J Pharm Innov
DOI 10.1007/s12247-012-9132-z
RESEARCH ARTICLE
Adaptive Design Space as an Integrated Component
of Quality by Design
Benoît Igne & Zhenqi Shi & Sameer Talwar &
James K. Drennen III & Carl A. Anderson
# Springer Science+Business Media, LLC 2012
Abstract
Introduction The US Food and Drug Administration requires
pharmaceutical companies to develop extensive process
understanding prior to routine manufacturing of drug prod-
ucts. Through development and validation, drug manufac-
turers enhance their process understanding and identify an
acceptable range of process parameters for each unit opera-
tion; this is referred to as the design space. Typically, limited
work is done to study the effect of long-term raw material
variations on the robustness of the design space. In the present
study, the development of a design space for a tablet formu-
lation containing two APIs (acetaminophen, caffeine) through
a direct compression process was investigated.
Material and Methods A design of experiment including
different excipient ratios of microcrystalline cellulose and
lactose, two croscarmellose sodium levels, four tablet com-
pression forces, and four blend parameters was created using
an industrial-size press to define a knowledge space. Quality
attributes (disintegration time, dissolution, radial tensile
strength, and friability) were measured and a design space
derived. In order to test the robustness of the design space, raw
material properties, specifically particle size of acetaminophen
and ratio of lactose anhydrous to monohydrate, were modi-
fied. Also, compression parameters were varied.
Results Tablets were analyzed for relevant critical quality
attributes (CQAs) to investigate how variability in raw
materials can change the design space. The modification of
B. Igne : J. K. Drennen III : C. A. Anderson (*)
School of Pharmacy, Duquesne University
Duquesne Center for Pharmaceutical Technology,
600 Forbes Avenue,
Pittsburgh, PA 15282, USA
e-mail: andersonca@duq.edu
Z. Shi : S. Talwar : J. K. Drennen III : C. A. Anderson
Graduate School of Pharmaceutical Sciences,
Duquesne University,
600 Forbes Avenue,
Pittsburgh, PA 15282, USA
the process parameters was used as a means of compensat-
ing for raw material variability to produce tablets that met
CQA requirements. An adaptive design space approach
based on the adaptation of critical process parameters is
proposed to facilitate the creation of tablets meeting speci-
fications despite variation in raw material properties.
Keywords Quality by design . Knowledge space . Design
space . Adaptive design space . Raw material variability
Introduction
Pharmaceutical Quality by Design (QbD) is a “systemic ap-
proach to pharmaceutical development that begins with pre-
defined objectives and emphases product and processes
understanding and process control” [1]. It consists of under-
standing the impact of formulation and manufacturing on
product critical characteristics and identifying all sources of
variability to implement a flexible and robust process that can
adapt and produce a consistent product over time. This stands
in stark contrast to quality by testing, where only the final
product characteristics are considered. The goal of QbD is to
utilize clinical relevance to determine product characteristics.
In addition, under the QbD paradigm, batches may not be
actually tested against specifications as the process under-
standing and process control provide sufficient evidence that
a given batch will meet the specifications if tested [1].
The implementation of a QbD system involves the inves-
tigation of all the factors that can impact the critical quality
attributes (clinical performance) of a drug product. It entails
studying the effect of excipient and drug substance variabil-
ity, exploring the impact of process parameters and the
determination of the critical process parameters (CPP) and
finally the development of a design space in the presence of
interacting CPPs [2]. The International Conference on Har-
monization tripartite guideline on pharmaceutical develop-
ment Q8(R2) defines design space as “the multidimensional
 J Pharm Innov

