Fallout from the outbreak of COVID-19 continues to ripple across all sectors, and the photonics industry is no exception. But while the virus has raised challenges for many businesses, it has created opportunities for others. Unlike FTIR spectrometers, NIR instruments are capable of analyzing pharmaceuticals after the drugs are packaged in glass vials, blister packs, or plastic bags. Courtesy of iStock.com/Fahroni. Innovative treatments and vaccines to combat the virus are in huge demand, and the need for technical support for the testing of raw materials and final products is unprecedented. As a result, crucial analytical tools such as optical spectroscopy are well positioned to gain new ground. A recent report on MarketWatch valued the global pharmaceutical testing and analytical services market at around $3.5 billion in 2019 and predicts a growth rate of more than 11% between 2020 and 2027. The use of optical spectroscopy is critical at every stage of pharmaceutical manufacturing, from identifying and inspecting raw materials to development and formulation, where exact concentrations of ingredients are measured. More recently, spectroscopy has also begun to focus on the structural composition and distribution of pharmaceutical products. It has additional applications in quality control, where it helps to validate that both the manufacturing process and end products meet strict compliance and regulatory controls. Optical spectroscopy for the pharmaceutical market amounts to around 15% of total business for Ibsen Photonics. The main driver, according to Thomas Rasmussen, the company’s vice president of business development and sales and marketing, is the need to increase efficiency in the industrial chain, improve consistency of the final product, and reduce waste. An NIR fiber optic accessory connected to a Fourier transform infrared (FTIR) spectrometer enables the examination of samples through container walls. This feature can be used in pharmaceutical labs to protect technicians from exposure to drugs. Courtesy of Thermo Scientific. “Customers want to move to real-time and in-line monitoring and adjustments of their processes,” he said. “In general, optical spectroscopy, like near-infrared and Raman, can be used for in-line, real-time, and nondestructive monitoring of manufacturing processes. In contrast, many traditional methods require a sample to be taken to a laboratory for a time-consuming and destructive test.” Current optical technology allows for only a fraction of tablets to be analyzed in real time. This presents a challenge for pharmaceutical companies that strive for continuous manufacturing, which by definition calls for uninterrupted production. James Rydzak — who previously managed the process analytical technology groups at Colgate-Palmolive and GlaxoSmithKline and now heads his own consultancy firm, Specere Consulting — highlighted the competitive importance of faster analysis. “Continuous manufacturing is a developing way of manufacturing and has the benefit of reducing development time, time to market, [and] release of product, and it ultimately has a major impact on the cost of our pharmaceuticals,” he said. “Added sensitivity could be utilized to improve the speed of analysis, which is key to more complete analysis of some active pharmaceutical ingredients [APIs], which are extremely potent and must be dosed in lower quantities to avoid adverse reactions.” Optical spectroscopy can reveal the chemical composition of a sample, with near instantaneous noncontact measurements. What’s more, most spectroscopy methods are simple to combine with microscopic imaging to map chemical content in detail. These attributes bring irreplaceable value at every point in the pharma chain. “I don’t think it’s hyperbole to put a flag in the ground here and say that ‘quality by design’ would not be possible in pharma without optical spectroscopy,” said James Carriere, product line manager at Coherent Inc. “It really does underpin every stage of pharma from discovery through to final quality control.” There are a number of optical spectroscopy techniques, and each excels at various stages of manufacture. While some methods enjoy wide acceptance, such as near-infrared (NIR) and Fourier transform infrared (FTIR) absorption spectroscopy, broader adoption of newer techniques — such as terahertz Raman spectroscopy — could also benefit pharmaceutical production. Somewhere in between is Raman spectroscopy, which enjoys a strong foothold in the industry, but still confronts barriers to market. FTIR spectroscopy Among the most venerable optical spectroscopy technologies, FTIR spectrometers have been a regular feature in laboratories for materials analysis for over 70 years. Comprising an IR source, an interferometer, beamsplitter mirrors, a detector, and a computer, the FTIR spectrometer is mechanically simple, with only one moving part, and it provides reliable results at a reasonable cost. FTIR spectroscopy is so reliable, in fact, that it can identify virtually any molecule, and it is sensitive enough to detect even the smallest of contaminants. This makes it a common tool for pharmaceutical companies and often inspires an “if it’s not