Quality-by-Design II: Application of Quantitative Risk Analysis to the Formulation of Ciprofloxacin Tablets

Abstract

Abstract. Qualitative risk assessment methods are often used as the first step to determining design space boundaries; however, quantitative assessments of risk with respect to the design space, i.e., calculating the probability of failure for a given severity, are needed to fully characterize design space boundaries. Quantitative risk assessment methods in design and operational spaces are a significant aid to evaluating proposed design space boundaries. The goal of this paper is to demonstrate a relatively simple strategy for design space definition using a simplified Bayesian Monte Carlo simulation. This paper builds on a previous paper that used failure mode and effects analysis (FMEA) qualitative risk assessment and Plackett-Burman design of experiments to identity the critical quality attributes. The results show that the sequential use of qualitative and quantitative risk assessments can focus the design of experiments on a reduced set of critical material and process parameters that determine a robust design space under conditions of limited laboratory experimentation. This approach provides a strategy by which the degree of risk associated with each known parameter can be calculated and allocates resources in a manner that manages risk to an acceptable level.

Quality-by-Design III: Application of Near-Infrared Spectroscopy to Monitor Roller Compaction In-process and Product Quality Attributes of Immediate Release Tablets

“…This behavior can be explained by differences in the particle size and surface area of monohydrate (10.6 μm) and dihydrate forms (14.3 μm) as reported by Okoye et al (24). Batches 1, 12, 3, and 13 from site 1 (Table II) and 15,19,20, and 22 from site 2 have the same formulation composition and were processed under same RP conditions. This data clearly indicates that the granules size obtained at two manufacturing sites were statistically different; this occurred despites our best efforts to keep the experimental conditions the same at both sites.…”

“…In this study, spectral region 1,600-1,700 nm was selected to construct PLS blend uniformity model, where the CIP spectrum predominates and where there are minimal overlapping spectral peaks from the excipients. The raw NIR spectra of the granules obtained at different RPs (20,80, and 140 bar) were overlaid Fig. 10.…”

“…Prior to the calibration model development, PCA was performed on the samples. A total of 54 tablets was selected from nine different lots (batches 1-3, Table II) processed at different RC pressures (20,80, and 140 bars) and compressed at three different compression force (8, 12, and 16 kN). The 3D PCA score plot results (Fig.…”

“…Steps 1 and 2 were studied in the first manuscript (10). Next, the authors examined the use of quantitative risk models to assess the risk and define the design space (20). The objective of this paper is to study critical factors identified from our earlier studies in more detail to gain better process understanding and use NIR spectroscopy coupled with multivariate chemometric models (principal component analysis (PCA) and partial least squares (PLS)) to monitor the product quality attributes that were identified from our earlier studies in order to establish process control strategy.…”

“…Two binder types, hydroxypropyl cellulose (Klucel® EXF and Nisso®-L) and two lubricant types, magnesium stearate (MgSt-M and MgSt-D) are the formulation variables evaluated. Three RPs (20,80, and 140 bar) and three compression force (8,12, and 16 kN) were studied as processing parameters. In addition, binder and disintegrant levels were evaluated leading to total of 42 different lots.…”