REVIEW

Excipient Variability and Its Impact on Dosage Form Functionality

VIVEK S. DAVE,1 SUPRIT D. SAOJI,2 NISHIKANT A. RAUT,2 RAHUL V. HAWARE3
1
St. John Fisher College, Wegmans School of Pharmacy, Rochester, New York, USA
2
Department of Pharmaceutical Sciences, R.T.M. Nagpur University, Nagpur, India
3
Campbell University College of Pharmacy and Health Science, Buies Creek, North Carolina, USA

Received 15 September 2014; revised 30 October 2014; accepted 14 November 2014

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24299

ABSTRACT: Pharmaceutical excipients are essential components of most modern dosage forms. Although defined as pharmacologically
inert, excipients can be thought of as the true enablers of drug product performance. Unintentional variability in the properties of the
excipients may be unavoidable, albeit minimizable. The variability may originate from the source, the excipient-manufacturing process, or
during the manufacturing of dosage forms. Excipient variability may have a range of influences on their functionality and performance in the
dosage form. A better understanding of these influences on the critical quality attributes of the final product is of prime importance. Modern
analytical tools provide a significant assistance in characterizing excipient variability to achieve this understanding. The principles and
concepts of Quality-by-Design, process analytical technology, and design space, provide a holistic risk-based approach toward manufacture
and application of excipients in pharmaceutical formulations. The International Pharmaceutical Excipients Council (IPEC) has developed
guidelines for proper selection, use, and evaluation of excipients in pharmaceutical products.  C 2015 Wiley Periodicals, Inc. and the

American Pharmacists Association J Pharm Sci

Keywords: excipients; formulation; physical characterization; physicochemical properties; process analytical technology (PAT); Quality
by design (QBD)

INTRODUCTION from various sources, including plant, animal, mineral, biotech-

nology, and chemical synthesis. Pharmaceutical excipients are
Various agencies like the United States Food and Drug Ad-
a diverse group of materials such as solids, semisolids, liquids,
ministration (US FDA), the United States Pharmacopeia
and gases. Each excipient has a unique development process
(USP), and the International Pharmaceutical Excipient Council
and associated know-how. Excipients are used in a variety of
(IPEC) broadly define pharmaceutical excipients as any phar-
dosage forms and routes of administration. Excipient man-
macologically inert component other than the active pharma-
ufacturing processes typically involve harvesting, extraction,
ceutical ingredient (API) added intentionally to the pharma-
synthetic chemistry, agglomeration, size reduction, and fer-
ceutical formulations.1 These intentions are associated with
mentation. They are quite often manufactured on dedicated
one or more domains of the drug product development. Excip-
equipment, frequently using some form of continuous or batch
ients are used to improve processing (e.g., improving powder
manufacturing. The scale of manufacture may be very different
flow,2,3 powder compactibility,4–6 etc.), enhance aesthetics (e.g.,
to that typically encountered in the manufacturing of a phar-
identification,7 branding, etc.), optimize product performance
maceutical drug product.16 The discovery and development of
(e.g., modified drug release8–11 ), and/or to facilitate patient com-
a new chemical excipient undergoes an extensive regulatory
pliance (e.g., taste masking12–15 ). Excipients are found ubiqui-
review process similar to a new drug.17 This is carried out to
tously as an indispensable part of virtually every pharmaceu-
evaluate safety and toxicity in humans. Thus, all excipients are
tical formulation to serve one or more of the above-mentioned
required to fulfill a plethora of safety, quality, and functionality
purposes. They may constitute anywhere from 1% to 99% of
criteria issued by regulatory agencies before their adoption in
the total formulation mass. Therefore, excipient properties may
actual formulations. The US FDA maintains a database of ex-
have significant impact on the resulting formulation properties.
cipients (inactive ingredients or IIG) present in approved drug
As a major component of the pharmaceutical development,
products. This database serves as a guideline to the preformu-
preformulation scientists invest a substantial amount of time
lation and formulation scientists for a rational selection and
on the careful evaluation of various excipient-related parame-
use of excipients in the drug product. The approval of an ex-
ters such as drug–excipient compatibility and excipient pro-
cipient by the FDA for implementation in formulation design
cessability. Furthermore, the cost of an excipient and its
entails cross-referencing to pharma/food/cosmetic compendia.
consistent availability has been other important factor in the
Additionally, excipients are cross-referenced in an abbreviated
excipient selection.
new drug application, new drug application, and/or biologic li-
A majority of pharmaceutical excipients are supplied by the
cense application for a particular function in a drug product.
food and the chemical industry. Excipients are manufactured
Excipient approval also includes announcing of substances to
be “GRAS” (generally recognized as safe) or approving a “FAP”
(food additive petition).18
Correspondence to: Vivek S. Dave (Telephone: +443-789-8649; Fax: +585-385-
5295; E-mail: viveksdave@gmail.com)
The commercial manufacture of excipients is required to fol-
Journal of Pharmaceutical Sciences
low stringent current good manufacturing practices (cGMP)