broken, don’t fix it” kind of loyalty. By interrogating an analyte with a broadband beam — typically spanning the wavelength range from 2.5 to 14 µm — and measuring how much of that beam the sample absorbs or transmits, a unique molecular fingerprint is created. Since no two molecular structures produce the same unique signal, FTIR can help to identify unknown materials, determine the quality or consistency of a sample, or quantify the ratio of components in a mixture. This makes it invaluable for quality control and assurance applications, whether for batch-to-batch comparison of quality standards or for analysis of an unknown contaminant. Mike Bradley, product manager at Thermo Fisher Scientific, has observed that FTIR spectroscopy is often cited as the definitive tool in pharmaceutical analysis. “For pharmaceutical companies, the primary focus is on the results. The specific tools used to achieve those are much less relevant,” he said. “If FTIR can provide an answer faster with the requisite sensitivity, then it will be implemented.” But there are drawbacks to FTIR technology. Its targeted sample cannot be packaged during analysis. Some sample contact is needed, which prolongs its exposure to environmental contaminants. Furthermore, FTIR is poorly positioned to distinguish differences in some compounds, such as those with polymorphic forms. This can be important because polymorphic form often dictates the efficacy and bioavailability of active ingredients in a pharmaceutical formulation. NIR spectroscopy Unlike FTIR spectrometers, NIR instruments deliver real-time data through the container wall, whether the container is a glass vial, a blister pack, or a plastic bag. This ensures no product is wasted before shipment. “NIR spectroscopy can be used to derive the quantitative concentration of many common organic compounds,” Rasmussen said. “The benefit of the method is that it can be used to provide real-time data without the need for destroying the sample.” The principal drawback is that NIR spectra can be quite complex, with many smooth and overlapping peaks. If several formulation components need quantification, then multivariate numerical methods, such as chemometrics, are required. This can add significantly to the time needed to build a complete analytical method. Recently, digital micromirror devices based on technology from Texas Instruments have enabled the development of compact, high-performance NIR spectrometers that cost less than traditional benchtop spectrometers. The devices consist of an array of hundreds of thousands or even millions of tiny micromirrors that, when inserted into the optical path within a spectrometer, permits selection of specific wavelength regions. These chosen wavelengths can then be measured by a single element detector. Turning columns of these mirrors on or off allows the use of a more cost-effective single-element detector versus a multi-element array, without sacrificing agility, speed, or mechanical stability during wavelength selection. While advancements in optical componentry continue to improve the cost and performance of NIR spectrometers, partnerships between instrument vendors and pharmaceutical customers can also benefit all involved. For example, adding NIR spectroscopy to blenders and extruders has recently been shown to deliver valuable new insights at critical points in pharmaceutical manufacture. Thermo Fisher Scientific’s Bradley explained that blending and extruding are critical for producing dosage materials, and NIR technology now plays a novel role in these processes. A battery-powered NIR unit can be attached to a window at the vertex of a V blender, for example. This simple addition of optical analysis helped to disclose that the number of turns required was far less than expected, potentially saving manufacturers considerable time and money. During extrusion, APIs and other ingredients can heat up, potentially affecting a pharmaceutical formulation’s efficacy. By positioning an NIR fiber probe at the outlet of the extruder, the material can be checked in-line as it emerges. Terahertz Raman spectroscopy While the use of FTIR and NIR spectroscopy is well established in pharmaceutical production, as well as in more fundamental drug development, the merits of Raman spectroscopy are yet to be fully exploited — particularly Raman systems that operate in the terahertz range. “Raman has long suffered due to a lack of familiarity and the complexity and expense of the instruments,” Bradley said. “This has changed in the past few years as simpler instruments at lower price points have become available and a massive amount of information is now available around applications and training.” Raman spectroscopy combines the capability of NIR instruments to examine a product through container walls with FTIR technology’s ability to provide highly detailed information about chemical composition. While Raman currently remains more expensive than its spectroscopic cousins, it is evolving in both its value and price points. The most apparent change has been the rapid evolution of hand-held Raman devices. FTIR, NIR, and Raman all offer hand-held options, which extends spectroscopy to the loading