European Journal of Pharmaceutics and Biopharmaceutics 194 (2024) 159–169

Contents lists available at ScienceDirect

European Journal of Pharmaceutics and Biopharmaceutics

journal homepage: www.elsevier.com/locate/ejpb

Design space determination of pharmaceutical processes: Effects of control

strategies and uncertainty
Margherita Geremia a, Fabrizio Bezzo a, Marianthi G. Ierapetritou b, *
a
CAPE-Lab – Computer-Aided Process Engineering Laboratory, Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131 Padova, PD, Italy
b
Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, USA

A R T I C L E I N F O A B S T R A C T

Keywords: The identification of process Design Space (DS) is of high interest in highly regulated industrial sectors, such as
Feasibility analysis pharmaceutical industry, where assurance of manufacturability and product quality is key for process development
Design space and decision-making. If the process can be controlled by a set of manipulated variables, the DS can be expanded in
Surrogate models
comparison to an open-loop scenario, where there are no controls in place. Determining the benefits of control
Pharmaceutical manufacturing
Process control
strategies may be challenging, particularly when the available model is complex and computationally expensive –
which is typically the case of pharmaceutical manufacturing. In this study, we exploit surrogate-based feasibility
analysis to determine whether the process satisfies all process constraints by manipulating the process inputs and
reduce the effect of uncertainty. The proposed approach is successfully tested on two simulated pharmaceutical case
studies of increasing complexity, i.e., considering (i) a single pharmaceutical unit operation, and (ii) a pharma­
ceutical manufacturing line comprised of a sequence of connected unit operations. Results demonstrate that different
control actions can be effectively exploited to operate the process in a wider range of inputs and mitigate uncertainty.

1. Introduction manufacturing data are available, the process DS can be identified by

building an empirical model (e.g., partial least-squares regression), and
Process Design Space (DS) is defined as the subset of combinations of using model inversion to determine the input conditions to attain all
input parameters that have been demonstrated to provide assurance of product requirements [5–7]. In the context of data-driven modeling, the
product quality and satisfy all the relevant operating and production use of response surface methodologies [8,9], multivariate experimental
constraints [1]. Determining the DS of a pharmaceutical process is a design [10], and high-dimensional model representation [11] have been
central step for the implementation of the Quality by Design (QbD) proposed to support the identification of process DS. More recently,
initiative advocated by the pharmaceutical regulatory agencies, which other approaches based on available historical data have been efficiently
consists in systematic approaches for product development based on adopted, such as Retrospective Quality by Design (rQbD) [12]. When the
predefined objectives and emphasizes process understanding and con­ system is well-characterized and the underlying principles are known,
trol. The QbD paradigm aims at guaranteeing that (i) the final phar­ the DS can be determined via predictive first-principle or semiempirical
maceutical product meets all quality requirements, and (ii) that the models. The main advantage is the ability to simulate the process under
process can be safely operated within the entire DS with no need of any given conditions and directly evaluating the corresponding outputs
additional regulatory approval [2]. This is fundamental in a sector that of interest; Monte-Carlo simulations are usually used to test different
is as highly regulated as the pharmaceutical industry to ensure robust­ scenarios [13–15]. The capability of the process to be feasibly operated
ness in process operation and reduce economic loss due to out-of- over the whole domain of input factors can be supported by feasibility
specification products under strict regulatory quality requirements [3]. analysis [16–18]. Halemane and Grossmann [19] first proposed a
Different approaches can be used to assist the identification of the feasibility measure based on the formulation of a max–min-max opti­
process DS with the aim to ensure consistent on-target product quality; mization problem, and many approaches have been consequently
the most suitable strategy to any specific case should be selected based developed to solve this problem [20–23]. The mathematical incorpo­
on available literature, experience, and knowledge of the process [4]. If ration of process constraints in problem formulation could be

* Corresponding author.
E-mail address: mgi@udel.edu (M.G. Ierapetritou).

https://doi.org/10.1016/j.ejpb.2023.12.008
Received 16 November 2023; Received in revised form 13 December 2023; Accepted 15 December 2023
Available online 16 December 2023
0939-6411/© 2023 Elsevier B.V. All rights reserved.
M. Geremia et al. European Journal of Pharmaceutics and Biopharmaceutics 194 (2024) 159–169

