by Dean Stuart, Product Manager, Thermo Fisher Scientific
Raman spectroscopy is a common analytical technique used by researchers and manufacturers to verify the chemical composition of solid, liquid or gaseous materials. This rapid, non-destructive, accurate and versatile technology has been around for many years and is one of the most powerful and advantageous analytical tools available to ensure the quality of materials throughout the production process, from incoming raw materials to finished product. It continues to grow in popularity as advances in the field increase accessibility and remove the need for highly specialized equipment and expert technical knowledge.
A Mine of Information
In Raman spectroscopy, monochromatic laser light is directed at the sample to be analyzed and is absorbed, transmitted, reflected or scattered. Raman spectra are the result of light scattering. This can be either elastic – Rayleigh scatter – with the energy of the molecule unchanged after interaction with the photon, or inelastic Raman scattering, where the molecule absorbs some of the energy and the scattered photon loses energy. The inelastically scattered light is collected and interpreted by a detector, generating a Raman spectrum that is unique to each molecule. This “molecular fingerprint” enables both qualitative identification of a given substance and quantification of the amount of the analyte of interest present.1,2
Why Choose Raman Spectroscopy?
Increased regulatory scrutiny, the rise of global supply chains, and the drive toward lean manufacturing have all placed demands on pharmaceuticals and biotechnology to ensure the quality of materials from incoming raw materials through to finished product. Current Good Manufacturing Practices (cGMP) require that incoming raw materials and all in-process materials must be tested for identity, strength, quality, and purity throughout the manufacturing process. One way of achieving this is Raman spectroscopy, which can be used to identify and quantify unknown materials, understand molecular structure – such as crystallinity and polymorphism – and study spatial relationships between sample components, for example, failure/defect analysis and depth profiling. Raman spectroscopy can also be used to identify counterfeit pharmaceuticals, which pose a global health risk.
The fast, non-destructive nature of Raman makes it ideal for research, analytical and QA/QC activities in many sectors, including complex biopharmaceutical manufacturing processes, where it is suitable both for confirmation of the quality of incoming raw materials and continuous process monitoring.3 Samples can be measured in their native form – no preparation is required – and even in aqueous environments. Unlike other techniques where spectroscopic interference from water can overwhelm the signal from the analyte of interest, this interference becomes insignificant with Raman spectroscopy, allowing in situ measurements of wet materials such as biological tissues and cells. Samples can also be measured in transparent containers, since the technique uses lasers with wavelengths in the UV-visible region – 400-700 nm – which do not interfere with Raman readings taken through glass and quartz containers. This allows users to verify the identity of unopened packaged materials.4
Handheld Raman Analyzers – the Perfect Complement to Continuous Process Monitoring
Until recently, Raman spectroscopy demanded complex, bulky and expensive equipment, as well as a specialist technician to operate and maintain the instrument. There were also issues with reliability and cost. This changed with the introduction of compact, easy-to-use, reliable and affordable systems – such as the Thermo Scientific™ Ramina™ Process Analyzer – that are ideal for in-line, on-line, at-line and off-line continuous process monitoring. However, there are also other QC situations where fast and accurate verification of the identity of a material is required on the spot, most notably for incoming raw materials. This is where handheld Raman analyzers come into their own, perfectly complementing alternative systems used for process measurement.
Compact, lightweight, handheld Raman devices – such as the Thermo Scientific™ TruScan™ RM with TruTools – are now very accessible, enabling straightforward and effective field-based material identification and authentication for pharmaceuticals; simply walk up to a sample, scan it, read the results, and walk away. They can be used anywhere in a plant – including the loading dock, dispensing of materials during active pharmaceutical ingredient (API) manufacture, and final product inspection – allowing manufacturers to generate vital, actionable information for fast decision-making in critical situations, helping to sustain product quality and ensure regulatory compliance. Handheld devices enable raw materials to be identified on receipt in their packaging, avoiding the need to open the container, and reducing the risk of cross-contamination or exposure to the substance. At the same time, the raw material release time to production is improved as samples no longer have to be sent to a central laboratory for testing, enhancing efficiency and reducing costs.3
Away from the production environment, handheld Raman devices are employed to authenticate medicines by health agencies, and public sector and brand security teams. They can be used in the field anywhere that pharmaceuticals are distributed – no chemistry training is required – reducing the potential for backlogs and time delays often associated with lab testing. Medication can be authenticated directly through the packaging, to prevent falsified and substandard medicines from entering the supply chain, ensuring customer safety, and decreasing the health risk for patients. At the same time, it bolsters brand protection, avoiding costly violation of intellectual property rights for pharmaceutical manufacturers.3