C 2015 Wiley Periodicals, Inc. and the American Pharmacists Association guidelines and meet specifications regarding residuals (e.g.,

Dave et al., JOURNAL OF PHARMACEUTICAL SCIENCES 1

2 REVIEW
Figure 1. The impact of excipient variability on the CQAs of the drug product.
ethylene glycol in glycerine), degradation products (e.g., 5-
hydroxymethyl furfural in lactose), and so on. They require a
strict control over lot-to-lot excipient variability associated with
inherent discrepancies in the excipient sources. Manufacturers
need to implement built-in traceability in the supply chain to
ensure control of the overall quality. This is necessary to main-
tain safety, quality, and consistency in the product. Recently, it
has become increasingly important to clearly define the func-
tion of an excipient in a formulation along with the knowledge
of factors influencing its functionality. These requirements, to
a large extent, avoid unnecessary excipient-related variations
in the formulations apart from the APIs.
Other challenges include cost and awareness. Newer excip-
ients typically tend to be more expensive than traditionally
used excipients because of the associated development costs.
The excipient database needs to be updated often, a lack of
which may result in formulators not being aware of newly de-
veloped excipients with improved functionalities. Additionally,
limited manufacturing history [“Quality-by-Design” (QbD) type
studies] of new excipients presents an inherent risk of sourcing
and variability to the formulators. Thus, there exist develop-
ment and regulatory risks that may act as barriers to the use
of excipients, particularly newer excipients. This review aims
to provide a comprehensive overview of the trends in excipient
use and the influence of excipient variability on dosage form
functionality.
Pharmaceutical drug products are expected to deliver the
drugs to the patient in a required amount, required rate, and
with the same potency throughout their shelf-life. This depends
on the drug products’ resistance to changes in their properties
over the time. Changes in drug product properties are associ-
ated with various input parameters. These include variability
in the API, the excipients, and the process parameters.19–21 The
Dave et al., JOURNAL OF PHARMACEUTICAL SCIENCES
API and impact of the process parameters on the API is well
understood and controlled. Excipients comprise a substantial
mass of the formulation. As shown in Figure 1, excipients may
have a significant contribution to the variability in the criti-
cal quality attributes (CQAs) of the final drug product. Thus,
it is equally important to understand the impact of excipient
variability on the drug product manufacturability and perfor-
mance.
A sound understanding of the raw material and process vari-
abilities is essential to define a design space for a robust for-
mulation development. This can be achieved with two common
approaches.22 The traditional approach involves narrowing the
specifications with a tight control of input parameters, includ-
ing the API, the excipients, and the process variables. This
approach may not necessarily address the interactions of the
influencing variables. The sum of interactions, called interac-
tion factor, may lead to potential problems in developing a ro-
bust formulation. Another more modern approach is based on a
feed-forward control. In this approach, the assumed input vari-
ability is incorporated into the design space. This is followed by
utilizing a sufficient understanding of the process to define an
appropriate process end point. The second approach appears
to match the QbD intent in a better way. This approach might
provide a larger design space with a more flexible formulation
and process.22–24
Quality-by-Design is defined as a scientific, risk-based, holis-
tic, and proactive approach to pharmaceutical development.25
QbD along with process analytical technology (PAT) tools aims
to achieve a thorough understanding of the CQAs. These CQAs
also include the impact of raw material variability on the
quality of the finished product. This warrants an increased
excipient-supplier involvement in the formulation development
process. Traditionally, such involvement was either nonexistent
DOI 10.1002/jps.24299