combination and interaction of input variables (e.g., material the means to compensate for it. This study demonstrates the first
attributes) and process parameters that have been demon- step of a feed forward quality control system.
strated to provide assurance of quality” [3].
The establishment of a design space should rely on the
use of a design of experiment (DOE) for a single or multiple Material and Methods
unit operations where the relevance of process parameters is
investigated. Several DOEs might be necessary for complex Formulation and Manufacturing
processes. To understand the process, CPPs must be varied
and their associated product properties or critical quality A 2003 Excedrin® Tension Headache-like formulation contain-
attributes (CQA) determined. The information provided by ing acetaminophen (APAP) and caffeine was used. A design of
the DOE constitutes a knowledge space. The design space is experiment was created to optimize the formulation for
established as a subset of the knowledge space based on a direct compression. As shown in Table 1, four lactose mono-
CQA acceptance range [3, 4]. The QbD paradigm offers hydrate:microcrystalline cellulose ratios, two levels of croscar-
flexibility in process control as product quality will be mellose sodium (disintegrant), four sets of blend parameters,
ensured throughout a range of CPPs defined by the design and four tablet compression force targets were tested. The latter
space. It consequently offers the potential for reduced rou- was established by tablet force to failure testing at-line. To limit
tine quality testing and real-time release. the number of experiments, a D-optimal criterion was
Authors assert that over time the design space will need employed, reducing the number of runs from 128 to 16.
to be adapted in light of new knowledge gathered on the The formulation comprised 31.25 % of APAP (Mallinck-
product or due to adaptations in the manufacturing process. rodt Inc., Raleigh, NC, USA) with a median particle size of
For instance, the modification of a unit operation or the 100 μm, 4.05 % caffeine (anhydrous; Spectrum, Gardena,
selection of a different supplier for excipients or drug sub- CA, USA), from 12.44 to 50.56 % of microcrystalline
stance would require the derivation of a new knowledge cellulose (MCC; Avicel PH 102, FMC Biopolymer,
space and the adaptation of the original design space. Such
modifications would require appropriate supplementary
submissions and regulatory approvals.
Table 1 Design of experiment for the initial knowledge space
However, other subtle changes should be considered.
Lot-to-lot variability and physical form changes can signif- Run Run Excipient Croscarmellose Load RMSNV
icantly impact manufacturing processes and clinical perfor- # ordera ratiob sodium level force weightsd
mance [5, 6]. While pharmaceutical companies attempt to (%) (pound)c
include multiple sources of variability in their original 1 16 4:1 2 12,000 210
DOEs, it is typically not possible to envision all of them
2 6 4:1 2 6,000 111
(especially those as unpredictable or uncontrollable as raw
3 14 4:1 1 10,000 201
material variations). In such situations, the robustness of the
4 12 4:1 1 8,000 300
design space is challenged. When changes are significant
5 13 3:2 2 10,000 210
and adversely impact CQAs, the design space may need
6 1 3:2 2 8,000 111
to be adapted. In the present document, a two-step
7 5 3:2 1 12,000 201
approach was taken to study the potential use of an
8 9 3:2 1 6,000 300
adaptive design space. After initially developing a de-
9 15 2:3 2 8,000 201
sign space for a direct compressible formulation (blend-
10 11 2:3 2 12,000 300
ing followed by tableting), the impact of varying raw
11 10 2:3 1 10,000 111
materials on the design space was studied. The ability
12 3 2:3 1 6,000 210
to compensate for variations in raw material properties
13 7 1:4 2 10,000 300
by modifying CPPs and consequently adapting the de-
14 2 1:4 2 6,000 201
sign space as a function of the properties of the input
raw material was demonstrated. 15 8 1:4 1 8,000 210
A comprehensive feed forward control system must be 16 4 1:4 1 12,000 111
implemented to ensure patient safety and product efficacy. a
Order in which runs were manufactured
The possibility to adapt the manufacturing process to not only b
Ratio microcrystalline cellulose/lactose anhydrous
raw material properties but also equipment aging and environ- c
Tablets compression force target at the press (right after compression)
mental changes can provide pharmaceutical companies with d
Weights used in the RMSNV calculation. The first corresponds to the
relevant quality control tools and modeling systems establishing summed weight given to the APIs, the second is the summed weight
the relationship between a new factor affecting the process and for the two excipients, and the third is for the disintegrant
J Pharm Innov
Mechanicsburg, PA, USA), from 12.44 to 50.56 % of lac-
tose monohydrate (modified spray-dried; Foremost Farms
USA, Rothschild, WI, USA), either 1 or 2 % of croscarmel-
lose sodium (Spectrum, Gardena, CA, USA), and 0.5 % of
magnesium stearate (ThermoFisher Scientific, Waltham,
MA, USA). The batch size was 1 kg for each design point.
Blending
A 3.5-quart, stainless steel, custom-made V-blender was
used to mix the raw materials. The blender was charged in
the same order for each experiment, from the bottom of the
vessel using a funnel. All components were mixed at the
same time. Two SpectralProbe Process NIR spectrometers
(Thermo Fisher Scientific, Wilmington, MA, USA; Serial
numbers 1,277 and 1,502) were used to monitor the two arms
of the blender in real time. The instruments collect 100
absorption values between 1,600 and 2,400 nm in reflectance
mode (interpolation from 8.71 to 7.31 nm) and are triggered
by a light intensity sensor (intensity rises when powder falls
against the sampling window, enabling collection). Measure-
ments were made through a sapphire window in the top of
either arm of the blender. Spectra were sent wirelessly to a
computer and imported into a custom-made acquisition and
analysis system. The system had a response time of less than
2 s to allow real-time, online monitoring of the blend
homogeneity.
An adaptation of the root mean square error from the
nominal value (RMSNV) algorithm was used to monitor
blending [7]. Root mean square error from the nominal
value is a weighted, cumulative, pooled standard devia-
tion indicator that takes into account the deviation of
the predicted concentration of the major components of
a mixture from their target concentration, over a given
number of rotations. For an n component system, it is
defined as
vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
u   
u w Yb  Y 2 þ w Yb  Y 2 þ . . . þ w Yb  Y 2
t 1 1 1 2 2
RMSNV ¼ P
ð wÞ
where w is the weight given to a component, Yb is the
predicted value from NIR spectra and Y is the target
value for the nth component, i is the number of data
points used in a single window of data collection, t is
the latest collected data point, and j is an individual
prediction time. The RMSNV allows the evaluation of
the trends and distance from target concentrations for
not only the active ingredient but also for the major
excipients of the formulation.
To allow control of the blend endpoint when two or more
sensors are used, a pooled RMSNV (RMSNVp) statistic was
 
