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Advancing Development & Manufacturing
PharmTech.com
2014
SOLID
DOSAGE
AND
EXCIPIENTS
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Phar mTech. com
CONTROLLED RELEASE
4 Controlled-Release Technologies
Create Opportunities for
Solid-Dosage Drug Formulators
Cynthia A. Challener
GENERIC-DRUG FORMULATIONS
16 Selection of Excipients
in Generic Formulations
Aloka Srinivasan
HOT-MELT EXTRUSION
24 A Practical Guide to Hot-Melt Extrusion
Scale-Up for Pharmaceutical Applications
Justin R. Hughey
PRODUCT DESIGN
30 Safety by Design—Mitigating the Risk
of Medication Errors Through Product Design
An Interview with Kamlesh Oza and Perry Cozzone of Colorcon
MODULAR SYSTEMS
36 Using Modular Systems
in Solid-Dosage Manufacturing
Pär Almhem, Reiner Lemperle, and Camilla Sivertsson
GRANULATION
44 Obtaining User-Defined Particle
Size Distribution Using Dry Granulation
Dejan Djuric
QUALITY BY DESIGN
48 A Quality-by-Design Approach to Optimize
In-Process Curing of EUDRAGIT NM 30 D
Thomas Dassinger, Jessica Müller-Albers, and Sascha Jautze
52 Ad Index
Solid Dosage and Excipients 2014
Issue Editor: Rita Peters.
On the Cover: Robert George Young/Photographer’s Choice RF/Getty Images; Dan Ward
EDITORIAL
Editorial Director Rita Peters rpeters@advanstar.com
Managing Editor Susan Haigney shaigney@advanstar.com
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Eric Langer info@bioplanassociates.com; and Cynthia A. Challener, PhD challener@vtlink.net
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Sean Milmo (Europe, smilmo@btconnect.com), and Jane Wan (Asia, wanjane@live.com.sg)

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4 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Controlled Release
C
linical benefits, enhanced tolerability, better compliance,
and patent exclusivity are driving interest in modified-
release technologies. In addition, the need to meet qual-
ity-by-design (QbD) requirements is also affecting excipi-
ent manufacturers and pharmaceutical companies alike. Excipient
manufacturers and formulation service providers, including FranÇois
Scheffler, vice-president of global marketing for BASF’s Pharma In-
gredients & Services business unit; Randy Wald, a senior research
fellow with Bend Research, part of Capsugel’s Dosage Form Solutions
business; Don Loveday, strategic marketing manager with Celanese
Corporation; True Rogers, technologies leader at Dow Pharma & Food
Solutions; Firouz Asgarzadeh, director of technical services, Pharma
Polymers & Services – NAFTA Region with Evonik Corporation’s
Health Care Business Line; and Anil Kane, executive director of the
Global Formulation Sciences business of Patheon Pharmaceutical De-
velopment Services spoke to Cynthia Challener, contributing editor
to Pharmaceutical Technology, about the leading trends driving the
development of controlled-release technologies for solid-dosage drugs.
Polymers with the right mechanism of action
PharmTech: What types of excipients are best suited for the controlled/
extended release of active ingredients from solid-dosage formulations?
Kane (Patheon): Excipients play an important role in formulating
controlled-release/extended-release dosage forms. Most notably, the
properties of the excipients, such as their particle sizes, particle size
distributions, molecular weight swelling potential, binding properties,
porosity, and many others determine the behavior of the formulation
with respect to erosion and diffusion. Typically, an API embedded in
Controlled-Release Technologies
Create Opportunities for Solid-
Dosage Drug Formulators
Lifecycle management
opportunities including
clinical and compliance
benefits coupled with the
need for patent extensions
are impacting the
development of controlled-
release technologies for
solid-dosage drugs.
Cynthia A. Challener is a
contributing editor to
Pharmaceutical Technology.
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a matrix of excipients is slowly released over a 12- to
24-hour period.
Asgarzadeh (Evonik): The application of excipients
to modify the release of oral dosages is a several
centuries old practice. In the past, fatty acids,
waxes, keratin, zein, and numerous other natural
materials were used, while more recently modi-
fied cellulosic and fully synthetic methacrylate
polymers are employed to control the release of
APIs. Due to the tight manufacturing controls that
are possible, synthetic poly(meth)acrylates exhibit
extremely low batch-to-batch variations and nar-
rower specification ranges when compared to ex-
cipient polymers based on inherently more variable
natural raw materials.
Loveday (Celanese): Popular parenteral controlled-
release polymer excipients include ethyl vinyl ace-
tates (EVAs), silicone elastomers, and thermoplastic
polyurethanes. These polymeric excipients are used
as a controlled-release structure or membrane, and
the polymer is used to deliver active ingredients via
a dissolution/diffusion mechanism in which the API
is dissolved in and diffuses from the excipient.
Scheffler (BASF): Excipients enable the formulator
to tune the drug release according to the thera-
peutic and efficacy requirements of a given prod-
uct. For delayed-release formulations, where the
goal is to release the active ingredient in a certain
area of the gastrointestinal tract, the most com-
monly used excipients are acrylic polymers and
cellulose-derivatives, which dissolve at specific pH
levels. The polymer is coated onto the tablet, pel-
let, or particle and remains stable in the stomach
at acidic pH, but dissolves to instantly release the
active ingredient as soon as it reaches the targeted
alkaline pH area of the intestine. Pulsatile systems
undergo a moisture/liquid uptake process as soon
as they enter the gastrointestinal tract and up to a
point at which the dosage form bursts and releases
the active ingredient.
Extended- or sustained-release formulations tar-
get the release of the active ingredient over a period
of time and can be achieved in various ways, such
as through an insoluble but permeable or porous
film coat, by using a porous matrix of an insoluble
polymer, or through the use of an eroding matrix.
Wald (Bend Research): Polymeric functional ex-
cipients are broadly classified as either hydrophilic
(gastrointestinal soluble [some regionally]) and/or
swellable, or hydrophobic and generally insoluble.
There are three extended-release (ER) dosage form
architectures commonly used for which functional
excipients are enabling.
In ER matrix systems, the API and excipients—
which are generally a mix of hydrophilic polymers
(various cellulose derivatives, polyethylene oxides
[PEOs], and carbomers) with varying substitution
patterns and molecular weights (MW) to obtain the
desired diffusion, swelling, and erosion drug release
mechanisms—are comingled with the API and
other excipients. Hydrophobic polymers (ethyl cel-
lulose and various methacrylates) and lipids (stearyl
alcohol, Gattefosse Gelucires, and glycerol behe-
neate) are also used for matrix monolithic (capsule
Controlled Release
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Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 7
or tablet) and multiparticulate systems to produce
diffusion and erosion drug release mechanisms.