or limited. Excipients have the potential to demonstrate a vari-
ety of functionalities depending on the involved application, for
example, food versus pharma, solid versus liquid dosage forms,
and so on. They are generally treated by excipient suppliers as
mere commodities “use as you choose” rather than specialized
product components. Therefore, preformulation scientists are
often unaware of the excipient-supplier’s capabilities to manu-
facture and supply excipients meeting their requirements.
Excipients typically constitute a significantly higher fraction
of a formulation than the API. Consequently, the heterogeneous
nature of excipient primarily influences the final product at-
tributes. Regardless of this fact, excipients are relatively less
well characterized. This limitation is now being recognized.
QbD emphasized the role of excipients as that of enabling the
API to be converted into a pharmaceutical product rather than
mere inert ingredients. Several agencies, including the Inter-
national Pharmaceutical Excipients Council (IPEC), the Inter-
national Society of Pharmaceutical Engineering (ISPE), the
American Society for Testing and Materials (ASTM), and the
National Institute for Pharmaceutical Technology and Educa-
tion (NIPTE) have focused on excipient characterization.24–26
EXCIPIENT VARIABILITY AND PRODUCT/PROCESS
ROBUSTNESS
Product Quality Research Institute (PQRI) defines process ro-
bustness as the ability of a manufacturing process to tol-
erate the expected variability of raw materials, operating
conditions, process equipment, environmental conditions, and
human factors.27 Moreton22 similarly described a robust formu-
lation as the one being able to accommodate the typical vari-
abilities observed in the “API, excipients, and process” without
compromising the manufacture, stability, or performance of the
product. The risk of nonrobust product or process may become
significantly higher, if the inherent excipient variability is over-
looked, missed, or even underestimated. A detailed knowledge
of the excipient manufacturing history or the supplier process
capability may reduce such a risk. Pharmaceutical excipients
are typically manufactured at a large-scale using some form of
a continuous or a batch process. Manufacturing processes are
designed to produce material within a relatively broad range
of specifications. The manufactured excipient will inevitably
show some variation within this range. The robustness of the
final drug product is dependent on the ability of the formula-
tion and the process to accommodate this variability without
compromising the final product performance.21 This is the core
of the “Design Space” concept utilized in QbD. Incorporating
excipient variability into the design of experiments, used to es-
tablish the “design space” and possibly the “edge of failure” can
produce a robust formulation.24
Independent studies have been carried out over the years
to identify and quantify the influence of excipient variabil-
ity on their functionality and eventually on the final product
CQAs. Kushner et al.28 studied the impact of the excipient
material property variations for three common excipients, mi-
crocrystalline cellulose (MCC), spray-dried lactose, and mag-
nesium stearate on the performance and manufacturability of
an immediate-release, dry-granulated, solid oral dosage forms.
These studies showed that the variations in the MCC and the
lactose particle size led to statistically significant changes in
the intermediate (e.g., blend particle size, blend flow function
DOI 10.1002/jps.24299
REVIEW 3
coefficient values, ribbon tensile strength, etc.) and final prod-
uct (e.g., tablet breaking force) properties. However, the excip-
ient particle size range examined was not sufficiently large to
adversely influence the immediate-release dosage form CQAs
studied.
Rudnic et al.29 evaluated the effect of variation in the degree
of cross-linkage and extent of carboxymethylation on the disin-
tegration and dissolution properties of sodium starch glycolate.
The study results showed a substantial modification of disin-
tegrant properties as a function of relatively small changes in
molecular structure of sodium starch glycolate. The study also
highlighted the importance of specifications for commercially
available disintegrants.
LOT-TO-LOT/BATCH-TO-BATCH VARIABILITY
All excipients incorporated in pharmaceutical drug products
are subjected to a fairly detailed chemical analysis in order to
establish their purity as a part of the quality control protocol.
However, recently, it has been recognized that source-to-source
variability and batch-to-batch variability in the solid state and
the material properties of both the drugs and the excipients
can have profound effects on the final product performance.30–32
Batch-to-batch variation in the excipient properties and varia-
tion between lots obtained from different suppliers can lead to