2 n
calculated:
vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
u      
u k1 RMSNVt 2 þk2 RMSNVt 2 þ . . . þ kn RMSNVt 2
RMSNVptti ¼u
u
ti 1
P n
ti 2 ti n
ð2Þ
t kn
j¼1
where k is the weight given to an instrument, i is the number
of data points used in a single window, and t is the latest
collected data point [8].
Weights w and k in Eqs. 1 and 2 are set to vary the effect
of the homogeneity, individual predictions, and the instru-
ment position on the blender. In the present study, outputs
from both sensors were weighted equally, but the effect of
the homogeneity of each component on the RMSNV calcu-
lation, i.e., the w in Eq. 1, was part of the DOE (see Table 1,
column 6). The blend endpoint was determined by the trend
of the pooled RMSNV and defined as the time at which the
RMSNVp remained constant for a minimum of 2 min.
Models for predicting constituent values (Yb ) were devel-
oped using an efficient calibration approach [9] with CLS/
PLS [10]. Magnesium stearate content was not monitored in
the RMSNV calculations.
Tableting
Blends were subsequently compacted on a 38-station rotary
tablet press (Elizabeth-Hata International, Inc., North Hun-
tingdon, PA, USA). The stations were tooled using 3/8 in.
(9.5 mm) diameter, round beveled punches and the
corresponding dies. Only two stations were tooled to facil-
itate collection of the tablets post-ejection. Collection of
tablets was performed in bins of 1 min for the first 10 min
and in bins of 5 min until the end of the run. Target tablet
weight was 350 mg. The turret speed was left constant at 30
rotations per minute (rpm).
Quality Attributes and Design Space
ffi
Tablets were analyzed after aging for various attributes (as
n n
model CQAs). Aging is typically attributed to mechanical
relaxation following uniaxial compression. The magnitude
ð1Þ of these changes varies as a function of the relative ratio of
material having elastic and viscoelastic behaviors under
compression. A minimum of 2 weeks separated tablet com-
pression and data collection. Friability (18 tablets per design
point (1 per time bin ) — TA series, Erwera, Heusenstamm,
Germany), disintegration time (18 tablets per design point
randomly selected from each time bin — Van Kel Inc., Cary,
NC, USA), and dissolution profiles (six tablets per design
point; sampled at 0.5, 5, 10, 15, 30, 45, and 60 min, ran-
domly selected from each time bin — Dissolution system
2100B, Distek Inc., North Brunswick, NJ, USA) were mea-
sured following USP standards for APAP and caffeine tab-
lets [11]. Additionally, radial tensile strength (RTS) was
 J Pharm Innov

