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

Abstract

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.

1. Introduction

The recent approval of four drug products using continuous manufacturing technologies, e.g., Orkambi (lumacaftor/ivacaftor) in 2015, Prezista (darunavir) in 2016, Verzenio (abemaciclib) and Symdeko (tezacaftor/ivacaftor) in 2018, by United States Food and Drug Administration (US FDA) is a strong evidence of the on-going paradigm shift from batch to continuous manufacturing in the pharmaceutical industry. The US FDA Quality-by-Design guidance has also been widely acknowledged in providing directions with respect to product and process knowledge development, such as identifying critical process parameters (CPPs) in process design and linking critical material attributes (CMAs) to critical quality attributes (CQAs) (Yu et al., 2014). Control strategies that include specification of the drug substance, excipients, and drug products as well as controls for each step of the manufacturing process are also considered as important elements of the QbD concept. In addition to designing quality into the product during the early stages of drug development, the quality attributes must also be automatically and consistently controlled, in the presence of process uncertainties and disturbances, during drug manufacturing (Lee et al., 2015). This recognition has led to a call for Quality-by-Control, particularly in continuous manufacturing, consistent with the current Industry 4.0 or smart manufacturing approaches. The proposed QbC idea consists of the design and operation of a robust manufacturing system that is achieved through an active process control system designed in accordance with hierarchical process automation principles, based on a high-degree of quantitative and predictive understanding of product and process.

Our previous work has investigated the characterization of the compressibility of a model formulation, consisting of Acetaminophen (API, 10.0%), Avicel Microcrystalline Cellulose PH-200 (excipient, 89.8%), and SiO₂ (lubricant, 0.2%), using a Natoli BLP-16 tablet press (Su et al., 2018). System dynamics and hierarchical process control development for a direct compression line were also undertaken for this pilot scale tablet press. In this study, we demonstrate the use of the proposed QbC approach in transferring the product and process understanding generated with the Natoli BLP-16 to the commercial scale, Natoli NP-400, tablet press. The rest of the manuscript will first discuss the QbC concept, followed by a brief introduction of the features of the tablet press in a continuous direct compression process. The advantages of a QbC approach in continuous tablet manufacturing will be presented in the result and discussion section. Concluding remarks and considerations for future work are given at the end of the manuscript.

2. Quality-by-Control

In traditional batch manufacturing quality attributes of products are tested at the end of each batch manufacturing step, following the so-called Quality-by-Testing (QbT) approach, as shown in Figure 1. Under the QbD guidance, systematic understanding of drug quality, including identification of CMAs and CPPs, is developed and monitoring is employed to assure that the quality attributes are met. The QbD approach is also very important to advancing the adoption of continuous manufacturing. However, assurance of quality in the continuous manufacturing mode in addition requires the use of QbC concepts to actively drive reduction in the variance of quality attributes, in the presence of process disturbances, raw material property variations, or uncertainties introduced as a result of scale up or technology transfer. The QbC approach builds on QbD by employing quantitative and predictive product and process knowledge in the form of models of appropriate fidelity, together with process analytical technology (PAT), to actively and robustly control the CQAs at the specified levels by adjusting CPPs, thus, achieving real-time quality assurance. The on-going trend towards Industry 4.0 or smart manufacturing also demands a high-level automation in process operation and quality control, which is fully consistent with the QbC approach.

Figure 1.

The systematic progression in quality assurance via QbT, QbD, and QbC.

3. Continuous tablet manufacturing

3.1. Continuous direct compaction

The continuous direct compression process under study consists of two Schenck AccuRate PureFeed^® AP-300 loss-in-weight feeders which continuously feed the API and excipient ingredients into a Gericke GCM-250 continuous blender. A Schenck AccuRate DP4 micro feeder adds the lubricant into the powder blend exiting the continuous blender, which is then conveyed directly to a rotary tablet press (Su et al., 2017). The tablet press is a multi-stage process, in which each station undergoes the recurring major steps of die filling, metering, pre-compression, main-compression, tablet ejection and take-off, as shown in Figure 2. The tablet weight can be controlled by changing the dosing position subject to the variation of powder bulk density or filling time due to change in turret speed and/or feeder rotation speed. A Natoli BLP-16 tablet press (16 stations with flat-head punches) was employed in our previous work to characterize the formulation compressbility while a commerical scale Natoli NP-400 (22 stations with concave-head punches) was used in the present work for continuous tablet manufacturing. The two tablet presses are also different in size and design of hopper and feed frame, which may result in differences in powder bulk density at the die table.

Figure 2.