challenging since all these methods can be used only for processes with considering (i) a single pharmaceutical unit operation, and (ii) a phar­
closed-form and differentiable constraints [24]. A closed-form expres­ maceutical manufacturing line comprised of a sequence of connected
sion is given by a set of basic functions connected by arithmetic opera­ unit operations. Results demonstrate that manipulation of process var­
tions whose solution is given in a finite number of operations, while iables is suitable to operate the process in a wider range of operating
differentiability means that the derivative exists at any point in the input conditions and reduce the effects of variability in input factors.
domain, which implies that the mathematical function should be The remainder of this paper is organized as follows. In Section 2, we
continuous. However, in real case scenarios, we may need to handle provide the mathematical formulation of the feasibility analysis for DS
non-closed-form and/or non-differentiable constraints, either because description and introduce the presented methodology to study the ef­
they do not have a finite representation, or due to their complexity – fects of manipulation of process variables in presence of variability. In
which also implies high computational burden to simulate the process. Sections 3 and 4 we introduce the case studies and implement the pro­
This is typically the case of flowsheet models describing pharmaceutical posed workflow in order to analyze the benefits of manipulating process
manufacturing lines [25,26], such as the direct compaction process in variables towards the expansion of process DS, with critical discussion
Wang et al. [27], which will be further discussed in Section 3 of this on the results. Some final remarks in Section 5 will conclude the study.
manuscript. To cope against these limitations, Banerjee and Ierapetritou
[28] presented a novel approach based on the usage of α-shape surface 2. Methodology
reconstruction – that geometrically represents a family of piecewise
linear simple curves in the Euclidean space that are associated with a Feasibility analysis can be mathematically formulated as the
shape of a finite set of points. The approach suitably addresses complex maximum of the process constraint violation [37]:
nonconvex problems (e.g., any problem involving non-convex functions { }
φ(d, x) = minmax gj (d, z, x) s.t. x ∈ T, (1)
such as quadratic and exponential functions) even in presence of z j∈J
disjointed feasible regions. Adi et al. [29] applied a random line search
algorithm to reconstruct the boundaries of the feasible space, the basic where φ(d, x) is the process feasibility function; d is the vector of the
idea of which is to explore the solution space by randomly selecting process design variables, z is the vector of process variables that can be
points and compute the function that describes those points. Although manipulated, and x is the vector of critical input variables (e.g., critical
particularly effective when process constraints are not well-behaved process parameters and material properties); gj are the functions of the J
and/or derivatives are difficult to compute, both methods are compu­ process constraints in the form gj (d, z, x) ≤ 0 which must be satisfied
tationally demanding. Alternatively, for computationally expensive during process operation; T describes the range in which uncertain in­
models and in presence of black-box constraints (i.e., constraints puts can vary:
without an explicit mathematical form), surrogate-based feasibility { }
T = x|xL ≤ x ≤ xU , (2)
analysis methods – which rely on the construction of surrogate models to
approximate the original feasibility function – have been demonstrated
where xL and xU are lower and upper bounds, respectively.
to effectively support the identification of process DS [30–32].
Solving problem (1) determines whether for a given design d and
If the process can be controlled by a set of manipulated variables, the
critical input variables x, vector z can be adjusted to satisfy all the J
DS may be enlarged with respect to an open-loop scenario, where there
problem constraints gj and attain feasibility; vector z is determined such
are no controls in place. The importance of manipulation of process
that the maximum constraint gj is minimized.
variables in determining the process DS was first addressed by Mac­
In this study, we assume that design variables d are constant (e.g., the
Gregor and Bruwer [33], who highlighted the benefits of proper control
process is determined); thus, Eq. (1) simplifies as follows:
actions to hedge against changes in process inputs. This is of particular
{ }
interest with respect to raw material properties since they cannot be φ(x) = minmax gj (z, x) s.t. x ∈ T (3)
adjusted, as opposed to operating conditions [34]. Because of the z j∈J

inherent uncertainty, the permissible operational range of a process may

The value of the feasibility function in Eq. (3) indicates whether the
narrow to the extent that it becomes challenging to effectively operate.
process is feasible.
This can be due to many reasons; most commonly among them is the
change of certain process parameters during plant operation, the effect
• If φ(x) > 0, there is at least one constraint that is being violated. The
of external disturbances, and variability in raw materials. Process con­
process is not feasible.
trol, i.e., manipulation of process variables into the pharmaceutical
• If φ(x) ≤ 0 no constraint is being violated. The process is feasible.
environment can mitigate the negative effect of uncertainty towards the
When φ(x) = 0, vector x identifies the boundary of the feasible region.
final product quality. Therefore, analyzing the benefits of manipulated
variables in enlarging the process DS is fundamental to guide decisions
In order to identify the process DS, we need to determine the values
on suitable control strategies for pharmaceutical industrial processes.
of each variable xi in vector x, while adjusting the values of each
Establishing a proper control strategy may be challenging, particu­
manipulated variable zk in vector z, so that the condition φ(x) ≤ 0 is
larly when the manufacturing line is comprised of a set of connected unit
satisfied. Values of control actions zk in vector z minimizing the
operations and requirements on product quality are assessed through { }
additional test units. These systems are typically modeled through maximum of process constraints, max gj (z, x) , are computed through a
j∈J
computationally expensive models which might include various black- nonlinear sequential quadratic programming (SQP) optimization [38].
box constraints. Therefore, surrogate-based feasibility analysis can be Note that in case of an open-loop scenario, vector z is not present,
conveniently exploited to analyze the effects of control strategies for thus, the problem formulation in Eq. (3) reduces to:
determining the process DS. Although surrogate-based feasibility anal­ { }
ysis has been extensively adopted in identifying process DS [35], the φ(x) = max gj (x) s.t. x ∈ T. (4)
j∈J
effect of manipulated variables has not been included.
In this study we adopt the surrogate-based feasibility approach It is of our interest to analyze and quantify how the process DS expands
presented by Geremia et al. [36] with the objective of (i) analyzing and when a set of manipulated variables z can be adjusted (Eq. (3))
quantifying the benefits of a proper control action on the process DS for compared to an open-loop scenario, where there are no controls in place
pharmaceutical manufacturing development, and (ii) evaluating (Eq. (4)). Practically, the possibility to manipulate some process vari­
whether uncertainty can be mitigated. The methodology is tested on two ables z would lead to safely operate the process in a wider range of
simulated pharmaceutical case studies of increasing complexity, namely