Oral multiparticulate (MP) technology is increas-
ingly employed in pharmaceutical dosage forms to
provide both ER and delayed-pulsed release. Bio-
availability-enhanced, or taste-masked finished
dosage forms are comingled with API and other
excipients within capsules and tablets or in sachets
or bottles for suspension constitution. Functional
coatings, typically based on insoluble polymers such
as ethyl cellulose and methacrylates, are commonly,
but not exclusively, applied to MP systems, such as
granules, drug-layered, or extruded spherical matrix
pellets. Diffusion, osmotic pressure, pH, or meta-
bolic triggers can serve to release the active agent.
Plasticizers and soluble polymer and small molecule
excipients are commonly used to modulate the me-
chanical and diffusion characteristics of the films.
Lipid multiparticulate technology using a process
such as melt-spray-congeal (MSC) can also be em-
ployed as-is or subsequently functionally coated for
ER in order to enhance bioavailability or for abuse-
deterrence or taste masking.
Finally, osmotic systems generally use different
MW polyethylene oxide polymers with inorganic
salts or sugars as osmogens (i.e., the tablet core), and
cellulose acetate with polyerthylene glycol polymers
as the semipermeable membrane coating. In effect,
osmotic systems are comprised of closely coupled
hydrophilic matrix and coated ER systems, and
several products have been commercialized using
this base system in single or bilayer tablet core con-
figurations. Osmotic systems also provide abuse-
deterrence due to the architecture and nature of
the excipients.
Rogers (Dow): Hydroxypropyl methylcellulose
(HPMC) matrix tablets are the most commonly
utilized modified-release (MR) oral solid dosage
forms due to cost efficiency and ease of manufac-
ture. HPMC is a soluble cellulose derivative that
takes on water from the gastrointestinal media
and forms a swollen HPMC layer at the surface of
the matrix tablet through which API is released
by both diffusion and erosion. There are different
grades of HPMC that can be used to modulate re-
lease to different extents as well as facilitate matrix
tablet manufacture.
The importance of proper excipient selection
PharmTech: How are specific excipients for extended
release chosen for a given API?
Scheffler (BASF): In general, the various decision fac-
tors on the choice of excipients to be used in a for-
mulation can be summarized with three main di-
mensions: indication and necessary dose, the active
ingredients’ characteristics, and the preference of the
target patient group for the type of solid dosage form.
Within these dimensions, a formulator will identify
which excipients cover the specific needs.
The active ingredients’ mechanism of action to be
formulated can require the release of the active in-
gredient to take place in a certain area in the gastro-
intestinal tract. A sensitivity of the active ingredient
against acidic environments can require an initial
delay to ensure that the extended release only starts
when the dosage form arrives in the intestinal tract.
Furthermore, the chemical nature of a certain active
ingredient can suspend the use of certain excipients
due to risk of interaction.
The medication of specific patient groups can
require the formulation of extended release multi-
particulates rather than tablets to ensure compli-
ance while avoiding unintended misuse. And, for
particular active ingredients with risk of abuse by
8 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
patients (i.e., opioids), excipients should ensure that
even improper handling of the dosage form will not
lead to intoxication.
Rogers (Dow): API dosage and solubility as well as
pharmacokinetic (PK) aspects influence selection
of the MR dosage form. An API exhibiting a short
half-life or narrow therapeutic index is a good can-
didate for formulation into an MR delivery system.
The MR delivery system will enable the formulator
to ultimately achieve the desired PK profile. Fol-
lowing dosage form selection, one must consider
the excipient needed to modulate release to achieve
the desired PK profile. Water-insoluble polymers
or polymers exhibiting pH-dependent solubility
are used for barrier-coatings. A swelling polymer,
like high-molecular weight polyethylene oxide, is
included in the push layer in an osmotic push-
pull system. Although water-insoluble polymers
are sometimes used to make inert matrix tablets,
HPMC is most commonly employed to make hy-
drophilic matrices and is necessary for formation
and erosion of the swollen diffusion layer.
Kane (Patheon): Specific excipients are chosen based
on the target rate of release required for a certain ac-
tive drug substance. A water-soluble drug would be
difficult to formulate as compared to a hydrophobic
drug with poor aqueous water solubility. The func-
tionality of the excipients required for the type of
dosage form will determine which excipients should
be considered in the pre-screening stage. For exam-
ple, for a controlled-release dosage form being devel-
oped using the osmotic release principle, we would
use water-soluble excipients and buffers to create
the osmotic pressure and a semi-permeable mem-
brane that is used with organic solvents to create the
push–pull mechanism in the core. The mechanism
of action such as swelling, osmosis, erosion, diffu-
sion, disintegration, or ionic binding will determine
the selection of the right quality and grade of the
material. The chemical and physical stability of the
API, when mixed with the excipient, is also a key
criterion for selection.
Loveday (Celanese): Parenteral polymeric excipients
can be chosen based on the solubility of the API,
the inertness of the polymer, the purity of the ex-
cipients, and the ease of processing. Most important
is the solubility and bioavailability of the API in a
reference biological system (e.g., blood, the GI tract,
mucosal fluid). In addition to the API solubility and
diffusion rates, the target API release rate and du-
ration, the total API loading, and the form factor
of the delivery vehicle must be considered. Local
delivery is important for some applications in order
to reduce the effective dosage.
In recent years, thermoplastics like EVA have be-
come popular due to their ease of use in hot-melt
extrusion processing. Currently EVA is only used in
parenteral applications, such as transdermal patches,
transmucosal inserts, and subcutaneous implants,
but it has been well-studied and referenced for oral
applications, and we believe it can also be used in
combination with other polymers, including water-
soluble systems.
Controlled Release
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Controlled Release
Asgarzadeh (Evonik): The excipients and release-
controlling polymers must be chemically compat-
ible with the API. Early pre-formulation studies
can identify many incompatibilities. In the case of
incompatibility with enteric or reverse enteric poly-
mers, the issue can usually be resolved by the appli-
cation of a thin neutral compatible barrier film prior
to applying the desired modified release polymer.