Major steps in a Natoli rotary tablet press.

3.2. Formulation compressibility

The classical Kawakita model was employed to characterize the formulation compressibility in the Natoli BLP-16 tablet press (Su et al., 2018), as shown in Figure 3,

$$\frac{CF}{1-{\rho }_{\text{c}}/{\rho }_r}=\frac{CF}{a}+\frac{\pi D^2/4}{ab}$$ (1)

$${\rho }_r=\frac{4W_t}{\pi D^2{\rho }_{t}T}$$ (2)

Figure 3.

Compressibility characterization by a classical Kawakita model.

where CF is the main compression force, kN; ρ_c is the critical relative density, -, ρ_r the calculated in-die relative density from tablet weight W_t, and ρ_t the known a prior true density of the powder, g/cm³; parameters a and b (MPa) are interpreted as the maximum degree of compression and the reciprocal of the pressure applied to attain the maximum degree of compression, respectively; D is the diameter of the die (mm) and T (mm) is the minimum in-die tablet thickness pre-set by the main compression thickness for B tooling punches with flat cylindrical punch surfaces.

3.3. Hierarchical control system

A three-level hierarchical control system, shown in Figure 4, was developed based on the product and process understanding developed using the Natoli BLP-16 tablet press (Su et al., 2018) and was transferred to the NP-400 tablet press. The CQA and CPP measurement data were collected using an Emerson DeltaV DCS system to support the process control system design following the ISA 95 standard (Su et al., 2017). Specifically, the vendor built-in machine control at Level 0 manipulates the dosing position, pre-compression thickness, main compression thickness, and turret speed. At Level 1, the DCS system employs four PID controllers, controlling the tablet weight, pre-compression force, main compression force, and production rate by manipulating the above four Level 0 variables, respectively. A Level 2 data reconciliation module was implemented which serves to reconcile the tablet weight measured by an in-house adapted load cell with the main compression force measurement using the constraints imposed by the Kawakita model, Eqs. (1) and (2) (see Su et al., 2018). Specifically, the model parameter ρ_c was continuously re-estimated and updated during data reconciliation to account for variation in the powder bulk density due to material property changes (particle size, water content) or differences in equipment scale (hopper and feed frame, etc.) that also results in changes in powder bulk density at die table.

Figure 4.

A hierarchical three-level process control for direct compaction.

4. Results and discussion

With a QbC approach based on a quantitative model of compressibility, the Level 2 data reconciliation approach was able to reduce the uncertainty in real-time tablet weight measurement from the load cell for both tablet presses (see the reconciled measurement matched the at-line measurement of tablet weight), as shown in Figure 5. More importantly, the model parameter of critical density (which is related to powder bulk density) in the Kawakita equation (1), which was first estimated from BLP-16 runs, was readily updated from NP-400 tablet press real-time data. The shift in the critical density which was observed in the transfer from BLP-16 to NP-400 may be a result of changes in the bulk density at the die table due to different scale of hopper and different feed frame design. Assurance of model validity and parameter updating are the common concerns in most technology transfers and these results demonstrate that these concerns can be managed within a QbC approach. The high-level understanding of the process dynamics of the tablet press and resulting control structure design, such as the pairing of the control input and output variables, were readily transferable from the pilot to a larger scale press. Specifically, the control structure in which tablet weight was controlled by manipulating the dosing position and the production rate was controlled by adjusting turret speed (the feed frame stirrer speed also changes accordingly), resulted in effective control performance of both tablet presses. Both tablet presses could reach their tablet weight set points steadily. For instance, as shown in Figure 5, when the production rate was increased at 600 s from 3 kg/hr to 5 kg/hr after start-up of the NP-400 tablet press or reduced at 1000 s from 5 kg/hr to 4 kg/hr, the tablet weight was maintained at nearly constant levels.

Figure 5.

Control performance of Natoli BLP-16 and NP-400 tablet press.

5. Conclusions and future work

A Quality-by-Control approach was implemented in a continuous tablet manufacturing process based on the product and process understanding gained through the previous Quality-by-Design studies on a pilot unit. Compared to rigid process operation within a predefined design space, active process control response to common process variations, disturbances, or uncertainties can be automatically achieved under the QbC paradigm in a quantitative and predictive way to maintain consistent product quality. The systematic implementation of a hierarchical process control system in continuous direct compression process was highlighted, leveraging QbD understanding of the product and process to achieve robust and efficient process operations and real-time quality control of oral solid dosages. Future efforts in systematic sensor network maintenance, control performance monitoring and continuous improvement should be pursued to further advance QbC implementation.