Ensuring raw material quality in drug production and manufacturing

In this interview, Thermo Fisher Scientific discusses how to ensure the high quality of raw material in the drug production and manufacturing pipeline.

Please can you introduce yourselves and tell us about the analytical techniques you work with at Thermo Fisher Scientific, which can ensure the quality of raw materials?

Suja Sukamaran:

I am Dr. Suja Sukamaran, Product Manager for Fourier transform infrared spectroscopy (FTIR). I will speak about FTIR instrumentation and application for material identification and quantitation for the pharmaceutical industry.

Sudhir Dahal:

I am Dr. Sudhir Dahal, Raman Product Manager. I will cover the important role that Raman spectroscopy plays in raw material analysis in the pharmaceutical industry. I will focus on using laboratory Raman instruments, covering both spectrometers and Raman microscopes.

Eden Couillard:

I am Eden Couillard, an Application Scientist at Thermo Fisher Scientific based in Tewksbury, Massachusetts. I will discuss utilizing Raman spectroscopy for raw material identification in the pharmaceutical industry using our handheld TruScan RM analyzer.

Mike Garry:

I am Mike Garry, the NIR infra Product Manager at Thermo Fisher Scientific. I will be talking about NIR infrared techniques for incoming raw material analysis.

What is FTIR and how does it work?

Suja Sukamaran:

FTIR has truly transformed infrared spectroscopy. When you look at an FTIR spectrum, you see the wave numbers on the X-axis and the absorbance or the transmittance on the Y-axis. FTIR is a form of vibrational spectroscopy. Atoms are moving and the vibrational energy is recorded.

The two key principles of FTIR spectroscopy are that the mass is inversely proportional to the vibration frequency, and the bond strength is directly proportional. This is why we can see each molecule with a unique fingerprint. We can use this fingerprinting for identification as well as purity.

What are the key areas or pathways that FTIR can be used for in the pharmaceutical industry?

Suja Sukamaran:

You can use FTIR for raw material qualifications, in-process control, intermediates, or finished product qualification and identification. We receive answers about identity purity or quantity when applying FTIR instrumentation to any of these steps.

When we say identity, we look at the material type by searching. We can use this process to check incoming raw material or to decide if the right mix of ingredients is in a final product.

We can also look for purity. The purity refers to determining if the material matches the reference material or if it meets the pass-fail criteria you've established, often assessed through peak positions and intensity. What you are trying to see is the purity of the material and whether the material is stable.

The last thing is quantity. Quantity is where you are looking at whether the starting and final material amount is in the right proportion and if the ratio of the ingredients is correct in the final product.

We achieve this using two groups of instrumentation. The first group is the FTIR benches, which we call the bulk analysis instrumentations. Then there are the FTIR microscopes. The FTIR benches are typically used for quality control or research purposes. Microscopy helps you in pharmaceutical forensics or when looking at distribution and analysis.

How is FTIR used for raw material identification?

Suja Sukamaran:

Raw material identification can be done using attenuated total reflectance (ATR). In ATR, you use a minimal sample, barely enough to cover a one-millimeter surface of ATR crystal, to identify identification and purity.

For example, say we are screening polymorphs and have used acetamidophenol, if you look at different types, whether amorphous, monoclinic, or orthorhombic, you can compare to a library spectrum using the library search function and get the correct answer because the peaks are well-defined and well-separated.

For raw material identification and final quality control, you can use the QCheck option in our instruments, a spectral correlation-based algorithm available in the OMNIC and the OMNIC Paradigm software.

It is also possible to carry out quantitation. Take the example of ethanol, a very commonly used material in the pharmaceutical industry, whether in the starting product or the end material.

Whether you have incoming raw material and you want to see the identity and purity of this particular ethanol, or whether you want to see if you have the right concentration of ethanol in the final product, you can do all this in just a matter of seconds by creating simple workflows where you are selecting the type of material you are using and with what pathways you want to analyze it.

