The operator doesn't have to interact with the device other than to say, "What type of material am I testing?" and then the instrument designs an experiment to ensure that you are getting high quality and reproducible results, which is very important to pharmaceutical manufacturers.

MC: What complex material analysis problems can be overcome using both the TruScan RM Analyzer and TruTools™ chemometrics package?

AF: With TruScan for example, we’ve been able to identify polysorbate 20 and 40, and other samples of polysorbate 80 and polysorbate 20 in their native packaging without needing to sample.

We’re also really excited to be working with chemically defined media and being able to differentiate between very small differences in components. For example, we've put in known amounts of amino acids, sugars, buffers and even other growth material into a media. Now we know the exact makeup of the media and can detect the subtle changes that have been made.

With TruTools, we turned a standard handheld Raman spectrometer into a fully capable benchtop spectrometer. We're now able to do complex analysis using PCA or PLS-DA as a way of discriminating between different classes of materials. It also has the ability to do quantitative analysis. So, for example, if you received a delivery of 80% ethanol and a delivery of 100% ethanol, we can now discriminate between those two based upon their concentration and not only on their fundamental spectroscopy fingerprint.

MC: Please can you tell us about the development of the Thermo Scientific microPHAZIR? How have you taken NIR spectroscopy out of the lab and into the warehouse to create a handheld device?

AF: The microPHAZIR uses a different technology called near infrared spectroscopy, which is a lower energy technique than FTIR spectroscopy, but it is probing the same types of fundamental vibrations.

While NIR requires a little more model building to compensate for the weaker vibrations, it can be used to test fluorescent materials that are not really amenable to Raman. Its best used as a complementary technique with Raman to provide a better amount of material coverage than we would with just one.

NIR excels with materials like celluloses, or when we want to measure water in a raw material, as it is very sensitive to the amount of moisture we see. There are a number of applications beyond raw material identification where moisture is really important. One is "freeze drying" when we are trying to stabilize a protein-based drug. This is where the product is frozen and pulled under a vacuum to stabilize that drug. We can measure the residual moisture very easily here. There are also granulation steps in terms of small molecule tablets, where you may add water into a mixture of the API and excipient to form granules so that you can later compress that into a tablet form. It is important to understand the moisture in those granules to know that you have a good quality tablet that is not overly dense, that is not going to have fractures or breakage later in the process.

MC: What needs do both the TruScan RM Analyzer and microPHAZIR products meet in the QA process?

AF: We're really focused on replacing existing costly and time-consuming laboratory analysis with techniques that can be used either at line or where the product is sampled. The goal with these handheld analyzers is to accelerate the process, as we can measure through the primary packaging (so long as it is transparent) and then we also want to replace, from a PAT perspective, time consuming tests that are done in the laboratory. Whether that is solvent quantitation, moisture analysis, or replacing identity tests later in the process. These are our key focus areas with this portfolio of devices moving forward.

Ana Fiadeiro, Senior Marketing Manager, Pharmaceutical Vertical Leader at Thermo Fisher Scientific was speaking with Molly Campbell, Science Writer, Technology Networks.