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critical input factors x, which in turn could enhance robust process

operation and may allow making changes to manufacturing process with
no need of additional formal regulatory approval.
The focus of this work consists in analyzing how the process DS can
expand when a pre-specified control system is present, e.g., a feedback
control loop [39]. If the transmitted signal differs from the setpoint, a
corrective action on the final control element should be taken (e.g.,
opening/closing of a valve). The case studies that will be presented in
Section 3 are simplified by ideally assuming that manipulation of vector
z allows to instantly and perfectly track the setpoint.

2.1. Accounting for stochastic variation of critical input factors

In real case scenarios, some critical input factors in vector x might not
be exactly determined/known. Stochastic description of vector x may be Fig. 1. Evaluation of the effects of manipulation of process variables in the
due to uncertainty, which arises when one is not completely certain about expansion of process DS: (a) closed loop-scenario compared to (b) an open-loop
which exact values to rely on. This is the case of measured quantities scenario, (c) closed-loop scenario in presence of uncertainty.
affected by measurement errors; accounting for the extent of uncertainty is
open-loop scenario (Fig. 1b). We, then, include variability in some critical
aimed at more reliably describing the system of interest [40]. Instead,
input factors (e.g., raw material properties) and describe the probability
variability refers to unforeseen changes in critical input factors (e.g.,
that process constraints are satisfied using a stochastic approach, as
alteration of physical or chemical characteristics of raw materials, pres­
described in Section 2.1 (Fig. 1c).
ence of contaminants, changes in composition) [41]; how such variations
Since the solution of Eq. (3) might be computationally challenging
impact on process operation and product quality has been explicitly
(e.g., models characterized by nonconvex feasible space), we approxi­
identified as one of the challenges that pharmaceutical industry has to face
mate the original feasibility function using the surrogate-based
[42]. As a consequence of uncertainty and variability, output variables
approach proposed by Geremia et al. [36]. This approach is suitable to
should be also described using a stochastic approach, and this affects the
guide the selection of the best surrogate model for feasibility approxi­
characterization of process DS, i.e., the range within which the process can
mation and attain a specific level of accuracy with the minimum
be safely operated may be smaller, reducing robust process operation.
requirement of additional training data, while significantly reduces the
Accounting for all possible variations in critical input parameters is key to
computational burden. The proposed methodology is fully described in
provide assurance of product quality and safety in process operation.
the Supplementary Material.
Uncertain inputs can be suitably described as a distribution around
an expected value. Having the ability to simulate the process by
randomly drawing values from those distributions allows to evaluate the 3. Case studies
level of uncertainty that propagates to the product quality requirements
and process constraints, i.e., the process DS. Since the information The case studies we have analyzed in this work are presented in the
needed for exact description of uncertainty/variability is rarely avail­ following subsections. They consist of two pharmaceutical problems of
able in industrial practice, uniform distributions of uncertain inputs are increasing complexity, namely considering (i) a single pharmaceutical
here assumed. The probability that all J process constraints gj are unit operation, and (ii) a pharmaceutical manufacturing line comprised
of a sequence of connected unit operations. These examples are chosen
satisfied can be quantified using a probability figure of merit p [43,44]:
being representative of real-case problems and provide insight to guide
Pr(φ(x) ≤ 0 ) = p, s.t. x ∈ T, p ∈ [0, 1]. (5) decisions on convenient control strategies for industrial processes.