The quantitation is based on a calibration curve. These calibration curves can be created in advance, and then the final product, or even the initial material, can be looked at.

There is also microscopic analysis. Say we have a commercially available insulin product dried on a barium fluoride window and analyzed in transmission. We need to analyze and understand the distribution of insulin and cholesterol.

This can be applied to powders, liquids, or any other form. The biggest advantage of using FTIR microscopy is getting visual and infrared images for that particular material. Visual and infrared data are available, and each spot being analyzed can be further evaluated.

The use of FTIR is for identity, purity, and quantity. You can use it for bulk or microscopic analysis, and you can use the analysis for the identity of contaminants, which can help you in failure analysis.

All these instrumentations, as well as the software, are 21 CFR compliant.

What is Raman spectroscopy and why is it useful? What important information can it provide?

Sudhir Dahal:

Raman spectroscopy is an optical technique in which a sample is excited with a laser, and the energy scattered from the sample is analyzed. Raman spectroscopy looks at the interaction between the excitus, laser light and covalent bonds within molecules in the sample.

It can provide detailed molecular information. The best represented using this technique tend to be highly symmetric bonds, most commonly found in the backbones of molecules or crystal lattices.

Raman is also very sensitive to the slightest change in bond, angle, or strength, making it an excellent means for distinguishing similar compounds, including polymorphs. These characteristics make it an excellent means of characterizing drug molecules and various chemicals used in the pharmaceutical industry.

Raman spectroscopy and microscopy offer many advantages. The technique is extremely fast, with no or minimal sample prep required. All that is needed is for the sample to be appropriately positioned in the instrument. It is also possible to sample directly through glass or blister packaging because they exhibit only a few weak Raman spectra. It is even possible to sample in or through aqueous media as well.

Why are laboratory Raman systems advantageous?

Sudhir Dahal:

While handheld and portable Raman systems offer portability and simplicity, laboratory Raman instruments have unique advantages.

They offer research-grade data and flexibility. For example, our ability to measure using various laser exciters and sources is needed when high spectral or high spatial resolution is needed. Laboratory Raman systems provide these flexibilities.

For example, parameters such as laser power exposure time and exposure area in laboratory Raman instruments can be altered according to sample form, shapes and sizes. In addition, various accessories can be used for automation. Extensive data analysis, chemometrics, and the flexibility to create and expand spectral libraries are some of the key features provided by laboratory systems.

Raman is complementary to infrared (IR), another technique widely used in raw material identification and analysis in the pharmaceutical industry. The information which cannot be obtained by IR spectroscopy can often be obtained with Raman and vice versa.

For example, FTIR could indicate the function group in a polymer and the Raman spectrum can identify the backbone structure. Both techniques can be performed quickly and efficiently. Laboratory systems and data analytics can be used together to obtain extremely valuable sample information rapidly.

Laboratory environment systems are also used to measure, sample, institute and process measurements. The environmentally controlled cells are designed to control temperature, pressure, flow and other appropriate sample conditions to help understand reaction processes.

Finally, with laboratory Raman microscopes, areas of samples as small as one micron can be measured. This provides risk information from sample surfaces with high spatial resolution. The confocal microscope systems can measure within the sample or carry out depth profiling without slicing the sample.

Can you give us an example of analysis using a laboratory Raman system?

Sudhir Dahal:

Raman analysis of samples can be done through a container. Measuring samples through a container provides a considerable advantage, such as not needing to open the packaging of hazardous substances and carrying out general quick and accurate analysis.

In one particular example, we used our DXR3 Raman spectral leader, the Thermo Scientific SmartRaman equipped with a fiber optic probe operating with a 785-nanometer wavelength excitation laser. Spectra were obtained for the contents, the container, the combination, and the contents spectrum with the container spectrum subtracted. Spectra were then compared to a library.

Raman systems are effective for this type of measurement, providing the flexibility to adjust power and select the appropriate excitation laser wavelength to help measure the container according to the thickness and type of container material.

Data resolution is also beneficial when trying to subtract one spectrum from another. All those parameters can be altered with laboratory systems.