In sustained-release applications, chemical incom-
patibilities are more difficult to overcome because
the active ingredient has to diffuse through the
sustained-release polymer membrane. Poly(meth)
acrylate-based sustained release polymers are some
of the most versatile systems because API release
can be controlled not only by varying the film
thickness, but also by mixing these polymers at dif-
ferent ratios. Further modifications to release can be
made by adjusting the ionic strength through the
incorporation of salts or acidic or basic ingredients
within the active core.
Wald (Bend Research): We have developed a decision
tree based on fundamental science methodology for
choosing the most appropriate/effective technology
and formulation. Key factors considered include: the
desired API pharmacokinetic performance, often
determined using biomodeling; intestinal perme-
ability, which can be regional for the small intestines
and the colon; the biotransformation and physico-
chemical properties of the API; the dose; and the
chemical stability.
These factors determine the target drug release
profile (e.g., first/zero order, pulsed release, delayed
or targeted release, immediate and extended release).
In addition, along with the known characteristics
of the various ER technologies and marketing con-
straints, these factors impact the preferred physical
form of the drug (e.g., crystalline vs. amorphous
dispersion or solubilized; particle size), ER design
architecture, and drug release mechanism(s). Simul-
taneously, the preferred drug product presentation
is chosen: tablet, capsule, or sachet. This process
greatly narrows the choice of excipients preferred
for the technology and manufacturing process.
Bioavailability,
continuous processing, and more
PharmTech: What key trends are driving development
of excipient technology for extended release solid
dosage formulations today?
Loveday (Celanese): The excipient development driv-
ers are the bioavailability of poorly soluble drugs
and the delivery of biologics. The opportunity to
extend patent coverage using improved controlled-
release delivery technologies is also a factor in the
demand for novel excipients.
Rogers (Dow): QbD and the push towards continu-
ous manufacturing and better process control are
key trends. It is important for the drug product
manufacturer to understand proactively how raw
material and process variability can impact dosage
form performance and manufacturability. Excipient
manufacturers are learning with the drug product
manufacturers how to best work together to address
these challenges. In other words, there is still work
to be done.
Wald (Bend Research): There are two current indus-
try trends that can be cited as impacting ER dosage
forms. One is continuous processing, where mul-
tiple continuous unit operations are coupled into
an integrated system. To date, the interest has been
focused on immediate-release tablets and capsules,
although some ER technologies like hydrophilic gel
matrix tablets, are directly amendable to such pro-
duction methods. We expect this trend to quickly
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expand into other ER process technologies. For ex-
ample, there is a current gap in continuous process-
ing with respect to functional coatings; yet, there
are very promising prototypes under development.
An additional trend is increasing regulatory re-
quirements for abuse-resistance drug formulations,
particularly extended-release products, due to the
higher doses. Excipient technologies, such as thick-
ening agents, taste modifiers, waxy or high melting
point excipients, are increasingly employed to meet
product profiles, including abuse resistance.
Asgarzadeh (Evonik): Patient compliance can be im-
proved through a reduction of the number of re-
quired doses per day using sustained-release poly-
mers. Another key trend is to increase the efficacy
of existing products with the use of enteric coatings
that facilitate delivery to the site of best absorption
or the site of action. In addition, product lifecycle
management is an increasingly hot trend in the de-
velopment of new products.
Scheffler (BASF): In general, the driving force be-
hind development of extended-release technologies
is the desire to offer more convenient and compli-
ant medication solutions to the patient, which at the
same time is a means to differentiate products from
the competition. Growing interest in extended-
release multi-particulates and fixed-dose combi-
nations with more than one active ingredient are
impacting the requirements for excipients. Abuse
prevention of extended release formulations is also
an important issue.
Room for improvement
PharmTech: What are some of the limitations of
current excipient technology for controlled-release
formulations?
Loveday (Celanese): Areas in need of improvement in-
clude API solubility limits, super-saturation, recrys-
tallization, and the thermal stability and processing
characteristics of API and excipient combinations.
Asgarzadeh (Evonik): Because sustained-release for-
mulations are designed to ensure a continuous API
delivery over a longer period of time, each dosage
unit contains more API than an immediate-release
dosage. Any film defects such as mechanical cracks
can therefore result in more API being released than
intended, which can negatively impact a patient’s
health. In order to overcome such issues, the sus-
tained release polymers are generally applied onto
active particles or pellets before filling into capsules
or undergoing tablet compression (i.e., a multiple-
unit pellet system [MUPS]). When compressing
a MUPS, the coating’s functional integrity must
remain unchanged. In addition, most controlled-
release coatings are vulnerable to alcohol-induced
dose dumping.
Wald (Bend Research): The continued industry pres-
sures on costs, facile development programs, and
the streamlining of manufacturing has created a
continued need for excipients with a broader range
of chemical and physical properties that are directly
usable for a wide range of drug-release mechanisms
Controlled Release
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Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 13
and rates, but that do not require complex process-
ing during drug product manufacture. More op-
tions for polymer molecular weight and backbone
substitution, broader particle size ranges, lower re-
active impurity profiles, and aqueous latex coating
formulations for existing solvent-only products are
examples where incremental improvements con-
tinue to be needed.
Recent developments in
polymer chemistry and cooperation
PharmTech: What recent advances in excipient tech-
nology have been made in response to these issues?
Loveday (Celanese): The demonstrated suitability of
parenteral drug delivery has increased awareness in
the industry for direct to body delivery. Examples of
technologies that are expanding the potential range
of deliveries are polymer co-excipients, including
the utilization of new comonomers and blends;
functionalization of polymer excipients with hydro-
philic groups; excipients with multilayer structures;
and the delivery of multiple active ingredients in
one delivery vehicle.
Asgarzadeh (Evonik): Poly(meth)acrylate-based poly-
mers are the most suitable polymers for sustained-
release MUPS due to their high flexibility and over
700% elongation at break. These polymers do not
require a plasticizer and can resist high compression
forces without exhibiting any cracks in the films.
They may also be used to develop alcohol-resistant
sustained-release matrix formulations. Evonik has
also developed a proprietary alcohol-resistant bi-
layer coating formulation that addresses the alcohol
dose-dumping issues mentioned earlier.
Vcaps
®
Plus hypromellose capsules for
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14 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Wald (Bend Research): Excipient suppliers have re-
sponded to regulatory and industry forces and
trends by providing new excipients, additional
grades of existing excipients, and improved supply
chain (shipping and shelf life) products. Recent ex-
amples include new polymers and polymer grades
designed specifically for hot-melt extrusion process-
ing. Other examples include more MW and viscos-
ity grades for cellulosic polymers, the availability of
both aqueous latex and powder versions of meth-
acrylates, PEO with a much longer shelf life, and
new suppliers adding key excipients, and thus pro-
viding secondary sourcing options. Co-processed
excipients represent another advance in excipient
technologies; while there are certain regulatory as-
pects to be considered, these systems generally offer
improved functionality and simpler manufacturing.