processing challenges or changes in the CQAs of the finished
products. Such variability can be attributed to the modifica-
tion of the excipient manufacturing process, or adaptation of
a more economic source of the raw material to manufacture
an excipient. However, more subtle variability in the excipi-
ents can occur without the indicated process changes. This can
still present problems for the formulators and the production
units.33 Chemically and physically equivalent excipient batches
may exhibit variable processing performance. Studies carried
out by Ticehurst et al.34 on "-lactose showed that minor vari-
ations in the degree of surface crystallinity may result in lot-
to-lot variability. The authors measured the surface energies of
four physically and chemically equivalent batches of "-lactose
obtained from the same source. They used the absorption be-
havior of a range of polar and nonpolar probes in inverse gas
chromatography. The results showed minor differences in the
surface energies of lactose from different lots. These differences
were attributed to minor variations in the crystallinity and
purity of the batches. Martino et al.35 evaluated the lot-to-lot
variability in the compression behavior of seven lots of lactose
monohydrate with an aim of identifying the cause of variability.
They had hypothesized four potential causes to explain lot-to-
lot variability in the selected batches of lactose monohydrate.
These causes were the differences in particle size distribution,
presence of anhydrous lactose, presence of $-lactose, and varia-
tion in the crystalline behavior. The study results showed that
the particle size distribution was not significantly different be-
tween lots. The presence of anhydrous lactose and $-lactose,
although observed, was not found in quantities significant to
make an impact. The degree of the order of crystalline struc-
ture was found to be the main reason for the observed lot-to-lot
variation. Landin et al.36 studied the influence of particle size
on the dehydration behavior of dicalcium phosphate dihydrate.
Differences in the particle size were found to be responsible for
the interlot and intermanufacturer variability observed in di-
calcium phosphate dihydrate. Batch-to-batch differences in the
Dave et al., JOURNAL OF PHARMACEUTICAL SCIENCES
4 REVIEW
excipient properties has been shown to influence a broad range
of excipient functionalities used in the solid, semisolid, and liq-
uid dosage formulations.37–40 Alvarez-Lorenzo et al.37 compared
the physicochemical properties of three lots of high-viscosity
hydroxypropylcellulose (HPC). The results showed clear differ-
ences in molecular weight, molecular structure, particle size
distribution, particle shape, and water affinity for HPC lots
from the same supplier, as well as lots from different suppli-
ers. The study also demonstrated differences in the drug re-
lease behavior of the dosage forms prepared using these lots of
HPC. The authors hypothesized that lot-to-lot variation in the
physicochemical properties of HPC influences the compression
behavior and the rate and extent of water uptake by the dosage
forms. This was attributed to the resulting observed variability
in the drug release. O’Laughlin et al.39 studied the influence
of lot-to-lot variation in the physicochemical properties of glyc-
eryl monostearate on the stability of an oil-in-water cream. The
difference found in the “acid value” of glyceryl monostearate
lots was a major determinant of the stability of the prepared
cream. Lots with higher “acid value” demonstrated better sta-
bility. Perez Marcos et al.40 evaluated seven lots of Carbopol R
934, which is a high and a heterogeneous molecular weight
acrylic acid-based cross-linked polymer, commonly used as an
extended-release matrix former in tablets. No significant differ-
ences in the infrared profiles, density, or carboxylic acid content
between the lots were reported. However, the rheological prop-
erties of the aqueous dispersions were significantly different
between the lots. This difference can be because of the differ-
ences in the mean molecular weight between the polymer lots.
Maincent41 summarized that although excipients are used to
prepare dosage forms to meet official pharmacopoeial mono-
graph specifications, their properties may vary from batch to
batch. These variations can alter the physicochemical proper-
ties, as well as functionalities of the final dosage formulations.
Their study showed that the tablets prepared with the same
excipient (e.g., MCC) originating from several suppliers might
display dramatic differences in their functionalities. The main
difference was associated with the in vitro dissolution rate,
which may consequently affect the bioavailability. In a recently
published article, Kushner20 proposed a simple method of using
the quantitative certificate of analysis (CoA) data to assess the
