A perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing.

The Quality-by-Design (QbD) guidance issued by the US Food and Drug Administration (FDA) has catalyzed the modernization of pharmaceutical manufacturing practices including the adoption of continuous manufacturing. Active process control was highlighted recently as a means to improve the QbD implementation. This advance has since been evolving into the concept of Quality-by-Control (QbC). In this study, the concept of QbC is discussed, including a definition of QbC, a review of the recent developments towards the QbC, and a perspective on the challenges of QbC implementation in continuous manufacturing. The QbC concept is demonstrated using a rotary tablet press, integrated into a pilot scale continuous direct compaction process. The results conclusively showed that active process control, based on product and process knowledge and advanced model-based techniques, including data reconciliation, model predictive control (MPC), and risk analysis, is indispensable to comprehensive QbC implementation, and ensures robustness and efficiency.

Resilience and risk analysis of fault-tolerant process control design in continuous pharmaceutical manufacturing.

The shift from batch to continuous manufacturing, which is occurring in the pharmaceutical manufacturing industry has implications on process safety and product quality. It is now understood that fault-tolerant process control of critical process parameters (CPPs) and critical quality attributes (CQAs) is of paramount importance to the realization of safe operations and quality products. In this study, a systematic framework for fault-tolerant process control system design, analysis, and evaluation of pharmaceutical continuous oral solid dosage manufacturing is proposed. The framework encompasses system identification, controller design and analysis (controllability, stability, resilience, etc.), hierarchical three-level control structures (model predictive control, state estimation, data reconciliation, etc.), risk mapping, assessment and planning (Risk MAP) strategies, and control performance evaluation. The key idea of the proposed framework is to identify the potential risks associated with the control system design itself, the material property variations, and other process uncertainties, under which the control strategies must be evaluated. The framework is applied to a continuous direct compaction process, specifically the feeding-blending subsystem, wherein the major source of variance in the process operation and product quality arises. It is demonstrated, using simulations and experimentally, that the process operation failures and product quality variations in the feeding-blending system can be mitigated and managed through the proposed systematic fault-tolerant process control system design and risk analysis framework.

GSDMD-dependent neutrophil extracellular traps promote macrophage-to-myofibroblast transition and renal fibrosis in obstructive nephropathy.

Renal fibrosis is a common consequence of various progressive nephropathies, including obstructive nephropathy, and ultimately leads to kidney failure. Infiltration of inflammatory cells is a prominent feature of renal injury after draining blockages from the kidney, and correlates closely with the development of renal fibrosis. However, the underlying molecular mechanism behind the promotion of renal fibrosis by inflammatory cells remains unclear. Herein, we showed that unilateral ureteral obstruction (UUO) induced Gasdermin D (GSDMD) activation in neutrophils, abundant neutrophil extracellular traps (NETs) formation and macrophage-to-myofibroblast transition (MMT) characterized by α-smooth muscle actin (α-SMA) expression in macrophages. Gsdmd deletion significantly reduced infiltration of inflammatory cells in the kidneys and inhibited NETs formation, MMT and thereby renal fibrosis. Chimera studies confirmed that Gsdmd deletion in bone marrow-derived cells, instead of renal parenchymal cells, provided protection against renal fibrosis. Further, specific deletion of Gsdmd in neutrophils instead of macrophages protected the kidney from undergoing fibrosis after UUO. Single-cell RNA sequencing identified robust crosstalk between neutrophils and macrophages. In vitro, GSDMD-dependent NETs triggered p65 translocation to the nucleus, which boosted the production of inflammatory cytokines and α-SMA expression in macrophages by activating TGF-ß1/Smad pathway. In addition, we demonstrated that caspase-11, that could cleave GSDMD, was required for NETs formation and renal fibrosis after UUO. Collectively, our findings demonstrate that caspase-11/GSDMD-dependent NETs promote renal fibrosis by facilitating inflammation and MMT, therefore highlighting the role and mechanisms of NETs in renal fibrosis.

Design of condition-based maintenance framework for process operations management in pharmaceutical continuous manufacturing.