dock, where a simple go/no-go decision can be made about the quality of both raw and finished materials. Compared to other spectroscopic technologies, Raman tools have seen the biggest advancements — with new lasers, detectors, and miniaturized formats bringing new levels of specificity to incoming and outgoing materials, as well as quality assurance and quality control — at much faster rates than many entrenched methods, Bradley said. A recent report on MarketWatch valued the global pharmaceutical testing and analytical services market at around $3.5 billion in 2019 and predicts a growth rate of more than 11% between 2020 and 2027.Courtesy of iStock.com/MJ_Prototype. But Raman instruments offer one unique advantage over their brethren: the ability to easily distinguish polymorphs. Polymorphs are substances with the same basic molecular composition, but they differ in the way the molecules are packed within a crystal lattice. Different arrangements of the same molecules exhibit different dissolution characteristics in the gastrointestinal tract, which affects the drug’s bioavailability and hence efficacy. Traditional optical analysis methods, such as FTIR and NIR spectroscopy, that measure spectral peaks of submolecular bonds can have a hard time distinguishing between similar lattice structures. Consequently, methods such as powder x-ray diffraction or nuclear magnetic resonance, which both require complex instrumentation and preparation of samples, must supplement these methods. Terahertz-based Raman spectroscopy, which extends Raman analysis into the low-frequency terahertz domain, has shown itself to be highly effective at detecting low-energy intermolecular vibrations such as phonon modes and lattice vibrations in pharmaceutical samples. This means that it can identify even subtle differences in crystal forms. Extending Raman measurements into the terahertz range can determine both chemical composition and structure, which can help to predict a pharmaceutical’s dissolution rates in the human gastrointestinal tract and ensure that the drug’s potency matches the approved dosage from the FDA. Coherent’s Carriere emphasized that, unlike other methods, this approach comes with all the usual convenience and speed of optical spectroscopy. Optical spectroscopy is becoming critical to every stage of pharmaceutical manufacturing — from the inspection of raw materials to the development of medicinal formulations and the quality assurance of end products. Courtesy of iStock.com/gorodenkoff. “Terahertz Raman spectroscopy now provides structural information, including imaging where necessary, and in situ monitoring during processing,” he said. “Moreover, it can be performed with visible or NIR lasers, minimizing component and system costs and avoiding the technical pitfalls of direct terahertz measurements.” Despite clear advantages, displacing established but cumbersome techniques such as x-ray diffraction will not happen overnight. However, given the continuing demands on product discovery, quality, and safety, pharmaceutical companies are coming to recognize the need to observe, control, and analyze materials in all phases of product development. Rydzak would like to see the complementary natures of mid-IR, Raman, and NIR spectroscopy combined, which would require the coupling of hardware and software for a seamless data output. “I have seen various examples where the information content of Raman, which provides more information about the backbone structures and multiple bonds in a molecule, would enhance the knowledge of a reaction experiment by coupling it with the mid-IR data, which is rich in functional group information,” he said. Continuing education Two factors currently impede the pharmaceutical industry’s adoption of new spectroscopic developments — or, indeed, any new analytical technology. First, the industry’s practices and products face stringent evaluation, regulation, and certification. Drug efficacy and safety is the result of detailed and often laborious oversight that takes time and money. So, the path to introducing new technologies is not always a straightforward one. Second, it can be difficult to overcome the industry’s comfort level with existing “good enough” methods, even when a new technology offers clear advantages over such methods. According to Carriere, the solution to these challenges can be summed up in one word: education. Collaboration between spectroscopy providers and trade media is critical, he said, to educate the pharmaceutical industry about the value and utility of optical technologies and to prompt people to think in new ways about its potential. “Most potential users will not be actively searching for terahertz Raman spectroscopy,” Carriere said. “So, we can’t passively wait for traffic to come to our website. We have to be technology missionaries to actively target and engage relevant scientists and process engineers in appropriate forums.” Rydzak agrees that more education, broader publication of application examples, and discussions around the potential benefits of spectroscopy would foster a sense of its applicability to all synthesized products and help to grow the technology’s popularity.