Rogers (Dow): We see movement towards a team-
based approach in product development, where
the formulation and manufacturing groups are
engaging with their excipient manufacturers to
define the critical performance variables early in
the process and explore the material design space
in order to meet QbD filing expectations. Further-
more, we are seeing more emphasis on reducing
manufacturing costs through process simplifica-
tion and improved reliability. This need led us to
develop a new direct-compression HPMC product
line that enables formulators and manufacturers to
achieve exceptional tablet-to-tablet reproducibil-
ity while lowering the total cost of goods through
the use of semi-continuous dry powder processing
techniques, such as roller compaction and direct
compression.
Scheffler (BASF): With respect to new excipients,
BASF has introduced polyvinyl acetate, an excipi-
ent that is completely insoluble throughout the
gastric tract and applicable both as a matrix for
osmotic diffusion and as a porous film coating
around an active ingredient core. In combination
with a highly effective pore former such as mac-
rogol-poly(vinylalcohol) graft polymer, it can be
used in classical tablet formulations and advanced
dosage forms, such as multi-particulates or even in
liquids formulation.
It should also be noted that pharmaceutical
companies, formulation solution providers, and
excipient manufacturers have gained significant
experience on the interplay between production
processes and formulations, leading to new solu-
tions. For example, we have introduced polymers
and developed process know-how in the area of
hot melt extrusion, thus enabling the controlled
release of barely soluble/poorly bioavailable APIs.
Expect further incremental
advances for the most part
PharmTech: What excipient technologies are under
development today that could have an impact on
the formulation of controlled-release solid dosage
drugs in the future?
Asgarzadeh (Evonik): The development and com-
mercialization of new excipients for oral applica-
Controlled Release
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Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 15
tions is very challenging due to the significant
investment required, the global regulatory restric-
tions, and the fact that formulators prefer to work
with known excipients. As a result, incremental
advances are seen, rather than original break-
throughs. The industry has been focused on other
areas, such as the combination of known excipi-
ents, continuous coating and granulation, new
formulations and approaches for addressing the
low bioavailability of poorly soluble and/or poorly
permeable actives, and the development of poly-
mers that are resistant to alcohol dose dumping
and intentional abuse.
Loveday (Celanese): Working with pharmaceutical
companies, excipient manufactures are making
efforts to commercialize new excipient formula-
tions or forms with different chemistries, excipient
structures, and morphologies. To lower the finan-
cial, technical, and regulatory barriers, another
important area of development is the utilization
of well-known excipients in new applications. For
example, Celanese has provided material for nu-
merous developmental programs on the use of
EVA, such as in new oral dosage forms.
Rogers (Dow): Some of the polymers that have been
historically used to modify release are surprisingly
effective for enhancing API solubility, which is
necessary for achieving sufficient bioavailability.
I am hearing more and more about formulators
solubilizing APIs, but subsequently needing to
slow down release, either because the API has a
narrow therapeutic window or because the API has
a half-life in the body that warrants MR formula-
tion. We are currently developing cellulose-based
excipients that have dual functionality to allow
both solubility enhancement and modified-release
from a single polymer. Such polymers have the po-
tential to greatly enhance drug product efficacy
and streamline manufacturing.
Wald (Bend Research): Excipients under develop-
ment in the areas of amorphous solid dispersions
and lipids are important enablers for the future
because they provide enhanced in-situ solubil-
ity, dissolution rates, and permeation-enhancing
functions. Excipient vendors and formulation
scientists are challenged to couple these systems
with existing and potentially new ER formula-
tion and processing technologies; however, there
is synergy between the two genres since several
of the enhanced absorption excipients also have
modest intrinsic ER functionality, which allows for
higher doses and more drug release and dosage
form architecture design flexibility. As an example,
we continue the development of both amorphous
solid dispersion and lipid multiparticulate tech-
nology by combining excipients in new ways to
achieve bioavailability enhancement, taste mask-
ing, and/or ER.
Scheffler (BASF): Excipient suppliers, pharmaceu-
tical companies, and formulation service provid-
ers will leverage innovative combinations of ex-
cipients and process technologies. For example,
the use of software for modeling and testing
potential solutions and predicting the applica-
bility of excipients to address actual formulation
challenges is increasing. Further down the road,
we may see breakthrough technologies for con-
trolled release. One very interesting approach is
Philips’ IntelliCaps—an electronically controlled,
environmentally sensitive release vehicle that al-
lows the precise and conditional control of drug
release, fully adjusted to personal patient needs.
Such a technology could potentially reinvent con-
trolled release. PT
16 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Generic-Drug Formulations
E
xcipients (e.g., diluents, disintegrants, binders, lubricants, gli-
dants, coating agents, anti-oxidants, preservatives) frequently
constitute the major component of a drug formulation and
play a pivotal role in deciding the quality of the drug product.
In this paper, the author discusses some general concerns regarding
the right choice of excipient in a generic formulation based on her ex-
perience as an ex-regulator at the Office of Generic Drugs, FDA and a
consultant. Case studies, where the selection of the excipients, based on
quality and grade played a significant role in determining the quality of
the generic drug and the approvability of the applications, are presented.
It is common practice in industry to use the term “excipient” and
“inactive ingredient” interchangeably to reference the components in
the drug product, other than the API. Even Code of Federal Regulations
21 (CFR) 314.94 (a) (9) (ii), in relation to generic drugs, states that infor-
mation regarding the “inactive ingredients” in the generic formulation
need to be provided (1). The history of pharmaceutical development,
however, has shown that excipients are anything but “inactive,” and the
role played by the variability of the excipients in the manufacturing and
performance of the drug product has been well documented in literature
(2). With the introduction of quality by design (QbD), the importance of
the physical and chemical attributes of excipients in establishing quality
of a drug product and their role in the product life cycle has come more
to the limelight and the question-based review (QbR) for annotated new
drug approvals (ANDAs) has several questions related to the rationale
behind the selection of excipients in formulations (3).
Selection of excipients
The legal basis of selection of excipients in generic drugs is provided
by 21 CFR 314.94 (a) (9) (ii), which allows for flexibility in case of ex-
Selection of Excipients
in Generic Formulations
Aloka Srinivasan
The selection of excipients
is important in generic
formulations due to
the impact it has on the
risk and performance
of generic drugs.