p is the reliability factor representing the probability that process con­

3.1. Roller compaction case study
straints are satisfied for a given set x. So if p = 0, there is always at least
one constraint that is being violated. No combination of inputs allows the
The first case study concerns a pharmaceutical roller compaction
process to be feasibly operated; if p = 1, no constraint is being violated.
process. It is based on the model proposed by Hsu et al. [45,46], which
The process is feasible for any combinations of inputs. We will refer to this
combines the Johanson’s rolling theory [47] with a dynamic material
condition as robust DS; if 0 < p < 1, some combinations of inputs satisfy all
balance:
process constraints, while others do not. The closer p is to 1, the higher the ( )
( )
number of combinations of inputs that satisfy all J process constraints. ( ) ω[ρin cos(θin )(1 + hR0 − cos(θin ) ωuinR − ρexit hR0 ]
The stochastic DS is defined as the combination of inputs that satisfy d h0
= ∫ θin , (7)
the process constraints with a probability higher than the reliability dt R
0
ρ(θ)cos(θ)dθ
factor p and is defined as follows.
⎡ ⎤K
{x|Pr(φ(x) ≤ 0 ) ≥ p } s.t. x ∈ T, p ∈ [0, 1]. (6) ∫ α h0
W σexit R ⎢ ⎥
Ph = ⎢(
⎣
R ) ⎥ cos(θ)dθ,
⎦ (8)
A (1 + sin(δ))
2.2. Proposed approach 0
1 + hR0 − cos(θ) cos(θ)

In this study, we exploit feasibility analysis with the aim of evaluating

σ exit = C1 ρKexit (9)
the effects of manipulation of process variables z in the expansion of the DS
of a given process, as opposed to the case where there are no controls in
ρLexit ≤ ρexit ≤ ρUexit , (10)
place. We also include the effect of uncertainty and study how the
manipulation of z can hedge against variability, with the final goal of
hL0 ≤ h0 ≤ hU0 . (11)
guiding decisions on suitable control strategies. We first consider a closed-
loop scenario where some variables z can be manipulated and study the Eqs. (7)–(9) are used to predict the critical quality attributes of the
benefits of suitable control actions on process DS, i.e., the possibility to product, i.e., the ribbon density ρexit at outlet, and the ribbon thickness
operate in a wider range of operating factors x (Fig. 1a) with respect to an h0 , which must satisfy the process constraints in Eqs. (10) and (11). ρLexit ,

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Table 1 [ ( )]
Model parameters and values/ranges considered in this study.
α β
τco− mill = τmax
co− mill 1 − exp − − , (14)
Rco− mill − Rmin Finco− mill
Parameter Symbol Units Value/range

Roll radius R m 0.125 where Rco− mill is the co-mill blade speed; Rmin is the minimum value of
Roll width W m 0.05 impeller speed, and τmax
co− mill , α, and β are regressed parameters which are
Compression parameter K – 4.97
(1) determined from experimental data.
8
Compression parameter C1 Pa/(kg 7.5 × 10−
(2) m3)4.97 3.2.2. Convective blender
Compact surface area A m2 0.01 Similar to the co-mill sub-model, the flowrate entering the blender is
Effective angle of friction Rad 0.7069
equal to the sum of the flowrate out from the co-mill and lubricant
δ
Nip angle α Rad 0.173
Inlet angle θin Rad 0.40 flowrate, FLUB :
Inlet powder density ρin kg m− 3 300
Roll speed ω rad/s 0.524 Finblender = Fout
co− mill
+ FLUB (15)
Roll pressure Ph Pa 0.9 × 106–1.1 × 106
blender blender
Powder feed speed uin m s− 1 2.27 × 10− 2–4.27 × At steady-state, Fin equals the outlet flowrate, Fout , while the mass
10− 2 steady
Ribbon thickness h0 M 1.7 × 10− 3–1.9 × 10− 3 hold-up Mblender is computed using an empirical expression which de­
blender
Ribbon density ρexit kg m− 3
850–950 pends on the inlet flowrate, Fin , and the blender blade speed Rblender :

Rblender Finblender
and hL0 are the lower admissible values for the ribbon density and the steady
Mblender = a + bFinblender + cRblender + d(Rblender )2 + e , (16)
1000
ribbon thickness, respectively, while ρUexit and hU0 are the correspondent
upper bounds. ρexit and h0 depend on (i) roll pressure Ph , (ii) roll speed ω, where a, b, c, d, e are regressed parameters from experimental data.
(iii) inlet feed speed uin , (iv) inlet density ρin . At steady-state, the outlet concentration of each component – which
The objective of the steady state feasibility analysis is to account for would be equal to final concentration in the tablet – can be calculated as:
the combined effect of the critical operating conditions Ph and uin (i.e.,
Fi
x = [Ph , uin ]T ) on the identification of the process DS, and the benefits of ci = blender
, (17)
Fout
manipulating the process variable ω (i.e., z = [ω]), while hedging against
variability in raw material properties (i.e., variability in ρin ). We assume
where i represents the component of interest, i.e., API, cAPI , excipient,
that ω can be manipulated between ±10 % its nominal value in order to cEXC , or lubricant, cLUB .
expand the process DS, and compare the results with an open-loop
scenario where the DS is only determined by the operating conditions 3.2.3. Tablet press
x. We, then, include the effect of variability in raw material assuming Pre-compression and main compression pressure are modeled ac­
that ρin fluctuates as powder enters the process around its expected cording to Kawakita and Lüdde [48]:
value; different levels of uncertainty are investigated. All model pa­
rameters are reported in Table 1, with indication of values/ranges Ppre = [
V0 − Vpre
], (18)
considered in this study [45]. bpre V0 (ε0 − 1) + Vpre

