Darren Andrews, business development director, Cobalt Light Systems, outlines the way that Transmission Raman spectroscopy is replacing HPLC and more in QC laboratories
How Transmission Raman works
Transmission Raman spectroscopy (TRS) has been used for over five years as an alternative to HPLC for API dose quantification and as a means to determine residual crystallinity quickly in intact tablets. It has earned its place in QC laboratories with well-matched analytical characteristics and by demonstrating cost-reductions of 75% for the more expensive end product tests. Using TRS, content uniformity and assay tests can be completed in minutes with no sample preparation or consumables used. TRS has gained regulatory approval for several products, replacing content uniformity (CU), assay and ID as the release method. As real-time release testing increases in interest by pharmaceutical companies and regulators TRS is beneficial because of its short analysis time – up to 10 tablets per minute.
Tablets and capsules are manufactured in hundreds of thousands per batch in campaigns that produce millions of dosages in total. The mandatory tests of uniformity of dosage units (UDU), assay and ID, are used to ensure that the patient receives the correct active ingredient at the right potency. Content uniformity testing is the most common method for UDU, traditionally using HPLC, which has become the industry standard method. HPLC is slow and resource-intensive and, as anyone who has visited a QC laboratory will know, manufacturing sites need tens of instruments and many people to service the numbers of batches produced by a typical plant. UPLC systems can reduce the run time of individual measurements but the cost and time is still dominated by the manual steps needed to prepare the tens of solute samples from each batch.
TRS is not an absorption technique, unlike near-infrared spectroscopy, but relies on the weakly interacting Raman scattering process. This means that TRS can measure through coated or uncoated tablets up to 10mm thick and also coloured gel capsules. The scattering process weakly interacts with the physical properties and is insensitive to moisture, which makes application development easier and measurements less prone to manufacturing variance. Because Raman spectra have sharp features, much like a mid-infrared spectrum, the data is easy to interpret and formulation problems can be easily diagnosed. Typically, Raman signals are greatest for the active ingredients compared with the excipients, which means that a low limit of quantification (<1%) is often possible.
A TRS100 transmission Raman instrument in use
Due to the ease of operation and fast measurement times with TRS the cost per test is reduced and, without a sample preparation step, the measurement error and reproducibility is significantly improved. For some products or for process validation, larger numbers of tablets might need to be tested. A single sample tray of a Cobalt Light Systems’ TRS100 can hold up to 200 tablets, which might take around 30 minutes to analyse – by comparison, HPLC would need at least four people and four HPLC instruments to complete the same number of measurements and would take around 30 hours to complete.
TRS is a non-invasive technique with no consumables and does not require extensive training to operate. This makes it ideal for use outside the QC laboratory. QC laboratories might analyse tablets three or four weeks after they are made, fitting it into other work they are doing, only then releasing batches to packaging and to sale. Putting a TRS instrument in a manufacturing area allows companies to do the most intensive tests with the highest failure risk (often CU and assay) during a batch run, allowing product to be released more efficiently and for companies to react more quickly to market needs. This kind of real-time release testing also enables an increase in quality; it is an interesting fact that the active ingredient content (by CU and assay) of a batch of 1 million tablets would normally be determined by testing as few as 20 of those tablets.
Implementing new technology in QC needs some internal development in QA and QC to create method submissions that can be approved by regulators. The view from US and European regulators is that the existing guidance on NIR submissions gives the appropriate starting advice for creating a TRS method. This is the usual route that has been taken to begin achieving regulatory approval for new methods, with relevant guidance appearing in USP1119, EP2.2.40 and EP2.2.48.
The growing interest in TRS and user-groups came together in a recent seminar in Oxford. Some of the talks, by leading industry experts, are available here https://www.cobaltlight.com/trs100seminar, including presentations about gaining regulatory acceptance for release test methods. Given the increase in production of pharmaceuticals and the drivers to reduce manufacturing costs with increases in testing, TRS has an important future in the pharmaceutical industry.