Aloka Srinivasan, PhD, is a
principal consultant with
PAREXEL INTERNATIONAL,
Aloka.Srinivasan@parexel.com.
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18 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
cipients for many dosage forms, as long as they do
not affect the safety and efficacy of the proposed
drug product (1). Thus, for solid oral dosage forms,
oral solutions, and oral suspensions, the generic-
drug manufacturer may use excipients that are
different from those in the reference-listed drug
(RLD). However, a drug product manufacturer
should make sure that the excipient proposed in
the formulation is part of the FDA Inactive Ingre-
dient Database (IID or IIG), which provides the
highest level of an inactive ingredient approved for
a single dose based on the proposed route of intake
(4). The use of inactive ingredients not mentioned
in the IID is not acceptable, unless additional
safety data are submitted.
The information in the IID website provides
the highest level of an ingredient approved for a
single unit dose (4). Thus, the ANDA sponsors
need to exercise caution in using this information
in formulating their drug product. The Office of
Generic Drugs (OGD) evaluates the maximum
daily intake (MDI) of the excipient based on the
maximum daily dosage (MDD) of the drug prod-
uct and frequently cites deficiencies, based on the
fact that the maximum daily intake of the excipi-
ent based on the MDD of the drug may be higher
than that for any FDA approved product. Under
such circumstances, ANDA sponsors are usually
requested to submit supportive data for the safety
of the excipient at the proposed level, following the
recommendations provided in the Guidance for In-
dustry: Nonclinical Studies for the Safety Evaluation
of Pharmaceutical Excipients (5). It is advisable for
an ANDA holder to follow the advice in QbR Fre-
quently Asked Questions and identify examples of
approved products in the market that have used
the excipient in question at the proposed levels (6).
If a formulation calls for the use of significantly
high amounts of a particular excipient, it may be
prudent of the ANDA sponsor to seek the advice
of OGD regarding the appropriateness of the use
though a Controlled Correspondence. However,
with growing challenges from the pharmaceuti-
cal industry (7), the usability of IID is on its way
to being updated by FDA. One of the significant
upgrades proposed is the standardization of the
ingredient names in the IID, which includes list-
ing of common cosmetic, brand, and trade names
of ingredients as well as their synonyms in the
database. The other update is the inclusion of the
maximum daily intake of the excipient in addition
to the potency per unit dose. Once completed, this
update of IID will resolve one of the significant
issues that are currently impacting the timely ap-
proval of ANDAs. Until then, however, a generic
firm should perform adequate studies to justify the
maximum daily intake of the excipients in their
formulation, based on FDA approved marketed
drug products.
Case studies
The first case demonstrates the importance of se-
lection of an excipient for a generic formulation
that has already been evaluated for safety.
Case study one. A drug product manufacturer pro-
posed a formulation with an inactive ingredient
A manufacturer should
make sure that the excipient
proposed in the formulation
is part of the FDA Inactive
Ingredient Database.
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20 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Generic-Drug Formulations
that was not present in IID. Based on the infor-
mation in the public domain, however, the excipi-
ent was considered generally recognized as safe
(GRAS). The justification for selection of the ex-
cipient was based on analysis of a number of over-
the-counter (OTC) products, which contained this
excipient. The fact that the excipient was not in the
IID database, however, showed that it had never
been evaluated for safety in any drug product ap-
proved by FDA. The drug product manufacturer,
therefore, was requested to submit safety data to
support their proposed formulation or reformulate
the drug product.
There is often a perception in the generic-drug
industry that manufacturing a generic drug with
excipients similar to that in the RLD may lead to
fewer problems. The truth is, sometimes, far from
this. The selection of the excipients in generic-drug
formulation should be based on proper under-
standing of the product and the process, and not
merely to emulate the RLD formulation. In most of
the case studies provided in this paper, the excipi-
ents selected for the generic-drug formulation were
the same as those in the RLD; however, the differ-
ence in the drug product manufacturing process
and the grade or quality of the excipients played a
significant role in the final drug product quality.
The next case study deals with the broad aspect
of having an excipient in the formulation that is
known to react with the API, based on the RLD
label. A common example of this is the use of lac-
tose in formulation for drugs products with APIs,
which are primary amines. There are several such
drugs in the market. The amount of the “amadori
complex” impurity formed in these products, how-
ever, vary greatly based on the amount of the lac-
tose used, grade and quality of the lactose, and the
manufacturing process. Similarly, it has been seen
that the use of glycerin as an excipient in liquid
formulations containing APIs with free carboxylic
acid groups lead to the formation of the glyceryl
ester. But, the amount of ester formed may vary
with slight variation of the critical process param-
eters such as the time and temperature during
mixing and some critical quality attributes such
as the pH of the formulation. There are numer-
ous publications regarding incompatibilities of ex-
cipients with certain APIs (8-10). Notwithstanding
what the innovator has proposed, whenever a drug
product is formulated with an excipient that may
have known incompatibility with the API, addi-
tional pharmaceutical development studies need
to be performed. Also, controls for the plausible
impurities formed by the API-excipient interaction
should be proposed in the drug product release
and stability based on ICH Q3B or safety data, in
case the amount exceeds ICH Q3B qualification
threshold. If the RLD contains the same excipi-
ent, the limit for the API-excipient complex may
be justified by comparison with the RLD close to
expiration date.
Case study two. An interesting case study of the
consequence of using lactose with a primary amine
based on the formulation of the RLD was seen in
the generic version of a drug that has a primary
amine functional group. The information available
in the public domain showed that the RLD, which
was a primary amine, was initially formulated with
Formulating a generic drug
with excipients similar to that
in the RLD is not always the
answer.
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 21
lactose. This drove numerous generic-drug firms
to use lactose as a diluent and binder in their ge-
neric formulation. Depending on the quantity of
lactose in the formulation and the manufactur-
ing process, however, the amount of the ‘amadori
complex’ was found to vary over a large range in
these generic formulations. Also, the matter was
complicated by the fact that the RLD was eventu-
ally reformulated by replacing lactose with micro-
crystalline cellulose. Thus qualifying the ‘amadori
complex’ impurity of the generic products based
on testing versus the reference product was not
possible. Many of the generic-drug firms reformu-
lated their products with the elimination of lactose,
while others qualified the ‘amadori complex’ im-
purity based on safety studies, both of which lead
to longer approval time.