Continuous manufacturing, an emerging technology in the pharmaceutical industry, has the potential to increase the efficiency, and agility of pharmaceutical manufacturing processes. To realize these potential benefits of continuous operations, effectively managing materials, equipment, analyzers, and data is vital. Developments for continuous pharmaceutical manufacturing have led to novel technologies and methods for processing material, designing and configuring individual equipment and process analyzers, as well as implementing strategies for active process control. However, limited work has been reported on managing abnormal conditions during operations to prevent unplanned deviations and downtime and sustain system capabilities. Moreover, although the sourcing, analysis, and management of real-time data have received growing attention, limited discussion exists on the continued verification of the infrastructure for ensuring reliable operations. Hence, this work introduces condition-based maintenance (CBM) as a general strategy for continually verifying and sustaining advanced pharmaceutical manufacturing systems, with a focus on the continuous manufacture of oral solid drug products (OSD-CM). Frameworks, such as CBM, benefit unified efforts towards continued verification and operational excellence by leveraging process knowledge and the availability of real-time data. A vital implementation consideration for manufacturing operations management applications, such as CBM, is a systems architecture and an enabling infrastructure. This work outlines the systems architecture design for CBM in OSD-CM and highlights sample fault scenarios involving equipment and process analyzers. For illustrative purposes, this work also describes the infrastructure implemented on an OSD-CM testbed, which uses commercially available automation systems and leverages enterprise architecture standards. With the increasing digitalization of manufacturing operations in the pharmaceutical industry, proactively using process data towards modernizing maintenance practices is relevant to a single unit operation as well as to a series of physically integrated unit operations.

A Quality-by-Control Approach in Pharmaceutical Continuous Manufacturing of Oral Solid Dosage via Direct Compaction.

The pharmaceutical industry has been undergoing a paradigm shift towards continuous manufacturing, under which novel approaches to real-time product quality assurance have been investigated. A new perspective, entitled Quality-by-Control (QbC), has recently been proposed as an important extension and complementary approach to enable comprehensive Quality-by-Design (QbD) implementation. In this study, a QbC approach was demonstrated for a commercial scale tablet press in a continuous direct compaction process. First, the necessary understanding of the compressibility of a model formulation was obtained under QbD guidance using a pilot scale tablet press, Natoli BLP-16. Second, a data reconciliation strategy was used to reconcile the tablet weight measurement based on this understanding on a commercial scale tablet press, Natoli NP-400. Parameter estimation to monitor and update the material property variance was also considered. Third, a hierarchical three-level control strategy, which addressed the fast process dynamics of the commercial scale tablet press was designed. The strategy consisted of the Level 0 built-in machine control, Level 1 decoupled Proportional Integral Derivative (PID) control loops for tablet weight, pre-compression force, main compression force, and production rate control, and Level 2 data reconciliation of sensor measurements. The effective and reliable performance, which could be demonstrated on the rotary tablet press, confirmed that a QbC approach, based on product and process knowledge and advanced model-based techniques, can ensure robustness and efficiency in pharmaceutical continuous manufacturing.

Sensor Network Robustness Using Model-Based Data Reconciliation for Continuous Tablet Manufacturing.

Advances in continuous manufacturing in the pharmaceutical industry necessitate reliable process monitoring systems that are capable of handling measurement errors inherent in all sensor technologies and detecting measurement outliers to ensure operational reliability. The purpose of this work was to demonstrate data reconciliation (DR) and gross error detection methods as real-time process management tools to accomplish robust process monitoring. DR mitigates the effects of random measurement errors, while gross error detection identifies nonrandom sensor malfunctions. DR is an established methodology in other industries (i.e., oil and gas) and was recently investigated for use in drug product continuous manufacturing. This work demonstrates the development and implementation of model-based steady-state data reconciliation on 2 different end-to-end continuous tableting lines: direct compression and dry granulation. These tableting lines involve different equipment and sensor configurations, with sensor network redundancy achieved using equipment-embedded sensors and in-line process analytical technology tools for the critical process parameters and critical quality attributes. The nonlinearity of the process poses additional challenges to solve the steady-state data reconciliation optimization problem in real time. At-line and off-line measurements were used to validate the framework results.

Steady-State Data Reconciliation Framework for a Direct Continuous Tableting Line.

Purpose: Reliable process monitoring in real-time remains a challenge for the pharmaceutical industry. Dealing with random and gross errors in the process measurements in a systematic way is a potential solution. In this paper, we present a process model-based framework, which for given sensor network and measurement uncertainties will predict the most likely state of the process. Thus, real-time process decisions, whether for process control or exceptional events management, can be based on the most reliable estimate of the process state. Methods: Reliable process monitoring is achieved by using data reconciliation (DR) and gross error detection (GED) to mitigate the effects of random measurement errors and non-random sensor malfunctions. Steady-state data reconciliation (SSDR) is the simplest forms of DR but offers the benefits of short computational times. We also compare and contrast the model-based DR approach (SSDR-M) to the purely data-driven approach (SSDR-D) based on the use of principal component constructions. Results: We report the results of studies on a pilot plant-scale continuous direct compression-based tableting line at steady-state in two subsystems. If the process is linear or mildly nonlinear, SSDR-M and SSDR-D give comparable results for the variables estimation and GED. SSDR-M also complies with mass balances and estimate unmeasured variables. Conclusions: SSDR successfully estimates the true state of the process in presence of gross errors, as long as steady state is maintained and the redundancy requirement is met. Gross errors are also detected while using SSDR-M or SSDR-D. Process monitoring is more reliable while using the SSDR framework.