3.2. Direct compaction process case study Pmain = [

Vpre − Vtablet
], (19)
bmain Vpre (εmain − 1) + Vtablet
The second case study concerns a direct compaction process to produce
oral solid tablets [27]. The manufacturing line consists of a series of unit where bpre and bmain are Kawakita parameters for pre-compression and
operations: active pharmaceutical ingredient (API) and excipient are first main compression pressure, respectively, and need to be estimated from
fed to the co-mill, which is used for de-lumping purposes; lubricant is then experimental data. V0 is the initial volume in the die; Vpre is the volume
added to improve flowability. All ingredients are mixed in a convective of the powder after pre-compression; Vtablet is the volume of the tablet; ε0
blender to ensure homogeneity. The powder mixture is finally fed to the and εmain are the porosity of the material prior pre-compression and
tablet press, which compacts powder into tablets. We assume that the main compression, respectively.
plant is running at steady-state conditions. The key equations of unit The tablet hardness is predicted according to Kuentz and Leuen­
operation sub-models considered in this study will be given in the berger [49]:
following. Readers are referred to the original paper for additional details. H = H0 [1 − exp(ρr − ρc + λ) ], (20)

3.2.1. Co-mill where H0 is the value of tablet hardness at zero porosity and need to be
The sub-model for the co-mill consists of a mass balance equation estimated from experimental data; ρr and ρc are the relative and critical
which relates the hold-up and flow-rates at inlet and outlet. The flowrate densities, respectively. λ relates the ρr and ρc as follows:
co− mill
entering the co-mill, Fin , is equal to the sum of the API flowrate, FAPI , ( )
1 − ρr
and excipient flowrate, FEXC : λ = log . (21)
1 − ρc
F co−
in
mill
= FAPI + FEXC . (12)
The flowsheet model is used to predict the critical attributes of the final
co−
At steady-state, Fin mill co− mill
equals the outlet flowrate, Fout , while the mass product, i.e., tablet hardness H, and API concentration, cAPI , while
steady
hold-up Mco− mill is given by the product between the mean residence guaranteeing that the process is safely operated:
time inside the co-mill, τco− mill , and the total inlet flowrate: HL ≤ H ≤ HU , (22)
steady
Mco− =τ co− mill
co− mill Fin . (13)
mill
cLAPI ≤ cAPI ≤ cUAPI , (23)
τco− mill is determined using an empirical expression:
where HL , and cLAPI are the lower admissible values for the tablet hard

