Active content determination of pharmaceutical tablets using near infrared spectroscopy as Process Analytical Technology tool
Graphical abstract
Introduction
The International Conference on Harmonization (ICH) has published several guidelines in order to help industries to enhance knowledge and understanding of their products and manufacturing processes. The ICH Q8 guideline on pharmaceutical development insists on the concept of Quality by Design (QbD) which is presented as a science- and risk-based approach for which the quality should not be tested into products but should be built in by design [1], [2].
Process Analytical Technology (PAT) is described by the Food and Drug Administration (FDA) as “a system for designing, analyzing, and controlling manufacturing through timely measurements (ie., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality” [3]. Consequently, this improvement of understanding and control of the manufacturing process gained by PAT implementation fits thoroughly with the QbD concept. Moreover, PAT enables real-time quality control by monitoring of Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs) during processing, leading to a reduction of end-product release testing [2].
Near infrared (NIR) spectroscopy is a vibrational spectroscopic technique covering a wavelength region from 14000 to 4000 cm−1. The absorption bands observed are due to overtones and combination of fundamental vibration of hydrogen bonds such as C–H, O–H, N–H and S–H leading to wide overlapping bands containing both physical and chemical information. Accordingly, mathematical pre-treatments and regression methods are used as main chemometric tools to extract the significant information [4], [5], [6].
NIR spectroscopy presents several advantages such as fast spectral acquisition, which allows to acquire real-time data from a manufacturing process without any sample preparation or alteration using optical fibers probes enabling in-line measurements [4]. In addition, it is also a cheap and a green analytical method since it does not use any solvent. Taking into account these advantages, NIR spectroscopy is a significant tool for the implementation of PAT and has already been described for various applications such as blend homogeneity, coating monitoring or moisture and active content determination [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19].
Validation is a mandatory step which must be performed in order to guarantee the laboratory and authorities accurate routine analyses in the future [20]. Based on β-expectation tolerance intervals, the accuracy profile enables a visual and reliable representation of the actual and future performances of the analytical method. Furthermore, it integrates all the useful required validation criteria such as accuracy, trueness, precision, limits of quantification and linearity [21], [22], [23], [24].
The aim of the present study was to develop a NIR method to determine the active content of non-coated pharmaceutical tablets manufactured from a proportional tablet formulation. This NIR method intends to be used for the monitoring of the active content of tablets during the tableting process. Firstly, methods were developed in transmission and reflection modes to quantify the API content of the lowest dosage form. Secondly, these methods were fully validated for an active content ranging from 70% to 130% of the usual active content. Then, the ability of the reflection mode to quantify the API content in the highest dosage strength was assessed. Furthermore, the ability of the method based on the transmission mode to monitor at-line the active content of tablets during the tableting process was tested in order to demonstrate that NIR method could advantageously support the current HPLC analysis to provide better insight of the API content during the process. Finally, the transfer of this method from a lab equipment (off-line) to a production one (on-line) was investigated.
Section snippets
Calibration samples
Pilot batches of non-coated pharmaceutical tablets were manufactured at UCB Pharma. The blending step was performed using a Turbula T2F mixer (WAB, Muttenz, Switzerland) and the tableting process was carried out with a single punch research press Styl’One Evolution (Medelpharm, Beynost, France) using a simulation profile corresponding to the production press. Two independent batches of the lowest dosage strength were manufactured for calibration purpose with an active content of 70%, 85%, 100%,
Calibration
Since the NIR methods intend to be used in routine, the calibration models have to include variability in order to guarantee the robustness of these methods. The included sources of variability are presented in Table 1. Two independent batches of the lowest dosage strength were manufactured with different batches of API and excipients. Various amounts of API were introduced to obtain five API levels such as 70%, 85%, 100%, 115% and 130% of the target API content, covering a large API
Conclusions
In this study, NIR methods based on the transmission and reflection modes were developed to quantify the API content in non-coated tablets. However, the model using the transmission mode showed a better ability to predict the right active content compared to the reflection one. Indeed, the NIR transmission model was thoroughly validated using the accuracy profile approach with acceptance limits set at ±10% over the active content range of 70–130% of the usual active content whereas the
Acknowledgments
Special thanks are due to members of the Method Development & Process Support department of UCB Pharma for their analytical support and to Anne-Françoise Perier and Christian Lesjours for their help during the manufacturing steps. Thanks are also due to Bruker Optics for the use of the Tandem device. A research grant from the Belgium National Fund for Scientific Research (FNRS) to Charlotte De Bleye is gratefully acknowledged. A financial support from the Walloon Region of Belgium is also
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