Mimicking the innovator’s formulation and
using the same inactive ingredient without un-
derstanding the impact of the critical attribute of
the excipient on the API has affected the quality of
many generic products. Based on the source and
grade of the excipient, the critical material attri-
butes may vary significantly, and this may, in turn,
affect the quality of the final drug product over its
shelf life. There are several interesting cases attest-
ing to this. These cases imply that a better under-
standing of the excipients and controls beyond the
compendia may sometimes be needed to assure the
quality of the final drug product throughout its
lifecycle. They also raise the age old question as to
whether meeting the United States Pharmacopeia-
National Formulary (USP-NF) criteria is enough to
consider the quality of an excipient acceptable, or
specifications of excipients should be tailored from
drug product to drug product based on the nature
of the drug substance and the formulation.
Case study three. A supplement was submitted to
an ANDA for a drug that contained a secondary
amine functional group, to incorporate an addi-
tional impurity in the drug product specification
release and stability. Postapproval stability lots for
this drug product had shown a significant rise in
this impurity over shelf life, which was initially
below detection limit. Thus, the impurity was
assumed to be a degradant of the drug product.
Structure elucidation by liquid chromatography-
mass spectrometry (LC-MS) and other techniques,
however, established the impurity as an N-acetyl
derivative of the drug substance. Further inves-
tigation showed that the impurity was present in
the RLD as well, although in lesser quantity. The
source of this N-acetyl impurity was not clear until
all the excipients were analyzed for acetic acid and
the source was identified as the capsule shells of
the generic product has well as the RLD. Finally,
the supplement was approved with inclusion of sat-
isfactory control of the N-acetyl impurity in the
drug product specification.
Case study four. A similar case was observed with
another drug product with amine functional
group. Based on information available in the pub-
lic domain, the RLD formulation contains polac-
rilin potassium. Polacrilin potassium is an ion
exchange resin frequently used in oral formula-
tions as a tablet disintegrating and/or tastemasking
agent and has a monograph in the USP-NF. Chemi-
cally, it is a partial potassium salt of a copolymer of
methacrylic acid and divinyl benzene (11). There
are several sources of polacrilin potassium in the
market, which meet the USP-NF criteria and the
ANDA holder had selected one of them for their
formulation of the drug product. Beyond the
twelfth month, the ANDA holder observed sig-
22 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Generic-Drug Formulations
nificant increase in the level of an impurity in the
exhibit batch, which was initially controlled as an
unknown. Isolation and limited characterization
of the impurity using LC-MS showed it to be a
complex of the drug substance and methacrylic
acid, though the exact structure could not be elu-
cidated. Analysis of the polacrilin potassium lots
used to manufacture the exhibit batches of the
drug product showed them to have about 4000
ppm of methacrylic acid. Further investigation by
the sponsor showed that the polacrilin potassium
available from various sources in the market may
vary significantly in free methacrylic acid content,
ranging from a few parts per million to a few thou-
sand parts per million. All these grades, however,
met the NF monograph because NF monograph
of polacrilin potassium does not have a control for
methacrylic acid content. Thus, to reduce the level
of the possible API-methacrylic acid adduct ob-
served in the drug product, the manufacturer took
several steps: the source of polacrilin potassium
was changed to make sure that the initial content
of methacrylic acid in this excipient was low; a
suitable control of methacrylic acid was included
in the specification of polacrilin potassium; the
manufacturing process, which involved wet granu-
lation, was modified. The polacrilin potassium was
added later in the process and the temperature for
drying the granulate was reduced. This case study
shows the importance of understanding the criti-
cal material attributes of the excipients that play a
key role in the manufacturing process and impact
on the quality of the finished dosage form. It also
highlights the importance of setting specification
for the excipients, which in addition to meeting
the USP-NF criteria, also include suitable controls
of these critical attributes.
Conclusion
Excipients are a significant part of the drug formu-
lation and play a crucial role in assuring drug prod-
uct manufacturability and consistency of quality
over its lifecycle. This is corroborated by the up-
dates to Question based Review-Quality Overall
Summary provided by Office of Generic Drugs
in FDA/GPhA Workshop of June 2013, which has
several questions in Section 3.2.P.2 related to the
impact of excipients on formulation and manu-
facturability (12). Understanding of the physico-
chemical properties of the excipients, which may
affect the critical process parameters in the manu-
facturing process and the critical quality attribute
of the drug products, are an integral part of the
QbD approach. What makes the role of excipient
selection in the QbD paradigm more complicated
is the variability in the excipients due to global na-
ture of the source and insufficient controls. It is the
responsibility of the drug product manufacturer to
understand the crucial physicochemical properties
of the excipients that might affect the formulation
or manufacturability and monitor these properties
as a part of their control strategy. Incorporating
the study of excipient variability on the formula-
tions early in the pharmaceutical development of
generic drugs may be the best way to ensure that
quality is built in the drug product.
In some cases, additional
controls, beyond those
proposed in USP-NF may
be required to assure the
performance of the excipients.
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 23
Acknowledgment
The author would like to acknowledge Robert Iser,
Director of Division IV, Office of Generic Drugs
and Acting Associate Director for Policy Develop-
ment, OPQ, FDA for his valuable input related to
the Inactive Ingredient Database and also some of
the case studies provided here.
References
1. FDA, 21 CFR 314 Applications for FDA Approval to
Market a New Drug, [Content and Format of an Ab-
breviated New Drug Application, Sec. 314.94 (9)].
2. P. Van Arnum, Supplement to Pharm Technology, pp.
s26-s28 (March 2013).
3. Office of Generic Drugs, QbR Quality Overall Sum-
mary Outline, www.fda.gov/Drugs/Developmen-
tApprovalProcess/HowDrugsareDevelopedandAp-
proved/ApprovalApplications/
AbbreviatedNewDrugApplicationANDAGenerics/
ucm120974.htm, accessed Mar. 10, 2014.
4. FDA, Inactive Ingredient Search for Approved Drug
Product, www.accessdata.fda.gov/scripts/cder/iig/,
accessed Mar. 10, 2014.
5. FDA, Guidance for Industry, Nonclinical Studies for
the Safety Evaluation of Excipients (Rockville, MD,
May 18, 2005).
6. FDA, QbR Frequently Asked Questions (June 4,
2007)
7. R. Iser, “Inactive Ingredient Database–FDA Update,”
GPhA Fall Technical Conference (Bethesda, MD,
Oct. 30, 2013).