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ness and the API concentration, respectively, while HU and cUAPI are the considered in this study [27].
correspondent upper bounds.
The objective of the steady state feasibility analysis is to account for the 4. Results and discussion
combined effect of the critical operating variables FAPI , Rco− mill and Rblender
(i.e., x = [FAPI , Rco− mill , Rblender ]T ) on the identification of the process DS, In both case studies, we start with an initial dataset of 5l points – with
and the benefits of manipulation of process variables FEXC and FLUB , while l indicating the problem dimensionality, i.e., the length of vector x –
hedging against variability in raw material properties – i.e., variability in which is obtained using a Sobol’s sampling strategy. This Design of
API density, ρAPI , which in turn affects the inlet flowrate. We first assume Experiments (DoE) strategy is selected to uniformly place points in the
that FEXC is the only process variable that can be manipulated between ±5 input domain, while bypassing the collapsing property of a regular grid
% its nominal value, i.e., z = [FEXC ]; results are compared with the case of space-filling design [50].
an open-loop scenario where the DS is only determined by the operating
conditions x. We, then, consider FLUB as additional manipulated variable to 4.1. Roller compaction process
study the benefits of the simultaneous manipulation of the two inlet
flowrates, i.e., z = [FEXC , FLUB ]T . We account for the effect of variability in According to Step 1 of the surrogate-based feasibility approach
raw material properties assuming that ρAPI fluctuates around its expected (Section S.1 of Supplementary Material), analysis of available dataset
indicates nonlinearity between predictors and response, which is
value; and different levels of uncertainty are investigated. The model pa­
consistent with model equations (7)–(9) and suggests to further train
rameters are reported in Table 2, with indication of values/ranges
nonlinear candidate surrogates at Step 2. Multicollinearity and het­
Table 2 eroscedasticity are not detected, which implies that neither regula­
Model parameters and values/ranges considered in this study. rization techniques nor variance-stabilizing transformation to the
response variable are needed. Algebraic topology reveals that no
Parameter Units Value/range
disconnected components are present (i.e., the Betti-0 number, β0 , is
API flowrate FAPI kg/h 2.7–3.3 equal to 1), namely, the process DS consists in one unique feasible
Excipient flowrate FEXC kg/h 25–28
Lubricant flowrate FLUB kg/h 0.2–0.4
region.
Co-mill blade speed Rco− mill RPM 1080–1160 After the addition of 186 adaptive points to the initial dataset (details
Blender blade speed Rblender RPM 230–270 in Sections S.2 and S.3 of the Supplementary Material) accuracy stop
API bulk density ρAPI kg/m3 250 criteria are met (i.e., Correct Feasible region (CF%) ≥ 98%; Correct
Maximum time co-mill τmax S 40
co− mill InFeasible region, (CIF%) ≥ 98%, Not Conservative feasible region
Co-mill parameter (1) α RPM 100
Co-mill parameter (2) β RPM 1
(NC%) ≤ 2%) using a Gaussian Process (GP ) with exponential kernel as
Blender parameter (1) a Kg 680 surrogate model. The surrogate-based prediction of the feasible
Blender parameter (2) b H 5.449 boundaries is shown in Fig. 2, and compared to the original contour, and
Blender parameter (3) c kg/RPM –1.875 the one obtained without manipulation of ω. It is evident that manipu­
Blender parameter (4) d kg/RPM2 1.760 × 10− 3
lation of the process variable ω can extensively expand the feasible re­
Blender parameter (5) e kg/(RPM h) –8.220 × 10− 3
Tablet hardness H MPa 4.47–4.94 gion and allows the process to be safely operated in a wider range of uin .
Initial volume in the die V0 m3 5.025 × 10− 7 For clarity purposes, values of ω with respect to uin for different levels of
Powder volume after pre-compression Vpre m3 2.010 × 10− 7 compaction pressure Ph are visualized in Fig. 3. We can observe that
Tablet volume Vtablet m3 1.260 × 10− 7 higher values of uin can be compensated by increasing ω. Linearity of ω
Pre-compression Kawakita parameter bpre MPa− 1 5.000 × 10− 2
with respect to uin indicates that the inlet–outlet speed ratio in Eq. (7),
Pre-compression porosity ε0 – 0.836 uin
Main compression Kawakita parameter bmain MPa− 1 1.000 × 10− 2 ω , should be kept constant in order to ensure all product quality re­
Main compression porosity εmain – 0.590 quirements. In other words, to guarantee that the ribbon thickness h0
Relative density ρr – 0.657 and density ρexit fall within the predefined range of acceptability this
Critical density 0.556
ratio should be constant.
ρc –
Hardness at zero porosity H0 Kp 50
Tablet hardness H Kp 4.45–4.95
API concentration in the tablet cAPI % 9.5–10.5

Fig. 2. Roller compaction process. Comparison between real contour plot of expanded feasible space (continue black line) and surrogate-based predictions (dotted
orange line) using GP with exponential kernel after the inclusion of 186 adaptive samples to the initial dataset. Blue dotted line represents the feasible space with no
manipulation of ω (ω = 0.524 rad s− 1).

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Fig. 3. Values of ω and effect on uin for different fixed value of compaction pressure Ph . Nominal value of ω (ω = 0.524 rad s− 1) is shown as continuous red line.

4.1.1. Change in DS considering variability in raw material properties the process DS is more evident (Fig. 4b). Clearly, higher uncertainty in
When variability in raw material properties is considered, the pro­ input factors reduces the width of the robust DS more consistently.
cess DS may be reduced. We assume that the inlet powder density, ρin , However, manipulation of ω is still suitable to operate the process in a
fluctuates as powder enters the process with a deviation of ±5 kg/m3 larger range of uin if compared to the open-loop scenario.
with respect to the nominal value of 300 kg/m3, i.e., values of ρin can be
randomly drawn from the uncertain range of 295–305 kg/m3. According 4.2. Direct compaction process
to the methodology described in Section 2.2, a stochastic DS can be
identified referring to the probability that the process constraints are Also in this case, preliminary analysis of the available dataset in­
satisfied for different values of ρin in the predefined range of varia­ dicates nonlinearity between predictors and response and leads to the
bility.N = 102 scenarios are simulated for any combination of operating training of nonlinear candidate surrogates. Multicollinearity and het­
conditions (Ph ,uin , and manipulated ω); 3600 evaluation points are used, eroscedasticity are not detected, while Topological Data Analysis (TDA)
which is found to be a sufficiently high number of points to evenly map uncovers that the process DS consists in one single feasible region (i.e.,
the input space [51]. Results are shown in Fig. 4a, from which it can be β0 = 1). The addition of 300 adaptive points to the initial dataset –
seen that a robust DS (i.e., p = 1) is slightly reduced if compared to the which is equal to the user-defined maximum number of iterations – leads
case where no variability was considered. to the approximation of the feasibility boundaries through a GP with
When higher uncertainty on the value of ρin is assumed – e.g., a exponential kernel. Metrics for accuracy assessment at final iteration
deviation of ±25 kg/m3 with respect to its nominal value – the effect on are: CF% = 97.58%; CIF% = 98.24%, NC%=1.77%. Although CF% is

Fig. 4. Stochastic DS considering two different levels of uncertainty from the expected value of ρin : (a) ±5 kg/m3, (b) ±25 kg/m3.