extent of lot-to-lot variability in excipients during drug product
development process. This study retrospectively carried out a
principal component analysis (PCA)-based multivariate anal-
ysis of quantitative physical-chemical properties found in the
CoAs of several commonly used tableting excipients such as
MCC, spray-dried lactose, and magnesium stearate. A large
number of CoAs for each material, that is, 968 for MCC, 439
for spray-dried lactose, and 168 for magnesium stearate, were
obtained from individual vendors and analyzed. The analysis
of the CoAs showed that although the lots of excipients were
manufactured within the vendor’s specifications, the PCA was
able to detect minor, site-to-site, and year-to-year variability in
these excipients. These examples demonstrate a strong need
for an adequate control of variability, even for the excipients
procured from the same manufacturer. The IPEC has drafted
the significant change guide for bulk pharmaceutical excipi-
ents. This guide directs the excipient manufacturer to evaluate
the significance of changes involving the manufacture of bulk
pharmaceutical excipients. This guide also steers to determine
the need for informing excipient customers and regulatory au-
thorities about the nature of the change.42
Dave et al., JOURNAL OF PHARMACEUTICAL SCIENCES
The increasing sophistication of the processing equipment
poses higher demands on the excipient quality than ever be-
fore. Uncontrolled variability in the excipient quality may lead
to inefficiencies during the development and production pro-
cess. This can also produce unacceptable variability in the end-
product quality. Therefore, adequate consistency of an excip-
ient property is essential to obtain a constant quality of the
final drug product and to facilitate a smooth production. The
batch-to-batch variations of excipients within specification can
be accommodated by good formulation practice. This includes
the use of different batches of inactive constituents during the
development and scale up. It might be a good idea to use the
batches of critical excipients at the outer limits of their specifi-
cations during the development stage.
SOURCE-TO-SOURCE VARIATION
Different suppliers are most likely the cause of variability in
excipient batches. Excipients may vary in quality because of dif-
ferences at the molecular and macroscopic level such as impu-
rity profile, molecular weight distribution (in case of polymers),
polymorphic form, particle morphology, particle size distribu-
tion, surface properties, hydration state, moisture content, and
so on.43
A large group of pharmaceutical excipients is derived from
natural products. This increases the excipient’s susceptibility
to seasonal as well as natural and artificial changes affecting
the end characteristics of the excipient.44,45 A given excipient
may be procured from a number of different manufacturers. It
is desirable for a pharmaceutical product to have more than
one source for each raw material because of the constant sup-
ply requirements. Excipients obtained from different suppli-
ers are often interchanged in the formulation. However, ex-
cipients of similar grade from different manufacturers often
show variability in their properties. Haware et al.46 carried
out a qualitative and quantitative analysis of the compression
behavior of similar grades of MCC using multivariate meth-
ods. They used Avicel PH 101 (FMC Biopolymer, Brussels,
R
Belgium) and Vivapur 101 (JRS Pharma, Rosenberg, Deutsch-
R
land, Germany) as representative grades obtained from differ-
ent vendors.46 The data obtained from the principle component
analysis (PCA) and the partial least squares (PLS) analysis was
able to demonstrate the variability in the physical and compres-
sion properties of MCC obtained from different sources (Fig. 2).
Parker and coworkers47–50 demonstrated the effect of the
source variation on the rheological behavior during the wet
granulation of two MCCs using rheological profiles in a series of
comprehensive studies. They also showed that dissimilar poly-
mers interact differently with cellulose substrates during the
wet massing process. In addition, for a second cellulose mate-
rial, variations were also observed in the pattern of interaction
between the binders and the excipient.
Landin et al.51 demonstrated the differences in the prop-
erties of MCC obtained from different source materials (wood
pulp) and different processing methods. These differences did
not significantly influence tableting parameters but were sug-
gested to be the potential causes of variability in the final phar-
maceutical products’ functionalities.51 Landin et al.45 also stud-
ied the characteristics of prednisone tablets prepared by direct
compression with six previously characterized MCCs from vari-
ous sources. MCCs of similar particle size produced tablets with
DOI 10.1002/jps.24299