calculated from force to failure measurements made on 18
tablets per design point randomly selected from each time
bin with a PTB 311 (Pharmatest, Hainburg, Germany).
Process parameters and formulation factors were then
related to quality attributes to first determine the critical
quality attributes and second to build a design space. Note
that no clinical data were available in this study and conse-
quently, CQAs were determined based on manufacturing
feasibility and USP standards [11, 12]. An optimal formu-
lation (excipient ratio and disintegrant level) was chosen
along with the best process parameters (compression force
target at the press and blend RMSNV weights). That optimal
set of parameters was subsequently used to test the robust-
ness of the design space.
Design Space Robustness
To test the robustness of that optimal system with respect to
raw material properties, three additional runs were created.
The effects of APAP particle size and/or the ratio of lactose
anhydrous to lactose monohydrate on the CQAs and ulti-
mately on the design space were investigated. For each of
the three runs, a 3-by-2 full factorial design was generated
where the impact of tablet press speed and compression
force were evaluated. Table 2 presents the additional DOE.
Note that in the knowledge space DOE, the compression
speed was left constant (30 rpm). A larger particle size
APAP (median particle size of 600 μm) was obtained by
using APAP crystal (Rhodapap, Rhodia Organique, Rous-
sillion, France) and the physical form of lactose was mod-
ified by mixing lactose monohydrate with lactose anhydrous
(1:1 ratio) (51808TT, Sheffield Bio-Science, Norwich, NJ,
USA).
JMP 8 (SAS Institute Inc., Cary, NC, USA) was used to
generate the D-optimal design, and knowledge and design
spaces were drawn with MATLAB 2010a (The Mathworks,
Natick, MA, USA). Calibration models used to calculate the
blend endpoints were developed with the PLS_Toolbox v.
5.8 (Eigenvector Research Inc., Wenatchee, WA, USA) and
scripts written in-house.
Results
Prior to tableting and the determination of quality attributes,
the RMSNV was used to stop blending. Blend prediction
models had the following calibration and block cross-
validation model errors: root mean square error of calibra-
tion/cross-validation: 2.71/2.93, 1.44/1.52, 2.64/2.68, 4.32/
4.36, and 1.36/1.45 % w/w for APAP, caffeine, MCC, lac-
tose, and croscarmellose sodium, respectively.
The Knowledge and Design Spaces
Table 3 presents quality attributes for each design point of
the knowledge space experiments. All design points passed

Table 2 Design of experiments

to test the robustness of the de- Run # Sub-run # Acetaminophen Lactose forma Compression Compression force
sign space particle size (μm) speed (rpm) (pound)b

1 A 600 100:0 30 9,000

1 B 600 100:0 30 11,000
1 C 600 100:0 30 13,000
1 D 600 100:0 45 9,000
1 E 600 100:0 45 11,000
1c F 600 100:0 45 13,000
2 A 100 50:50 30 9,000
2 B 100 50:50 30 11,000
2 C 100 50:50 30 13,000
2 D 100 50:50 45 9,000
2 E 100 50:50 45 11,000
2 F 100 50:50 45 13,000
a 3 A 600 50:50 30 9,000
Monohydrate/anhydrous ratio
b 3 B 600 50:50 30 11,000
Tablets compression force tar-
get at the press (right after 3 C 600 50:50 30 13,000
compression) 3 D 600 50:50 45 9,000
c
Formulation composition be- 3 E 600 50:50 45 11,000
yond the capacity of the tablet 3c F 600 50:50 45 13,000
press; no tablets were produced
J Pharm Innov

Table 3 Critical quality attrib-

utes for each design point Run # Friability (%) Disintegration Radial tensile Acetaminophen Caffeine
time (s) strength (MPa) (min)a (min)a