Sometimes, a single point-and-suit analysis may not be enough. A given powder or solid sample may be homogeneous and the homogeneity may or may not be visible to our eye. So measuring at one point versus another could give very different results.

A Raman microscope is a powerful tool for general measurement of many points in a given area. Raman microscopes can carry out single point, point and shoot measurements collected from one point, usually no more than a few microns in diameter on both sides.

They can also carry out multi-point analyses. A typical example would be grain, particulate matter, or microplastics spread in a given sample. The software would identify those particles and direct the microscope to measure only at those points.

What is depth profiling using a Raman microscope?

Sudhir Dahal:

Sometimes analysis involves measuring the sample at different depths, rather than just the sample's surface. We had an example of a sample of polymer coating on a metal foil. This could be used for making wraps and packaging. We obtained SEM and Raman spectral data from the polymer-coated metal foil. SEM was not very revealing.

However, we could identify several layers and their thickness with the Raman microscope. Going from the outward layer of the metal foil, we had lower-density polyethylene nylon, another layer of low-density polyethylene and then polyethylene terephthalate, in this order.

Another big advantage of Raman spectroscopy that was apparent in this example is that no sample preparation is required as a confocal microscope can measure beneath the layers without having to slice the sample.

Please can you introduce the TruScan RM Handheld Raman Analyzer and tell us when it can be useful?

Eden Couillard:

Quality control testing is required on raw materials coming in for use in the manufacturing of pharmaceuticals. A technician has to quarantine the material, take a sample, and run various wet chemistry tests on the sample before getting a result.

Once passing, the material can be released for use. TruScan RM was designed to put the scientists in the box and produce quick and accurate results in the field within seconds. This leads to a more efficient process.

Each lot of components, drug product containers, and enclosures are withheld from use until the lot has been sampled, tested or examined as appropriate and released for use by the quality control unit. Federal regulations, such as 21 CFR, state that raw material ID is required.

The TruScan RM is 21 CFR part 11 compliant. It includes different levels of user access: an audit log, reports for all scans, and all the required documentation.

What are the advantages of using a handheld Raman?

Eden Couillard:

With the TruScan RM, you not only get the advantages of a Raman spectrometer in your hands, such as non-destructive testing and the ability to go through containers such as plastic bags, bottles and glass bottles, but you also get what we call the scientist in a box.

A non-Raman expert can easily use this product and get an answer. You get a readout, which we call a P-value, and if your readout is above the threshold, you will get a pass. If it is below, you get a fail.

Method transferability is highly important. If a company wants more than one analyzer, you can easily transfer methods from one device to the other with high confidence, and then you have an entire fleet utilizing the same methods.

What does the manufacturing workflow look like and where can the TruScan RM be implemented?

Eden Couillard:

TruScan RM is used in several places throughout the manufacturing process. However, arrival and prep are critical steps for raw material ID. Using the TruScan RM when materials arrive and are quarantined means they can be sampled and then run in vials with the vial holder attachment or processed directly through the container if applicable.

To walk you through running a TruScan RM method, I want to describe the key steps. A user will create methods for the material they receive that are Raman active, such as cyclo hexane, by collecting reference spectra of known good samples.

Once your methods are created, you select a method to run. The analyzer takes a sample spectrum and compares it to the reference spectrum. Then utilizing the embedded algorithm, what we also call the scientist in the box, a user will get a pass or a fail for an answer.

They can repeat the sample if they want to or move on to the next one. All this is tracked in an audit. There is the option to run what we call a true tools method, which utilizes offline chemometrics to optimize methods further.

Overall, the handheld Raman is smart, rapid and accessible. Smart by driving toward quality and automating time-sensitive tasks. Rapidly, by quickly giving an answer to the user and cutting out several steps from the quarantine to validation of a sample. It is accessible by enabling non-experts to use the technology.

What are the fundamentals of NIR infrared spectroscopy?