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slightly lower than the stopping value of 98%, a good level of accuracy 4.2.1. Change in DS considering variability in raw material properties
in approximating the feasibility boundaries is attained. High reliability In presence of variability in material properties, the process DS may
is proved by values of NC% and CIF%, which satisfy accuracy criteria be reduced. We assume that the inlet API density, ρAPI , enters the process
and suggest that overestimation of feasible region in surrogate model is with a deviation of ±2.5 kg/m3 with respect to the nominal value of 250
not significant. kg/m3, i.e., values of ρAPI can be randomly drawn from the uncertain
Due to the increase in problem dimensionality, the surrogate-based range of 247.5–252.5 kg/m3. A stochastic DS is identified based on the
prediction of the feasible region can be visualized using a matrix of probability to guarantee that all process constraints are satisfied when
contour plots (Fig. 5). First, we can clearly observe that the main effect ρAPI changes. As for the previous case study, N = 102 scenarios are
of manipulating FEXC is to enlarge the range within which FAPI can vary simulated for any combination of operating conditions (FAPI ,Rblender , and
(Fig. 5a, b); a slight increase is also visible with respect to Rblender manipulated FEXC ) and 3600 evaluation points are used to evenly map
(Fig. 5b, c). Instead, no beneficial effect on the co-mill blade speed, the input space. Results are shown in Fig. 7a, from which it can be
Rco− mill , is detected (Fig. 5a, c). Thus, it is reasonable to fix Rco− mill to its noticed that the range of the Rblender is not affected by variation in API
nominal value – as we do for the following analyses. For clarity purpose, density, while the range of FAPI clearly is. A very slight deviation of ρAPI
values of FEXC and the correspondent effect on FAPI defining the feasible from the expected value is capable of strongly reducing the area within
DS at different levels of Rblender and nominal value of Rco− mill are shown in which Pr(φ(θ) ≤ 0 ) = 1 and highlights the need of measuring the
Fig. 6. Higher values of FAPI entering the system can be compensated by properties of raw material entering the process.
an increase in FEXC , that basically represents a dilution effect towards When higher uncertainty on ρAPI is considered – e.g., a deviation of
which the target concentration of API, cAPI , in the final product can be
±5 kg/m3 with respect to its expected value – the effect on the identi­
guaranteed.
fication of process DS is more evident (Fig. 7b), resulting in the smallest
robust DS. However, a proper manipulation of FEXC is still effective in

Fig. 5. Flowsheet for the direct compaction process. Comparison between real contour plot of expanded feasible space (continue black line) and surrogate-based
predictions (dotted orange line) using GP with exponential kernel after the inclusion of 300 adaptive samples to the initial dataset. Blue dotted line represents
the feasible space with no manipulation of FEXC (FEXC = 26.7 kg/h).

Fig. 6. Values of FEXC and effect on FAPI for different fixed value of Rblender , at nominal value of Rco− mill = 1120 RPM. Nominal value of FEXC (FEXC = 26.7 kg/h) is
shown as continuous red line.

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Fig. 7. Stochastic DS considering two different levels of uncertainty from the expected value of ρAPI : (a) ±2.5 kg/m3, (b) ±5 kg/m3.

mitigating variability, (i.e., it still leads to larger range of FAPI in com­ visualized in Fig. 8b. It can be observed that the nominal value of
parison with the open-loop scenario). lubricant flowrate (FLUB = 0.3 kg/h) is not the one minimizing the
feasibility function but operating at lower flowrates of lubricant is
4.2.2. Change in DS considering additional control variable recommended.
For this case we assume that the lubricant flowrate, FLUB , can be When uncertainty in API inlet density is considered, the process DS
manipulated in the range [0.2–0.4] kg/h, in addition to the excipient can be identified using the stochastic approach. Results considering the
flowrate, FEXC , and compare new results with the case in which we as­ same levels of uncertainty as those in Section 4.2.1 are shown in Fig. 9.
sume that only FEXC could be manipulated (Fig. 5b). The new DS is Similar considerations can be drawn regarding the effect of different
visualized in Fig. 8a, from which it can be seen that not only is the levels of uncertainty, and the benefits of manipulating process variables
feasible range of FAPI larger, but also the range for the feasible values of z in mitigating the decrease of robust DS.
Rblender is enlarged, i.e., all process constraints are satisfied for any value
of the blender blade speed.
4.3. Computational details
For clarity purpose, the values of FLUB and its relation to the FAPI
values that define the feasible DS at nominal values of blender blade
All computations were performed using MATLAB® R2021b on an
speed (Rblender = 250 RPM) and excipient flowrate (FEXC = 26.7 kg/h) are
Intel Core 17-11850H CPU @2.50 GHz processor with 64 GB RAM.