1 0.31 34 0.89 5 10
2 0.39 45 0.97 10 10
3 0.23 35 0.84 5 5
4 0.26 381 1.92 15 45
5 0.12 129 1.65 15 15
6 0.26 17 0.78 30 30
7 0.17 191 1.24 30 10
8 0.22 66 1.10 5 10
9 0.14 20 0.72 5 5
10 0.25 120 1.47 10 15
11 0.13 203 1.68 5 10
12 0.16 27 1.01 10 10
13 0.24 116 1.50 5 10
14 0.12 36 1.23 45 10
15 0.28 60 1.22 5 10
a
Time at which USP criterion 16 0.19 76 1.99 10 30
was reached

the friability and dissolution tests based on USP standards
[11, 12]. However, disintegration time and RTS demonstrat-
ed significant variability. These two parameters were signif-
icantly influenced by tablet compression force target and
excipient ratio. The RMSNV weights and the level of dis-
integrant used during processing were not demonstrated to
have a statistically significant effect on the quality attributes
(α00.05). Consequently, RTS and disintegration time were
used as critical quality attributes, compression force target
as critical process parameter, and excipient ratio as a critical
formulation factor (the latter will be included in the CPPs in
later discussion). Note that CQAs and CPPs were selected
solely based on manufacturing considerations and not clin-
ical relevance. This is important as the dissolution profile
would have been taken into account if a certain pharmaco-
kinetic/pharmacodynamic model or release profile was of
interest.
Figure 1 illustrates knowledge spaces created from the
information presented in Table 3 and represents the relation-
ship existing between the critical process parameter (com-
pression force target and excipient ratio) and each of the two
CQAs:disintegration time (Fig. 1a) and RTS (Fig. 1b). Both
knowledge spaces show areas of significant variations in
CQAs with a nonlinear combination and interaction of the
critical formulation factor and critical process parameter. It
is interesting to note that tablets made with an excipient ratio
of 4:1 (MCC/lactose) were the hardest tablets, but with very
limited resistance to disintegration due to the swelling effect
that water has when disrupting particle–particle bonds when
MCC is present in high concentration [13].
Table 4 summarizes CQAs acceptance criteria used in the
present study. The limits for disintegration time and RTS
were set to span median CQAs values and consequently
specify tablets that are neither too soft nor too hard and
have a reasonable disintegration time. Note that these limits
should be set based on desired drug release patterns, and
authors realize that in many situation, a tablet disintegrating
as quickly as in 80 s might not be suitable. Figure 2 presents
the design space generated when acceptable CPP ranges
(defined in Table 4) were overlapped onto the knowledge
spaces.
Effect of Raw Material Properties on the Robustness of the
Design Space
The robustness of the design space with respect to raw
material variability was tested based on the design of exper-
iment shown in Table 2. The formulation chosen had an
excipient ratio of 2:1 (41.3 % of MCC and 20.7 % of
lactose) and 2 % of croscarmellose sodium. Compression
force target at the press was set to 11 kp and RMSNV
weights were 1-1-1 for APIs, excipients, and croscarmellose
sodium, respectively. This formulation and set of parameters
were chosen because they were near of the center of the
design and constituted typical target points for routine man-
ufacturing. Given these CPPs, the corresponding CQAs
were 1.53 MPa and 104 s for RTS and disintegration time,
respectively.
Design points 1B, 2B, and 3B correspond to the resulting
CQAs for the above defined CPPs (11 kp and 30 rpm).
While the RTS of the tablets was slightly reduced for all
conditions, CQAs remained within the limits of the design
space. However, the disintegration time of design points 1
and 2 (corresponding to change in APAP and change in
 J Pharm Innov

Fig. 1 Two-dimension knowledge spaces. Each critical quality attribute is expressed as a function of the critical process parameters (tablet compression
force target and formulation excipient ratio)

