Anton A. Kiss, Edwin Zondervan, Richard Lakerveld, Leyla Ozkan (Eds.

)
Proceedings of the 29th European Symposium on Computer Aided Process Engineering
June 16th to 19th, 2019, Eindhoven, The Netherlands. © 2019 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-818634-3.50222-8

A Quality-by-Control Approach in Pharmaceutical

Continuous Manufacturing of Oral Solid Dosage
via Direct Compaction
Qinglin Su,a Sudarshan Ganesh,a Dan Bao Le Vo,a Anushaa Nukala,3 Yasasvi
Bommireddy,b Marcial Gonzalez,b Gintaras V. Reklaitis, Zoltan K. Nagya,*
aDavidson School of Chemical Engineering，Purdue University, West Lafayette, IN
47907, United States
bSchool of Mechanical Engineering, Purdue University, West Lafayette, IN 47907,
United States
znagy@purdue. edu

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.
Keywords: Quality-by-Design, Quality-by-Control, Continuous manufacturing, Process
control, pharmaceutical

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-
1328 Q. Su et al.

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 SiC)2 (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.
A Quality-by-Control approach in pharmaceutical continuous manufacturing 1329
of oral solid dosage via direct compaction

Smart manufacturing

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operations

twe Continuous manufacturing

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Batch manufacturing

QbC
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• Batch-to-batch variation

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• Quantitative and predictive
ai QbD understanding leveraged for
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Figure 1.UO
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The systematic progression in quality assurance via QbT, QbD, and QbC.
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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.
Main-compression
f /\ force

Feeder
參 • •
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Dosing 1 ••••
position •:*
Main
comp. ■｛浴
10 Scraper

thickness
Turret
speed ▲

Ejection

Die filling Metering Pre-compression Main-compression Ejection & take off

Figure 2. Major steps in a Natoli rotary tablet press.

1330 Q. Su et al.

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,

CF CF ttD2/4
1 - pc/ pr a ab ⑴

4W4
pr=^D^T (2)

where CF is the main compression force, kN; pc is the critical relative density, pr the
calculated in-die relative density from tablet weight Wt, and pt 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.
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0.65 0.7 0.75 0.8 0.85 0.9 0.95 < 200 220 240 260 280 300
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Relative density >j Tablet weight (mg)

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Figure 3. Compressibility characterization
.e by a classical Kawakita model.
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3.3. Hierarchical control system
ras
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 pc 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.
A Quality-by-Control approach in pharmaceutical continuous manufacturing 1331
of oral solid dosage via direct compaction

supervisory control
[ dr ] f mpc [ rt° [娜]:
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Data acquisition and implementation level
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• Single/multiple unit operations

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Level 0
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QMS: Quality m«n«cement system

Blender
□
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.
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
1332 Q. Su et al.

monitoring and continuous improvement should be pursued to further advance QbC

implementation.
Natoli BLP-16 closed-loop control Natoli NP-400 closed-loop control
280
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26 } 260 - Set point
24 o 5
22
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6 240 A- I
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Levdinocom[rol At-lim table* wvight
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00 60 800 1400

s
400 IL' 180
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QL

AJISSP
3 a 3
0.2 5
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8 .25
-
J
0 0 500 1000 1500 2000 2500 0 200 400 600 800 1000 1200 1400 1600 1800
Time (s) Time (s)

Figure 5. Control performance of Natoli BLP-16 and NP-400 tablet press.

Acknowledgement
Funding for this project was made possible, in part, by the Food and Drug Administration
through grant U01FD005535. Views expressed by authors do not necessarily reflect the
official policies of the Department of Health and Human Services; nor does any mention
of trade names, commercial practices, or organization imply endorsement by the United
States Government. This work was also supported in part by the National Science
Foundation under grant EEC-0540855 through the Engineering Research Center for
Structure Organic Particulate Systems. Purdue Process Safety and Assurance Centre
(P2SAC) and technical support from Douglas Voss of Natoli are also appreciated.

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