Easing the Burden of Quality Control
Raman technology is ideal for pharmaceutical manufacturers, who are required to follow regional compliance regulations to verify the quality of their materials throughout the manufacturing process, verifying not only the identity of incoming raw materials, but also testing the identity, strength, quality, and purity of materials during all phases of production. One example of this is the Federal Food, Drug and Cosmetic Act (FD&C Act), implemented by 21 CFR (Code of Federal Regulation) 210 & 211, which requires conformity with cGMP. This specifies minimum requirements for the methods, facilities and controls used in manufacturing, processing, and packing of a drug product, to ensure that a product is safe for use, and meets the defined specifications. Manufacturers may also engage with schemes such as the Pharmaceutical Inspection Co-operation Scheme (PIC/S), Annex 8, a non-binding, informal co-operative arrangement between regulatory authorities involved in GMP of medicinal products for human or veterinary use that aims to standardize inspection procedures worldwide. In contrast to the traditional practice of composite sampling and testing of a statistical subset of a batch, individual samples are taken from all incoming containers and tested separately to verify their identity, to release the batch to manufacturing.3
Handheld Raman spectrometers have fundamentally changed how the pharmaceutical industry works to achieve compliance, enabling streamlining of QA/QC procedures. In a traditional workflow, samples are either sent to a centralized laboratory for analysis at each step of the manufacturing process – a costly, time-consuming process requiring a lot of sample handling and expert personnel – or process analytical technology (PAT) is employed. Today, handheld analyzers using state-of-the-art optics combined with multivariate residual analysis offer an effective chemometric solution for material identification, even in challenging environments and sampling conditions. Systems are available that are compliant with 21 CFR Part 11 and cGMP5 – with biometric login, complex password options and audit trail features – as well as the specifications for Raman spectroscopy incorporated in the United States and European Pharmacopeias.6 This straightforward “point-and-shoot” sampling technique can be used to analyze materials on demand on the warehouse floor, and at-line at any inspection point throughout the manufacturing process to increase inspection intervals, improve inventory management, and reduce global supply chain risk. Intuitive operator interfaces allow non-expert field technicians to literally go from barrel to barrel and bag to bag, testing on the spot to identify and quantify raw materials, intermediates, and finished products on site in seconds.
All Round Benefits
The continuous manufacturing revolution has driven a demand to find ways to reduce the burden of QC procedures, fueled by a need for real-time release testing to help prevent costly quality control failures and product recalls by identifying any issues sooner so that appropriate action can be taken earlier. Advances in technology have made Raman spectroscopy a key tool to help address these inherent challenges.6 The ability to complement at-line and in-line PAT with handheld analyzers used at the point of need could, in the future, remove the need for a dedicated quality control lab. This, in turn, would increase the capacity of the lab by freeing up instruments for alternative analyses and time for experienced scientists to undertake other tasks.
References
- Spectroscopy Academy – Raman. Thermo Fisher Scientific. https://www.thermofisher.com/uk/en/home/industrial/spectroscopy-elemental-isotope-analysis/spectroscopy-elemental-isotope-analysis-learning-center/molecular-spectroscopy-information/raman-technology.html. Accessed 20.10.22.
- D. Stuart. Raman process monitoring – more options with fewer barriers. Processing Magazine. In press.
- Thermo Fisher Scientific. What You Need to Know About Field-Based Material Identification and Authentication for Pharmaceuticals. http://assets.thermofisher.com/TFS-Assets/CAD/Scientific-Resources/pharma-raman-nir-ebook.pdf. Accessed 20.10.22.
- Thermo Fisher Scientific. 6 Reasons to Adopt Raman Spectroscopy. https://assets.thermofisher.com/TFS-Assets/MSD/Flyers/6-reasons-adopt-raman-spectroscopy-FL52343.pdf. Accessed 20.10.22.
- Thermo Fisher Scientific. Handheld Raman analyzer for material identification. http://assets.thermofisher.com/TFS-Assets/CAD/Specification-Sheets/TS-RM-SpecSheet-2016-Final.pdf. Accessed 20.10.22.
- A. Silge, K. Weber, D. Cialla-May, L. Müller-Bötticher, D. Fischer, J. Popp. Trends in pharmaceutical analysis and quality control by modern Raman spectroscopic techniques. Trends in Analytical Chemistry, 153 (2022) 116623. https://doi.org/10.1016/j.trac.2022.116623. Accessed 20.10.22.
About the Author: Dean is a Product Manager for Thermo Fisher Scientific passionate about the advancement of scientific instrumentation. Throughout his career, Dean has shown a special interest in sustainable quality improvements for the pharmaceutical industry. His prior roles include a quality control scientist and an analytical methods developer. Dean currently specializes in the development of portable Raman, Near Infrared Spectroscopy (NIR), and X-ray Fluorescence (XRF) technologies.