lactose respectively) was outside the design space. Thus, the space developed from the knowledge space (for excipient
variability in raw materials that may be present when raw ratio of 2 only); a green square corresponds to a batch that
materials are inadequately characterized prior to entering the met the specification and a red square represents a batch out
manufacturing process can produce tablets that do not meet of specification. When the particle size of APAP was mod-
CQAs and, consequently, would not deliver the desired ified, only the use of a higher compression force (outside of
therapeutic effect. the design space) at low compression speed generated ap-
propriate tablets. Data for design point 1F are not available,
Adaptive Design Space to Adjust for Raw Material but based on RTS for 1E, it would not have met the spec-
Characteristics ifications. When the ratio of lactose anhydrous to monohy-
drate was modified, increasing the compression speed
The potential to adapt the CPPs to compensate for an unan- resulted in in-specification tablets. Finally, as seen before,
ticipated variance in raw materials and consequently adapt- the combination of variability in APAP and lactose raw
ing the design space was explored. As described in Tables 2 materials compensated each other and original settings were
and 5, tablet compression force target at the press and
compression speed were modified and the corresponding
CQAs determined. The use of higher compression forces
and higher compression speed generated harder tablets that
were also more resistant to disintegration. However, based
on the limits set on Table 4, some tablets were too hard and
thus would fall outside of the design space. Note that fria-
bility and dissolution time were not taken into account.
Figure 3 illustrates how each design point falls with
respect to tablet specifications (Table 4) and the design

Table 4 Critical quality attributes acceptance criteria

Critical quality attribute Criterion

Friability <0.8 % weight lossa

Dissolution >75 % of label claim after 60 minb
Disintegration >80 s
Radial tensile strength >1.25 MPa and <1.60 MPa Fig. 2 Binary two-dimension design and knowledge spaces. The
a
highlighted area corresponds to the design space created from a deter-
Data taken from [12] mined acceptable range of critical quality parameters. The dark area
b
Data taken from [11] was studied and resulted in out-of-specification tablets
J Pharm Innov

Table 5 Critical quality attributes for each design point of the second- formulation and process parameter changes were fortuitous
ary design of experiment
and were not an intentional design characteristic.
Run # Sub- Disintegration Radial tensile Results
run # time (s) strength (MPa)
Discussion
1 A 21 1.06 Fail
1 B 63 1.45 Fail
When developing knowledge and design spaces, phar-
1 C 195 1.91 Pass maceutical companies cannot envision all the sources of
1 D 54 1.14 Fail variability that will be encountered throughout the drug
1 E 244 1.75 Fail product life cycle. Thus, despite the creation of an
1a F – – – appropriate design space, robustness issues will appear
2 A 41 1.14 Fail when unplanned variations emerge, such as instances
2 B 68 1.40 Fail where excipient suppliers modify their production con-
2 C 200 1.75 Fail ditions, a new supplier is employed, storage conditions
2 D 72 1.20 Fail change (relocation of a production line), etc. The same
2 E 131 1.45 Pass approach could have been taken to simulate the effect
2 F 299 1.83 Fail of other process perturbations. Process drifts, due to
3 A 25 1.05 Fail equipment aging and environmental changes, can have
3 B 98 1.40 Pass similar effects and adaptation.
3 C 437 2.26 Fail While only a limited number of critical quality attrib-
3 D 85 1.26 Pass utes were considered in this study, the general idea that
3 E 330 1.83 Fail one can achieve consistency in outcome by modifying
3a F – – – critical process parameters with respect to incoming raw
a
material variability is an important concept that should
Combination not compressible with considered tablet press
be addressed by both pharmaceutical companies and
regulatory bodies as process parameters considered not
sufficient to obtain good tablets. Increasing the compression critical in the original design space might become crit-
speed and reducing the compression force yielded the same ical to maintain product quality. The general consensus
results (outside of the design space). Note that the results of that tends to lock the design space should be revised
given that an appropriate process monitoring and control
system is employed to validate the new settings. One
can easily envision a system in which batches of vari-
ous excipients are characterized prior to entering the
manufacturing line. This characterization would trigger
the selection of CPPs that would allow the production
of consistent drug products, robust to lot-to-lot variabil-
ity, to manufacturer-to-manufacturer production proto-
cols, and changes in environmental conditions.
The generalization of such a dynamic system would
heavily rely on process analytical technologies. One can
envisage their use to not only characterize raw material
variability but also to track the state of a process (con-
tinuous or batch based) in an online fashion. For in-
stance, one could generalize this adaptive design space
approach to changing drying parameters based on parti-
cle size, moisture content of a granulation to reach
Fig. 3 Graphical representation of raw material challenges to the
consistent powder properties throughout the drug manu-
design space. Green squares represent a batch that met specifications
while red squares point to out-of-specification trials. White crosses are facturing life cycle no matter the numerous sources of
trials that could not be completed. Not all design points belonged to the variability that can impact the resulting material from
design space generated for a microcrystalline cellulose/lactose ratio of various unit operations. Such process control approaches
2:1. Trial 1 corresponds to large particle of APAP, trial 2 to 1:1 lactose
have already been developed [14, 15] and will play an
anhydrous/monohydrate, and trial 3to both modifications to the origi-
nal design. A to F represents variations in compression force and speed. increasing role in the development of safe and efficient
See Table 2 for more details drug products.