Data reconciliation in the Quality-by-Design (QbD) implementation of pharmaceutical continuous tablet manufacturing.

Data provided by in situ sensors is always affected by some level of impreciseness as well as uncertainty in the measurements due to process operation disturbance or material property variance. In-process data precision and reliability should be considered when implementing active product quality control and real-time process decision making in pharmaceutical continuous manufacturing. Data reconciliation is an important strategy to address such imperfections effectively, and to exploit the data redundancy and data correlation based on process understanding. In this study, a correlation between tablet weight and main compression force in a rotary tablet press was characterized by the classical Kawakita equation. A load cell, situated at the exit of the tablet press chute, was also designed to measure the tablet production rate as well as the tablet weight. A novel data reconciliation strategy was proposed to reconcile the tablet weight measurement subject to the correlation between tablet weight and main compression force, in such, the imperfect tablet weight measurement can be reconciled with the much more precise main compression force measurement. Special features of the Welsch robust estimator to reject the measurement gross errors and the Kawakita model parameter estimation to monitor the material property variance were also discussed. The proposed data reconciliation strategy was first evaluated with process control open-loop and closed-loop experimental data and then integrated into the process control system in a continuous tablet manufacturing line. Specifically, the real-time reconciled tablet weight measurements were independently verified with an at-line Sotax Auto Test 4 tablet weight measurements every five minutes. Promising and reliable performance of the reconciled tablet weight measurement was demonstrated in achieving process automation and quality control of tablet weight in pilot production runs.

Robust state estimation of feeding-blending systems in continuous pharmaceutical manufacturing.

State estimation is a fundamental part of monitoring, control, and real-time optimization in continuous pharmaceutical manufacturing. For nonlinear dynamic systems with hard constraints, moving horizon estimation (MHE) can estimate the current state by solving a well-defined optimization problem where process complexities are explicitly considered as constraints. Traditional MHE techniques assume random measurement noise governed by some normal distributions. However, state estimates can be unreliable if noise is not normally distributed or measurements are contaminated with gross or systematic errors. To improve the accuracy and robustness of state estimation, we incorporate robust estimators within the standard MHE skeleton, leading to an extended MHE framework. The proposed MHE approach is implemented on two pharmaceutical continuous feeding-blending system (FBS) configurations which include loss-in-weight (LIW) feeders and continuous blenders. Numerical results show that our MHE approach is robust to gross errors and can provide reliable state estimates when measurements are contaminated with outliers and drifts. Moreover, the efficient solution of the MHE realized in this work, suggests feasible application of on-line state estimation on more complex continuous pharmaceutical processes.

Variation and Risk Analysis in Tablet Press Control for Continuous Manufacturing of Solid Dosage via Direct Compaction.

A continuous rotary tablet press is a multi-stage process with many punch stations running in parallel, in which each punch undergoes the following steps: die filling and metering, pre-compaction, main-compaction, tablet ejection, and tablet take-off from lower punch. Process uncertainties or disturbances within a punch station or among stations in the tablet press are a major source of variation in final product quality attributes, e.g., hardness, weight, etc., which in turn imposes challenges for the real-time release in pharmaceutical continuous manufacturing of solid dosage. In this study, the direct compression line at Purdue University was investigated and a Natoli BLP-16 tablet press was used to characterize powder compressibility, system dynamics and variation, as well as the interaction effects on process control development. The compressibility of tablets made from a blend of Acetaminophen (API), Avicel Microcrystalline Cellulose PH-200 (excipient), and SiO2 (lubricant) was found to be largely independent of tableting speed. By contrast, filling depth or dosing level, turret speed, feed-frame speed, and compression force were interacting and significantly affected the die-filling process and the final product quality attributes. Thus, the design of the process control structure plays an important role in reducing process and product quality variations. A hierarchical three-level control design was proposed and evaluated, consisting of Level 0 Natoli built-in control, Level 1 decoupled Proportional Integral Derivative (PID) cascaded control loops for tablet weight and production rate control, and Level 2 advanced model predictive control. Process variations, e.g., in powder bulk density changes, during continuous steady-state operation were also investigated. Finally, a risk analysis of the effects of the process dynamics on variation on the product quality control was briefly discussed and summarized.