Fig. 8. Flowsheet of direct compaction process. (a) Comparison between real contour plot of expanded feasible space (continue black line) and surrogate-based
predictions (dotted orange line) using GP with exponential kernel after the inclusion of 300 adaptive samples to the initial dataset. Blue dotted line represents
the feasible space with no manipulation of FEXC and FLUB (FEXC = 26.7 kg/h; FLUB = 0.3 kg/h). (b) Values of FLUB and effect on FAPI at fixed nominal value of blender
blade speed Rblender = 250 RPM and FEXC = 26.7 kg/h. Nominal value of FLUB (FLUB = 0.3 kg/h) is shown as continuous red line.

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Fig. 9. Manipulation of FEXC and FLUB . Stochastic DS when considering uncertainty in raw materials: (a) deviation of ±2.5 kg/m3 from the expected value of ρAPI ,
and (b) deviation of ±5 kg/m3 from the expected value of ρAPI .

When no uncertainty in raw material is considered, training of candidate value within the range. This is a clear simplification which is typi­
surrogates is the most time-consuming step, with an overall duration of cally the most straightforward strategy to describe stochastic varia­
few minutes. When we account for variability in input factors and tion when very little information is available [53]. However, based
identify a stochastic DS, simulations of N scenarios at each evaluation on the specific case-study, more complex distributions could be
point require higher burden, with an overall computational time of 2 h. considered to characterize the region of input variability, such as the
widely used Gaussian distribution [54]. In such scenario, variability
4.4. Discussion is not constrained within a pre-specified range, and the probability
figure of merit p will not be equal to 0.
The presented case studies demonstrated the effectiveness of the • The stochastic description of process DS requires to evenly map the
proposed approach in investigating the benefits of manipulation of input space – 3600 evaluation points were used in the presented case
process variables in the characterization of process DS, and in mitigating studies. If a reliable surrogate-based approximation of the feasibility
the effect of variability. Here are some additional comments. function φ(x) has been computed, it can be suitably exploited for
simulation purposes. Consequently, the total number of evaluation
• Proper manipulation of process variables leads to safely operate the points does not correspond to the number of real experimental runs.
process in a wider range of critical input factors, this in turn
enhancing robust process operation and allowing to make changes to 5. Conclusions
manufacturing process with no need of additional formal regulatory
approval. The presented surrogate-based feasibility approach is In this study, we efficiently implemented a systematic surrogate-
relevant to guide process development and support decision on based feasibility procedure with the aim of analyzing and quantifying
convenient control actions in real-case situations. the benefits of suitable manipulation of process variables in the expan­
• In this study, we have ideally assumed that manipulation of vector z sion of process DS, and evaluating whether uncertainty can be miti­
is instantaneous, and allows to perfectly track the setpoint as soon as gated. The work shows the benefits of a proper analysis in characterizing
a control action is taken. This simplification of the realistic condi­ the effect of manipulating variables on process DS and can be efficiently
tions may impact the characterization of process DS and should be exploited to guide decisions in real industrial environments.
considered explicitly in real industrial environments [52]. However, The presented surrogate-based feasibility approach relies on
when little knowledge is available, incorporation of process dy­ different mathematical tools, which are effectively used to include the
namics in the initial illustration of the presented framework may be influence of manipulated variables toward the identification of process
challenging and would be subject of further investigation. DS to account for realistic cases where control strategies can extensively
• Processes are typically affected by variability in input parameters, enlarge the process DS. Considering the effect of uncertainty is also
and accounting for their effect is key to provide assurance of prod­ relevant since it is difficult to predict and cannot be always adjusted. A
uct/process constraints. The decrease of process DS can be evaluated stochastic approach allows to quantify the probability that all process
using a stochastic approach, which is suitable to assess whether the constraints are satisfied.
process is robust in operation and to compute the probability that all Future work will aim at further investigating the effect of uncertainty
process constraints are satisfied. When higher variability in input and external disturbances towards the identification of process DS.
parameters is considered, the effect on the identification of process
DS is more evident, i.e., the robust DS reduces more considerably. In CRediT authorship contribution statement
this work, stochastic variation of critical input factors was described
assuming uniform distributions, which require pre-specified range of Margherita Geremia: Conceptualization, Formal analysis, Meth­
possible values and assume equal probability of occurrence for each odology, Writing – original draft. Fabrizio Bezzo: Conceptualization,

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M. Geremia et al. European Journal of Pharmaceutics and Biopharmaceutics 194 (2024) 159–169

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