Figure 2. The PCA score plots of the physical and compression prop-
erties of AvicelR PH 101 and VivapurR 101. The variables explain the
two principle components (PCs). The two displayed PCs explained 49%
and 21% of the variance, respectively. YPpl, yield pressure of plastic
deformation; YPelI , yield pressure of immediate elastic recovery; WoC,
work of compression; WoEI , work of immediate elastic recovery; d50,
mean particle size; HF, Hausner’s flowability ratio; and TS, tablet ten-
sile strength. Reproduced from Haware et al.46 with permission from
Pharmaceutical Development and Technology.
similar mechanical and microstructural properties. In contrast,
the dissolution rate of prednisone varied significantly with the
particle size and the chemical composition of MCC.45
The current national formulary (NF) monographs do not pro-
vide the tests reflecting the disintegrant functionality of sodium
starch glycolates. Thus, one cannot assume reliable perfor-
mance of the disintegrants from different sources meeting NF
standards.52 Bolhuis et al.53 demonstrated the differences in
the disintegration time of tablets containing sodium starch gly-
colate as a disintegrant. The sodium starch glycolate included
in the formulations were obtained from starch of different ori-
gins. The differences in the rate of penetration of water into
the particles of sodium starch glycolate were attributed to the
differences in the chemical composition, crystallinity, and par-
ticle size of the starches used in the manufacture of sodium
starch glycolates. Shah and Augsburger54 carried out similar
studies to characterize the physical properties of sodium starch
glycolate obtained from various sources. Differences in particle
sizes, surface area, porosity, surface morphology, and viscos-
ity between sources of sodium starch glycolate resulted in the
differences in the extent of liquid uptake by the disintegrant.
Landin et al.55 evaluated the characteristics of four brands
of MCC manufactured in Finland, India, Ireland, and Japan.
They found that the brands differed significantly in the chemi-
cal composition, crystal structure, and particle size of MCC. All
these differences were potentially relevant to the differences in
the powder flow properties and rheological behavior. Gamble
et al.56 quantified batch-to-batch and vendor-to-vendor varia-
tions in the solid-state characteristics of multiple batches of
anhydrous lactose obtained from three vendors. The study re-
ported the subsequent impact of these differences on process
ability and/or functionality.56 Thacker et al.57 investigated the
intermanufacturer and intramanufacturer variability among
the different grades and lots of xanthan gum produced
by two manufacturers. A significant intermanufacturer and
DOI 10.1002/jps.24299
REVIEW 5
intramanufacturer variability among the grades and lots of
xanthan gum was reported in this study. However, this vari-
ability was not reflected in the NF viscosity test specifications.
Whiteman and Yarwood evaluated six lactose-based mate-
rials as direct compression tablet excipients. The studied lac-
toses showed changes in the compaction properties to varying
degrees.58 These studies pointed out that although exchang-
ing one excipient for another in an existing formulation may
be economical, compendial specifications cannot adequately
differentiate between products with differing compaction
properties.
INFLUENCE ON FUNCTIONALITY
The excipients are included in the formulation to improve the
drug products’ processability, and to meet the required end-
product specifications. The desirable excipient properties relate
to the functional performance or the functionality. Excipient
functionalities are qualitative classifications describing the ra-
tionale or purposes or roles of an excipient inclusion in a drug
product formulation. Excipient functionality has been defined
in the IPEC Excipient Qualification Guide as: “A desirable prop-
erty of an excipient that aids manufacturing and improves the
manufacture, quality or performance of the drug product.”59,60
On the contrary, excipient performance is a broader term en-
compassing the excipient properties, including functionalities,
in a specific formulation.59,61
The main questions regarding the excipient functionality
are: how to assess and control it. Realistically, functionality can
only be assessed properly in the context of the finished phar-
maceutical product. Moreover, each application (formulation)
has unique requirements for functionality. The role of pharma-
copoeias in the assessment of excipient functionality is a topic
of current debate. There appears to be a general agreement that
excipient monographs have not addressed excipient functional-
ity or performance per se. Clearly, it was not the original intent
of the excipient monographs. The US and Europe are adopting
two very different approaches. The European Pharmacopoeia
has introduced a nonmandatory functionality related charac-
teristics (FRCs) sections in certain excipient monographs. This
is not an option in the US. Legally, all sections of a monograph
in both the USP, and the NF are mandatory.16,24,60 The current
regulatory environment including the QbD paradigm goes be-
yond simply identifying an excipient function. It emphasizes
excipient performance through the identification, evaluation,
and control of critical material attributes (CMAs) that assure