8. S.S. Bharate, S.B. Bharate, A.N. Bajaj, J. Excipients
and Food Chem., 1 (3), pp. 3-26 (2010).
9. R. Panakanti, A.S. Narang, Pharmaceutical Re-
search, 29(10), pp. 2639-2659 (2012).
10. K. Jackson, D. Young, S. Pant, Pharm. Sci. Technol-
ogy Today, 3(10), pp. 336-345 (2000).
11. USP, USP 36–NF 231 (U.S. Pharmacopeial Conven-
tion, Rockville, Md., 2014).
12. J.A. Maguire, Update on Question-based Review
(QbR), GPhA/FDA CMC Workshop (Bethesda, Md.,
June 04, 2013). PT
Advances in Hot-Melt Extrusion Manufacturing
Hot-melt extrusion using twin-screw extruders is a continuous process that is being used to produce solid-dosage
formulations. Twin-screw extrusion is a proven and well-understood manufacturing technology that has been used
for 50 years in the plastics and food industries, and has been embraced by the pharmaceutical industry in the past
decade. Charlie Martin, president of Leistritz Extrusion, speaks with Pharmaceutical Technology about the use of twin-
screw extrusion in pharmaceutical processing today and encourages the industry to understand and apply continuous
extrusion principles to process designs. Click on the player to hear the interview.
24 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Hot-Melt Extrusion
H
ot-melt extrusion (HME) is currently one of the fastest
growing technology platforms being used to solve
formulation challenges in the pharmaceutical industry.
Its f lexibility has resulted in products ranging from
bioavailability-enhanced immediate-release dosage forms to
controlled-release devices (1–5). In recent years, it has been used
extensively in solubility-enhancement applications, in which
polymer-based amorphous solid solutions are prepared (6–8). In this
respect, the technology competes directly with spray-drying and
offers advantages in terms of cost and throughput.
Due to extensive use of HME in the plastics industry, there are
numerous extruder types available for pharmaceutical applications.
The extruders primarily differ in the size, number, and relative
rotation of the screws, as well as the degree of intermeshing. The type of
extruder most commonly used for pharmaceutical applications is the
fully intermeshing co-rotating twin-screw extruder. A fundamental
characteristic of this extruder type is the opposing directions of
material flow in the intermeshing region, which creates a self-wiping
effect and facilitates conveyance through the extruder. As they are
widely used and most relevant to pharmaceutical applications, the
present discussion will focus on this type of equipment.
When referring to the size of an extruder, the outer diameter of the
screw (D
o
) is normally referenced. Extruders in the pharmaceutical
industry are available in a wide range of sizes, from laboratory units
with screw diameters of less than 5 mm to commercial units with
screw diameters greater than 50 mm. While the use of extruders
with diameters greater than 50 mm is certainly possible in pharma-
A Practical Guide to Hot-Melt
Extrusion Scale-Up for
Pharmaceutical Applications
Justin R. Hughey, PhD
The author discusses
various aspects of the
hot-melt extrusion process
and outlines a practical
approach to scale-up.
Justin R. Hughey, PhD,
is senior scientist – Particle
Engineering, Hovione,
40 Lake Drive, East Windsor,
NJ 08520, United States,
tel. 609.918.2434,
jhughey@hovione.com.
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Available in several model configurations, including new upgrade kits available for XP analytical balances that
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26 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Hot-Melt Extrusion
ceutical applications, smaller extruders are gener-
ally preferred due to quenching limitations, typical
batch size requirements, and risk mitigation. Ex-
truders in the 27 to 40 mm range are commonly
used in commercial pharmaceutical applications
while extruders in the 10 to 27 mm range are typi-
cally used during product development. When re-
quired throughputs exceed equipment capacity, it
is not uncommon to operate multiple extruders
of the same size in parallel rather than scaling-
up to a larger extruder. Scale-up, however, is often
inevitable at some point during the development
process. Having been used in the plastics industry
for decades, the technology is well characterized
and affords straightforward scale-up from devel-
opment extruders to those used to manufacture
commercial products (9–12). The following sec-
tions will discuss various aspects of the HME pro-
cess and outline a practical approach to scale-up.
Geometric similarity
To ensure that materials with similar properties are
prepared from scale-to-scale, geometric similarity
should be maintained between extruders. Main-
taining geometric similarity of the screw design
(i.e., equivalent conveying, distributive, and disper-
sive elements) as well as screw geometry itself is im-
portant and can have implications on average shear
input and residence times. One of the most criti-
cal screw measurements is channel depth, which is
more commonly thought of in terms of the ratio of
the outer diameter of the screw to the inner diame-
ter of the screw (D
o
/D
i
). As the D
o
/D
i
ratio decreases,
free volume within the extruder decreases (see
Figure 1a), and as a consequence, average shear in-
creases. In this configuration, larger screw shafts are
possible, which can effectively transmit more torque,
albeit at the expense of throughput. Conversely,
when this ratio increases (see Figure 1b), free vol-
ume increases at the expense of average shear rate
and torque capacity (13). Clearly, there is a tradeoff
between free volume and torque capacity with any
given D
o
/D
i
ratio. Equipment flexibility, particularly
in larger extruders, allows the balance to shift in
either direction for specific product needs. Regard-
less of the D
o
/D
i
ratio used at the development scale,
the value should be maintained during scale-up to
ensure similar average shear rates.
The length to diameter (L/D) ratio describes
how long the processing section is in terms of the
screw diameter. For instance, an extruder can be
configured in L/D ratios as low as 15:1 to the more
common 40:1 size and even longer for specialized
applications, with modular barrel sections being
the primary building blocks (i.e., 5 D
o
in length).
The L/D ratio chosen for a specific process is
dependent on the number and type of unit opera-
tions required during processing. For instance, an
L/D ratio of 25:1 may be used when operating in
the miscibility regime in which the processing
temperature is above the melting point of all
Figure 1: Cross-sectional view of screws having a (a) low and
(b) high ratio of outer to inner diameter of the screw (D
o
/D
i
).
A
L
L

F
I
G
U
R
E
S

A
R
E

C
O
U
R
T
E
S
Y

O
F

L
E
I
S
T
R
I
T
Z
a)
b)
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 27
components. Conversely, a ratio of 40:1 or larger
may be required when operating in the solubili-
zation regime or when multiple feed points are
used and additional unit operations are required.
Regardless what L/D ratio is used during develop-
ment at the small scale, it should be maintained
in larger units because it has implications on the
residence time distribution and shear input.
