Adequacy and verifiability of pharmaceutical mixtures and dose units by variographic analysis (Theory of Sampling) – A call for a regulatory paradigm shift

Abstract

In spite of intense efforts in the last 20 years, the current state of affairs regarding evaluation of adequacy of pharmaceutical mixing is at an impressive standstill, characterized by two draft guidances, one withdrawn, and the other never approved. We here analyze the regulatory, scientific and technological situation and suggest a radical, but logical approach calling for a paradigm shift regarding sampling of pharmaceutical blends. In synergy with QbD/PAT efforts, blend uniformity testing should only be performed with properly designed sampling that can guarantee representativity-in contrast to the current deficient thief sampling. This is necessary for suitable in-process specifications and dosage units meeting desired specifications. The present exposé shows how process sampling based on the Theory of Sampling (TOS) constitutes a new asset for regulatory compliance, providing procedures that suppress hitherto adverse sampling errors. We identify that the optimal sampling location is after emptying the blender, guaranteeing complete characterisation of the residual heterogeneity. TOS includes variographic analysis that decomposes the effective total sampling and analysis error (TSE+TAE) from the variability of the manufacturing process itself. This approach provides reliable in-process characterization allowing independent approval or rejection by the Quality Control unit. The science-based sampling principles presented here will facilitate full control of blending processes, including whether post-blending segregation influences the material stream that reaches the tabletting feed-frame.

Variographic Assessment of Total Process Measurement System Performance for a Complete Ore-to-Shipping Value Chain

“…Several publications exemplify and advocate the use of variographic characterization for evaluation and improvement of process measurement systems for a large variety of processes e.g., [7][8][9][10][11][12][13][14]. Variographic characterization is effective for evaluation of (i) measurement system performance [9], (ii) comparison between different measurement systems [15] and (iii) detection of adverse process variations [16,17].…”

Analyzing the Mixing Dynamics of an Industrial Batch Bin Blender via Discrete Element Modeling Method

“…Thief sampling interrupts the process and is invasive. It has also been shown to be unreliable [9]. Since the scale of the blender is large (800 liters), obtaining data about the bulk would also be challenging.…”

Evaluation of Analytical and Sampling Errors in the Prediction of the Active Pharmaceutical Ingredient Concentration in Blends From a Continuous Manufacturing Process

“…These terms come from the field of geostatistics and the theory of sampling where variographic analysis was developed [4]. The MPE is an estimate of the TSE and the total analytical error [38]. The MPE is calculated by extrapolating V(j) to intercept the Y-axis, to estimate Blag 0^as shown in the inserts in Figs.…”

“…The Bcorrected sill,^directly related to the residual heterogeneity of the blend, was calculated by subtracting the MPE from the sill for both the individual and the MB predictions (Table 8) [38,50]. Results showed a low and flat sill demonstrating that the variograms are showing a blend in the final state of mixing [38]. Thus, the variogram makes it possible to discern between the process variation and the sampling and analytical errors.…”

“…One of the advantages of using variograms is that all abnormalities in the process (e.g., changes in sampling error, trends, periodicities) will be reflected on the plotted variograms [4]. Therefore, variograms can be used to improve the sampling process in continuous manufacturing [38].…”