consistent performance throughout a product’s life cycle.59 The
development of appropriate functionality tests has been ham-
pered by numerous difficulties and complexities, including a
lack of a precise understanding of the mechanisms of excipient
functionality.
Zhao and Augsburger62 carried out a comprehensive study
on the function-related properties such as particle size, intrin-
sic and bulk swelling, water uptake ability, and the influence of
medium pH on these properties on five brands of croscarmellose
sodium. Studies specially emphasized on developing a discrim-
inating model formulation for the disintegrants performance
comparison and the quality control purposes.62 These studies
indicated that particle size, total degree of substitution, and the
ratio of basic to acidic substituents were among the most im-
portant factors affecting the disintegrants swelling efficiency.62
Dave et al., JOURNAL OF PHARMACEUTICAL SCIENCES
6 REVIEW
Figure 3. Analysis of excipient variability.
Rojas et al.63 studied the influence of the nature of MCC,
MCC I (prepared by acid hydrolysis of wood pulp) and MCC II
(prepared by mercerization of MCC I) on the physical properties
of tablets. Differences in the physical properties of MCC I and
MCC II dictated the powder and the tableting properties. These
findings emphasized the importance of selecting the right MCC
grade before formulating a drug in a solid dosage form. Shah
et al. studied relationships of physical properties differences
with the crospovidones functionality obtained from multiple
sources.64 The study observed major differences in the physi-
cal characteristics of crospovidone NF obtained from various
sources. These variations resulted in differences in the tablet
disintegration and dissolution containing insoluble crospovi-
done. Chamarthy et al.65 illustrated the influence of raw mate-
rial variability on the excipient’s functionality during process-
ing. Studies observed that differently processed starch samples
had essentially similar physical characteristics such as particle
size, specific surface area, and apparent crystallinity, and so on.
On the contrary, the compaction properties of the two lots were
distinctly different tested under all environmental and process-
ing conditions. Clearly, the two lots are diverse materials as per
the functionality point of view. The differences were attributed
to the altered surface energetic properties of the excipient.
Zhao and Augsburger66 observed differences in the disin-
tegration efficiency of the three classes of superdisintegrants.
The study concluded that the three disintegrants represent-
ing the three main classes of superdisintegrants (Ac-Di-Sol , R
Primojel , and Polyplasdone XL10) differed in their ability to
R R
disintegrate model tablets into their primary particles when
used at the same percentage by weight fractions. The study
further concluded that such differences could potentially affect
drug dissolution. Barra and Somma67 estimated the physico-
chemical property variation in thirteen commercial batches of
magnesium stearate from three vendors using various physico-
chemical tests. They found that the physical properties of mag-
nesium stearate varied between vendors as well as between
lots obtained from the same vendor. The study proposed uti-
lization of a standardized magnesium stearate mean particle
Dave et al., JOURNAL OF PHARMACEUTICAL SCIENCES
diameter and the use of talc in association with magnesium
stearate as two potential solutions to reduce the impact of
the variability of magnesium stearate. Recently, our labora-
tory studied the lubrication functionality of different lots of
bovine- and vegetable-derived magnesium stearates as a func-
tion of molecular and macroscopic properties using multivari-
ate analysis methods.68 These studies showed that molecular
properties such as crystallinity, moisture content, and macro-
scopic properties such as particle size and specific surface area
are mainly responsible for magnesium stearate lubrication
efficiency.68
The USP distinguishes four different HPMC grades by the
proportions of methoxy and hydroxypropoxy groups.69 The
properties of individual grades will furthermore depend on
their molecular weight. However, it has been demonstrated
that batches obtained from different suppliers of a similar
pharmacopoeial HPMC grade can lead to significantly differ-
ent performance.70
EXCIPIENT VARIABILITY ANALYSIS
Excipient variability may significantly affect the physicochem-
ical properties and the excipients functionality in final dosage
forms. Therefore, it is important to have analytical methods
in place for accurately assessing and identifying differences in
these materials.23
Figure 3 represents the different approaches used to assess
excipient variability at molecular and macroscopic level. Sev-
eral analytical techniques have been developed over the years
to accurately analyze and identify the excipient variability at
a molecular level. Some of the commonly utilized sophisti-
cated analytical techniques include moisture sorption analyzer,
differential scanning calorimetry/thermogravimetric analysis,
powder X-ray diffractometry, near-infrared spectroscopy, and
solid-state nuclear magnetic resonance (SSNMR). Vogt and
Williams in a recent paper-reviewed several advanced ap-
proaches for effective solid-state analysis of pharmaceuticals.71
DOI 10.1002/jps.24299

