Multiple measurements per sample can also be obtained. Measurement times per sample are generally < 1 min. Typically transmission Raman spectra of small white tablets require a ~20 second measurement.
Calibration spectra are then used in the model building (See section 4.) 3. Validation
Validation samples are essential for testing the calibration. Validation samples are independent from the calibration. Validation samples can be a mix of laboratory made and production material. Validation samples should adequately test the calibration design for it’s given application and be representative of the process that is intending to be measured.
These samples will be analysed as a confi rmatory test to ensure that the model works.
A typical validation sample set would be 10 to 20 separate batches and at least 10 samples per batch.
4. Reference measurements & model building.
Once all the calibration and validation Raman spectra have been acquired, reference measurements of the samples are then acquired using the primary technique. The primary analytical method is almost always HPLC (High Performance Liquid Chromatography), but it could be another technique e.g., UV. The reference values are used as the ‘true’ values of the sample. This removes any ambiguity over sample preparation and tablet to tablet variability.
A chemometric model is used to translate a Raman spectrum into a ‘prediction’ or result. In this workfl ow the result is a prediction of the reference technique, which as mentioned earlier, is typically the HPLC’s result of that sample.
Industry guidance for chemometrics is thoroughly described in USP <1039> Chemometrics [6].
For quantitative TRS applications Partial Least squares (PLS) is the most common quantitative multivariate model used. As part of the implementation spectral preprocessing is performed to exemplify spectral variation due to the API and minimise spectral contributions from irrelevant parameters. Pre-processing is often a baselining followed by a normalisation and then mean centring. Spectral regions are also refi ned. The model building process is an iterative process and varies on an application basis.
As part of the model building process, the Raman prediction of the validation samples are compared to the HPLC reference values and an uncertainty is ascertained, as well as suitability of the spectroscopic method. The acceptance criteria of a given model can be application specifi c depending on the requirements and if often multi-faceted. In general, a 2% - 5% error of the Raman prediction compared to HPLC is often used.
An example of incorporating the ‘true’ values into the chemometric model is shown in Figure 2. The fi gure on the left is the gravimetric model and assumed the values of each of the individual datapoints (individual tablet) are the same as the bulk of the material it was prepared from. The model on the right is the Raman PLS model which incorporates HPLC values, where the HPLC values give a ‘true’ value for each tablet. In this scenario incorporating the true HPLC values into the model improves its performance.
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Figure 2. Example of chemometric model development when HPLC reference values are incorporated. The HPLC model is improved with higher R2 and lower RMSECV.
5. Implementation
Once confi dence in the analytical method is achieved through rigorous feasibility testing, method development, verifi cation and validation, the technique in question can be implemented. The regulatory requirements will differ depending on application e.g., an in-process check will differ from a CU batch release test. Methods can be used and approved via internal pharmaceutical quality systems (PQS) or by external regulatory authorities as required.
6. Model maintenance
For any analytical method it is necessary to check it is working at set intervals; the same is true for multivariate spectroscopic techniques. Methods should be verifi ed routinely, at time intervals deemed fi t following a risk-based approach and checked according to the primary method. Models can be adapted and changed as the process changes and the change management can be via the PQS or external authorities.
References 1. USP Chapter <905> Content Uniformity Dosage Units 2. D. Andrews, K. Geentjens, B. Igne, et. al. J. Pharm. Innov. 13, 121–132 (2018). 3. J. Villaumié, D. Andrews, K. Geentjens, et. al. J. Pharm. Innov. 14, 245 – 258 (2019).
4. US Food and Drug Administration. Guidance Document; Development and Submission of Near Infrared Analytical Procedures Guidance for Industry. (FDA, Rockville, MD, 2021) FDA-2015-D-0868.
5. Römer, M. 4.5 Transmission Raman Spectroscopy - Implementation in Pharmaceutical Quality Control. In Solid State Development and Processing of Pharmaceutical Molecules, M. Gruss (Ed.). (2021). 6. USP Chapter <1039> Chemometric.
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