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« SPECTROSCOPY


samples. Spectral acquisition and modeling occur in the second phase, turning instrument signals into information. The third phase is the use of the calibration model to predict samples that come from the manufacturing process. This work process is captured in the FDA and EMA documents which state that submissions should clearly describe:


• a calibration model for creating the mathematical relationship between the changes in signal and the property of interest. This calibration model is the deliverable from the planning and modeling steps.


• a calibration test set for internal validation and optimization of the model. EMA defi nes internal validation as “the application of resampling statistics to cross-validate and provide an “internal check” of the performance of the model for the purposes of optimization”


• an independent validation for external validation of the model.


The main focus of this article is to examine the steps in the development of calibration models and discuss the challenges of obtaining inde- pendent validation samples. The FDA and EMA documents rightfully request independent validation samples; however, this “independence” requires further discussion.


Calibration Models


Calibration models require planning and a projection to the future. The calibration should contain all formulation components, include the expected concentration and be as similar as possible to the future samples that will be predicted.3,4,6


These tenets are well described in


the FDA and EMA documents. However, samples from the industrial process are usually available with only one drug concentration. Thus, one of the fi rst challenges in model development is to prepare calibration samples similar to the process but with an expanded drug concentration.4,7


The range in drug concentration has been expanded in several ways.4 This expansion may be performed by following diff erent experimental designs, permitting the calibration to encompass variations in excipient and active pharmaceutical ingredient (API) composition.8,9


The ex-


pansion may also be performed by taking granules or blends from the pharmaceutical process and spiking with API or excipients.7,10


The drug


concentration may also be varied in batches prepared within smaller production scale equipment.11,12


These approaches make it possible


to include the physical variation of the process within the calibration model and also expand the concentration range. Thus, the approach followed in developing calibration models capable of handling process variations should be explained within the regulatory submission.


Raman


Rxn2 Hybrid tm Dual Function Raman - Macro to Micro


Drug Products • Formulation Development • Raw Materials ID • Blending • Granulation • Drying • Tablets / Gelcaps • QA / QC


PAT / QbD Analyzer


On-Line or At-Line • API Low Dosage • Amorphous Content • Form Configuration • Coating Quality • Quantitation demonstrated to 0.05%


Drug Substance / API • API Development • In situ Reaction Monitoring • Reaction Pathway Understanding • Yield Optimization • Crystallization / Form Identification • Bioprocesses • Applicable to Water-Based Chemistries


COMPLIMENTARY


Register for Kaiser’s Customer Presented Raman Webinars, or View a Webinar Archive. Go to: www.kosi.com/webinars/


www.americanpharmaceuticalreview.com |


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