Excipient Variability Analysis at a Molecular Level
A molecular level excipient characterization such as poly-
morphic form identification, structural differences, crys-
talline/amorphous content, and water content variations can
be detected using SSNMR spectroscopy experiments. SSNMR
spectroscopy can be very useful during the preformulation
and the formulation stages. This is particularly important
when the source of an excipient changes, or the manufactur-
ing and/or storage conditions could potentially alter the excip-
ient functionalities.72,73 Sperger and Munson74 demonstrated
the applicability of SSNMR in detecting the differences in the
structural properties among common polysaccharide-based ex-
cipients in a recent study.
Near-infrared spectroscopy is another analytical technique
gaining popularity for analyzing excipient variability and
functionality.10,75–81 Gabrielsson et al.82 used NIR to quantify
the amount of lot-to-lot variability and its impact on the per-
formance of a new drug product. NIR was found to be useful in
confirming the robustness of their product in the face of exist-
ing excipient lot-to-lot variability. It is important to understand
the capabilities and limitations of the utilized technique while
choosing a technique for the excipient variability analysis. In-
strumental effects (instrument drift and aging, lamp changes,
etc.), environmental effects (changes in relative humidity in
storage facilities), and active ingredient(s) and excipients vari-
ability are likely to affect the analytical abilities of a technique.
Igne et al.83 studied the effects of instrumental aging, excipient
particle size distribution, excipient manufacturer variability,
and active ingredient physical transformation. The study con-
cluded that variation in the raw material properties had a sig-
nificant impact on the precision and the accuracy of predictions
from the model.
Excipient Variability Analysis at Macroscopic Level
The macroscopic excipient properties such as particle morphol-
ogy, and density (bulk, tapped, and particle) can be measured
by scanning electron microscopy and other official methods
mentioned in the USP.5,6 These measurements are used for an
indirect assessment of the variations in the excipient charac-
teristics. In addition to these compendial methods, the noncom-
pendial methods such as powder rheometry has been used to
evaluate the powder flowability of excipients.84 The variabil-
ity in excipient compressibility can be assessed with sophis-
ticated instruments such as the compaction simulator.4,9,85,86
Compaction simulators allow simulation of the controlled com-
pression parameters similar to industrial manufacturing con-
ditions. This technique produces a highly accurate, real-time
force-displacement data with a small sample-size requirement
of the materials. The parameterization of the obtained force-
displacement data with well-known global mathematical equa-
tions such as Heckel, Kawakita, or other energy descriptors
allow the evaluation of material’s deformation behavior.14,87,88
This approach has been commonly utilized to identify the vari-
ability in the deformation tendency of the excipients.89,90
Excipient Variability Analysis using Multivariate Techniques
Characterization of excipient variability at a molecular and
macroscopic level, using above-mentioned sophisticated instru-
mentation, generates a huge amount of data. Multivariate
analysis methods can be used to quantify excipient variability
both qualitatively (PCA) and quantitatively (multiple linear
DOI 10.1002/jps.24299
REVIEW 7
regressions, principle component regressions, and PLS
regressions).91 Haware et al.89,92,93 utilized multivariate meth-
ods to differentiate the variability in the functionalities of var-
ious grades of directly compressible celluloses and lactoses, as
well as lubrication efficiencies of varying sources of magnesium
stearate.
QbD AND EXCIPIENT VARIABILITY
Managing excipient variability is an essential element in the
designing and the manufacturing of a robust drug product. It
is an integral task in applying QbD principles.26 The US FDA’s
21st century cGMP initiative and ICH Q8 guidelines encour-
age the pharmaceutical excipient users to apply QbD princi-
ples in developing “flexible” formulations and processes. This
is necessary to cope with anticipated raw material variability
in producing robust and consistently performing products.24,94
One approach to achieve this could be to optimize and control
the process based on the raw material properties. Such process
control can compensate the incoming variability to yield the fin-
ished product, consistently meeting the quality target product
profile (QTPP). Another approach is to specify the raw materi-
als’ CQAs tightly enough to ensure a consistent performance to
the QTPP. Of these approaches, the first approach dealing with
adjustments during the manufacturing process to compensate
for inherent raw material variability appears to be more viable.
A fundamental concept within QbD is the design space. ICH
Q8 defines design space as follows: the multidimensional com-
bination and interaction of input variables (e.g., material at-
tributes) and process parameters that have been demonstrated
to provide assurance of quality. Working within the design
space is not considered as a change. Movement out of the design
space is considered to be a change and would normally initiate
a regulatory postapproval change process. Design space is pro-
posed by the applicant and is subject to regulatory assessment
and approval.24
Quality-by-Design is a relatively new approach in the US.
Correct applications of QbD allow industry to adopt better,
quicker, and more efficient working practices. This encourages
development of the robust formulations and processes.16 IPEC
Americas has formed a QbD product development committee to
address the following areas: proper selection and use of excipi-
ent performance tests (addressing functionality)—decision tree
approach; robust formulations development (including QbD,
PAT, etc.); and the introduction of coprocessed excipients with
customized functionalities (removal of regulatory barriers and
customer acceptance).16,60 QbD concepts emphasize the need
for characterizing CMAs (e.g., micromeritic, chemical, thermal,
rheological, and mechanical properties) and define their role
in the formulation and manufacturing processes. QbD concepts
also help in understanding the role of excipients in the for-
mulation and the process using the science and risk-based ap-
proach for excipient selection (compatibility and functionality)
and improved excipient characterization. QbD provides a clear
understanding of the tolerance limit of the excipient variability
by a process, to ensure a predictable, high-quality, reproducible,
and stable product. In addition, QbD defines relevant analytical
tools to assess the excipient variability impact on the formula-
tion, process, and product performance.24,26
Several researchers have now begun to incorporate
QbD principles for the characterization of excipient
Dave et al., JOURNAL OF PHARMACEUTICAL SCIENCES
8 REVIEW
variability. Fu et al.95 determined the intergrade and interbatch
variability of sodium alginate using appropriate rheological
methods and conditions. This provided insight into the delin-
eation of the design space as a part of QbD for sodium alginate-
based formulations.95
CONCLUSIONS
The use of excipients in drug products is ubiquitous and in-
dispensable. An unintentional variability in the excipients is
unavoidable. Excipients batch-to-batch, source-to-source, and
supplier-to-supplier variability can be present at both molecu-
lar as well as macroscopic levels. Thus, clear understanding and
quantification of the nature, source, and the extent of excipient
variability is critical for robust formulation development. It is
very important to understand the impact of these variabilities
on the excipient functionality and eventually on the CQAs of
the final product. An intelligent use of QbD and design space
principles helps understand this impact of excipient variability
on its functionality and performance. The application of multi-
variate analysis with sophisticated instrumentation serves as
important tools for the characterization and quantification of
excipient variabilities.
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