Conclusion
A two-step approach was taken to study the utility of an
adaptive design space. After first developing a design space
for a direct compressible formulation (blending followed by
tableting), the impact of varying raw materials was studied.
The potential to adapt to variations in raw material proper-
ties by modifying CPPs and consequently adapting the
design space was demonstrated.
This example showed that appropriate optimization of the
CPPs provides an opportunity for a manufacturing process
to adapt to variability in properties of raw materials. It also
demonstrates the necessity of flexibility of manufacturing to
accommodate changes that typically occur. Further, it
emphasizes that the best means of oversight of a process is
through supervision of the change control procedure for a
process rather than in inspecting the product.
Acknowledgments Authors would like to acknowledge Dr. Michael
Moore and Robert W. Bondi, Jr. for their help in operating the tablet
press to create the tablets used in this article.
References
1. Yu LX. Pharmaceutical quality by design: product and process
development, understanding, and control. Pharm Res.
2008;25:781–90.
2. Lionberger RA, Lee SL, Lee L, Raw A, Yu LX. Quality by design:
concepts for ANDAs. AAPS J. 2008;10:268–76.
3. International Conference on Harmonization. Pharmaceutical De-
velopment Q8R2. Available at http://private.ich.org/LOB/media/
MEDIA4986.pdf. Accessed 21 December 2010
J Pharm Innov
4. MacGregor JF, Bruwer MJ. A framework for the development of
design and control spaces. J Pharm Innov. 2008;3:15–22.
5. Chamarthy SP, Pinal R, Carvajal MT. Elucidating raw material
variability—importance of surface properties and functionality in
pharmaceutical powders. AAPS PharmSciTech. 2009;10:780–8.
6. Hlinak AJ, Kuriyan K, Morris KR, Reklaitis GV, Basu PK. Un-
derstanding critical material properties for solid dosage form de-
sign. J Pharm Innov. 2006;1:12–7.
7. Shi Z, Cogdill RP, Short SM, Anderson CA. Process characteriza-
tion of powder blending by near-infrared spectroscopy: blend end-
points and beyond. J Pharm Biomed Anal. 2008;47:738–45.
8. Igne B, Zacour BM, Shi Z, Talwar S, Anderson CA, Drennen
JK. Online monitoring of pharmaceutical materials using mul-
tiple NIR sensors—Part I: blend homogeneity. J Pharm Innov.
2011;6:47–59.
9. Zacour BM, Igne B, Drennen JK, Anderson CA. Efficient near
infrared spectroscopic calibrations for pharmaceutical blend mon-
itoring. J Pharm Innov. 2011;6:10–23.
10. Haaland DM, Melgaard DK. New classical least-squares/partial
least-squares hybrid algorithm for spectral analyses. Appl Spec-
trosc. 2001;55:1–8.
11. United States Pharmacopeia-National Formulary. Acetaminophen
and caffeine tablets, Official Monographs. USP24 NF19. United
States Pharmacopeia-National Formulary; 1999.
12. United States Pharmacopeia-National Formulary. <1216> Tablet
Friability. USP24 NF19. United States Pharmacopeia-National
Formulary; 1999.
13. Mereton R.C. Disintegrants in tableting. In: Augburger LL, Hoag
SW, editors. Pharmaceutical dosage forms: tablets, volume 2:
rational design and formulation, 3rd ed. New York: Taylor &
Francis; 2008. pp. 240.
14. Zacour B.M., Drennen J.K., Anderson C.A. Hybrid controls com-
bining first principle calculations with empirical modeling for fully
automated fluid bed processing. Journal of Pharmaceutical Inno-
vation; 2012 (in press)
15. Garcia-Munoz S, Dolph S, Ward II HW. Handling uncertainty in
the establishment of a design space for the manufacture of a
pharmaceutical product. Comput Chem Engng. 2010;34:1098–
107.