Mike Garry:

The NIR infrared region lies between the mid-infrared and the visible light regions. The wavelengths are shorter and more energetic than mid-infrared, but the interaction with molecular bonds is similar. Mid-infrared is absorbed by the molecular bonds at the natural vibrational frequencies of many chemical materials.

These are called primary or fundamental regions. NIR light is absorbed in the overtones of these primary frequencies, with the absorption strength lowering as you move to the first, the second and the third overtones. There is also a region where we see combination bands of the mid-infrared spectrum.

How is NIR useful for deriving analytical information for materials being used or produced by pharmaceutical manufacturers?

Mike Garry:

First, the selectivity is low since the overtone bands tend to be broad, giving the mid-infrared material identification advantage. However, this disadvantage is offset by the lower NIR absorption, meaning the light penetrates deeper into the sample, making it a better tool for analyzing bulk material properties.

Another advantage of the higher energy light is the ability to analyze samples through plastic containers and using long fiber optic cable runs.

Fourier Transform NIR (FT-NIR), instead of dispersing, has certain advantages due to the nature of the optical system and the instrument's design. A key feature is that we can analyze powders and liquids directly with no sample prep. This eliminates solvents and hazardous chemicals in sample prep.

You can sample through glass which provides non-destructive sample analysis, eliminates sample preparation, and allows you to run samples without exposing them to air, which can be an advantage for certain materials. It has a higher resolution than dispersal-filtered systems, giving it better specificity for many active pharmaceutical and other ingredients.

It has a simple, reproducible analysis that leads to reduced operator variability. It has faster analysis than many techniques so you can get results quicker and achieve more throughout. Further, you can do remote sampling via fiber optics to provide more flexible sampling access and analysis online in the production plant.

NIR applied to pharmaceutical analysis mostly focuses on small molecules, although work is done in the bio area. Applications include raw material identification, tablet content uniformity and coating analysis, lyophilized material moisture analysis, online process monitoring of fluid beds or powder flows, hot melt extrusion for blending consistency, and fermentation and cell culture monitoring.

NIR has been used in raw material analysis in this area for quite a long time. There is a problem in the critical workflow, which is that incoming materials need to be identified. This can lead to bottlenecks created in the laboratory as they can end up with a backlog of materials.

Material confirmation outside of the lab by non-scientists can speed up that process. NIR can help quickly identify materials without sample prep, reducing quarantine time and improving productivity.

You need to build a library of materials that needs to be validated through testing to ensure that you have no false positives or negatives. That is very important to the process, and that needs to be submitted to the Food and Drug Administration (FDA) or other regulatory agencies to ensure that you have done the proper work in getting your methods set up.

How does NIR compare to other techniques for looking at raw material ID?

Mike Garry:

NIR is a good technique for you if you do more than just raw material ID, like moisture content or other quantitative analysis. If you have existing methods and libraries already validated using your infrared, then it makes sense to stay with infrared.

Suppose you want to verify other physical properties, such as particle size. In that case, NIR is very sensitive to these changes, and these can be important parameters when you are judging the quality of incoming material, or if you have heterogeneous samples. The deeper penetration depth and high energy input to the sample can be an advantage over some other techniques, which are much more surface oriented.

Finally, it can save you time and money and provide a good return on your investment.

About the interviewees

Thermo Fisher Materials and Structural Analysis products give you outstanding capabilities in materials science research and development. Driving innovation and productivity, our portfolio of scientific instruments enable the design, characterization and lab-to-production scale of materials used throughout industry.

X-ray fluorescence spectrometers, FTIR spectrometers and X-ray photoelectron spectrometers enable researchers and material analysts to probe the chemical composition of materials ranging from ultra thin-films to bulk powders used in product development and materials troubleshooting. We offer a line of rheometry and viscometry instruments, as well as single- and twin-screw extruders, for laboratory benches that enable you to measure the physical property of semi-solids and liquids for shear flow and yield stress.

No other company offers the breadth of products and the depth of analytical capabilities for materials science and engineering.

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