Volumetric scale-up
When limited by throughput, or when increases
in throughput result in undesirable product
properties, scale-up to an extruder with a larger
free volume is usually necessary. Assuming
geometric similarity, the throughput that should
theoretically result in an identical product can be
estimated with Equation 1:
Throughput
large
= Throughput
small ( )
D
0, large
3
D
0, small

Equation 1
For example, assume that a process was developed
on an 11-mm extruder with a throughput of 1.0 kg/hr.
Based on this equation, an identical product
could be prepared on a geometrically similar 18-mm
extruder operating at a throughput of 4.4 kg/hr.
However, even if geometry is identical, differences
in critical quality attributes (CQAs) can arise due to
decreased heat and mass transfer at the larger scale.
This occurs because free volume of an extruder
increases as a function of D
o
3
while surface area
within the extruder increases as a function of D
o
2
.
While this effect may not have a significant impact
on CQAs when scaling from an 11-mm extruder
to an 18-mm extruder, it can become problematic
when the difference in extruder size is large. An
extreme example would be scaling from an 11-mm
extruder operating at 1 kg/hr directly to a 40-mm
extruder operating at 48 kg/hr. Clearly this
scale-up has the potential to result in substantial
differences in heat and mass transfer with impli-
cations on product quality. Specifically, reduced
heat transfer can impact product temperature,
homogeneity, and amorphous nature while reduced
mass transfer can limit devolatilization efficiency.
Heat and mass transfer limitations can be
combated, to an extent, by making adjustments to
process parameters or equipment design. Decreasing
the screw speed, increasing the L/D ratio, or
changing the screw design may allow for increased
heat and mass transfer without affecting product
quality. Alternatively, throughput can be lowered
to improve these characteristics. In this scenario,
the exponent in Equation 1 is normally adjusted
to a value between 2 and 3, depending on the
type and severity of the limitation (13). Although
necessary, changing process parameters to
improve heat and mass transfer may change
scale-independent responses and ultimately,
the CQAs of the final product.
Maintenance of scale-independent responses
When scaling up, scale-independent responses,
such as specific energy, residence time distribution,
and product temperature, should be maintained. As
previously discussed, deviations from ideality
during scale-up require adjustments to be made to
process parameters that can ultimately affect the
product. The use of process modeling and experi-
mental design during development to understand
the impact of these changes on scale-independent
responses will facilitate successful scale-up and
elucidate the edges of failure.
While operation at the edge of failure at the
development scale can result in materials with the
desired CQAs, problems may arise during scale-up.
28 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Hot-Melt Extrusion
A common pitfall encountered during early
development work is the use of a low throughput
relative to extruder capacity when drug substance
supplies are limited. In this situation, extruder
screws are “starved” if screw speeds are not
sufficiently low, effectively causing a high specific
energy input, which is defined as the energy input
per unit mass (Equation 2).
Specifc Energy =
Motor rating (kW) ⋅ % max. torque ⋅ % max. rpm ⋅ gearbox efciency
Throughput (kg / hr)
Equation 2
High specific energy situations are not ideal in most
pharmaceutical applications because they result
in long residence times and broad distributions
(see Figure 2, brown line), which can translate to
decomposition of the drug substance and/or poly-
mer, both of which are unacceptable from a commer-
cial product standpoint. Moreover, this scenario can
result in a false-positive result with respect to the
generation of an amorphous product when oper-
ating in the solubilization regime (i.e., processing
temperature below the drug melting point) due to
extended exposure to a high temperature.
On the other end of the spectrum, operating at
high throughputs relative to capacity results in the
screws being “full.” This scenario generally results
in low specific energy input and a short residence
time with a narrow distribution (see Figure 2, blue
line). While desired CQAs may be attained at the
development scale when operating in this state,
mass- and heat-transfer limitations after scale-up
may result in a product that is poorly mixed, or
one that contains crystalline material when an
amorphous product is required.
As emphasized, maintenance of the residence
time distribution between scales is often critical
due to solubilization and degradation limitations
at short and long residence times, respectively. For-
tunately, interplay between processing variables
allows for a degree control over residence time, albeit
at the expense of other scale-independent responses,
which may or may not be critical. For instance,
aggressiveness of the screw design can have a major
impact on residence time distribution (14). That is,
if a given screw design is made less aggressive by
the addition of conveying elements, it is expected
that the residence time will decrease and the dis-
tribution will become narrower at the expense of
average shear. Similarly, when screw speed is in-
creased at a constant throughput, residence time
decreases and the distribution becomes narrower
at the expense of higher specific energy input and
peak shear rates.
Characterization of materials manufactured
over a range of specific energy inputs allows for an
understanding of the effect specific energy has
on quality attributes. Given that specific energy
is proportional to screw speed and inversely pro-
portional to throughput, concurrent adjustment
allows for maintenance of specific energy and by
default, similar residence time distributions. In
addition to its usefulness at the development scale,
specific energy input can be used as a benchmark-
Figure 2: Residence time distributions as a function of
throughput and degree of fill.
FULL SCREWS
MEDIUM SCREWS FILL
SCREWS VERY STARVED
time/age
Q
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 29
ing tool during scale-up as values should remain
constant from scale-to-scale.
Prior to scale-up, it is also important to have
an understanding of how peak shear rates affect
product quality attributes rather than focusing
on screw speed. Peak shear rate is proportional
to screw speed and inversely proportional to the
overflight gap (i.e., clearance between screw and
barrel interface), as shown in Equation 3.
Peak shear rate (s
-1
) =
π ⋅ D
o
⋅ rpm
overfight gap ⋅ 60

Equation 3
To apply this equation, assume that an 18-mm
extruder with an overflight gap of 0.10 mm is op-
erating at 500 rpm. To scale to a 27-mm extruder
with an overflight gap of 0.15 mm, the same peak
shear rate would be obtained when the screw speed
is set at approximately 500 rpm. In this specific
case, screw speed happens to directly scale to the
larger extruder. However, if the 27-mm extruder
exhibited wear and the overflight gap was 0.25 mm
(i.e., the recommended wear limit), the required
screw speed would be about 800 rpm to achieve
the same peak shear rate. Generally speaking,
overflight gaps increase with extruder size as tip
velocity of the screw also increases.
Conclusions
Scale-up of HME processes is relatively straight-
forward when the extruders at both scales are
geometrically similar with respect to screw design,
D
o
/D
i
ratio, and L/D ratio. When these criteria are
met, a simple relationship between relative volumes
is used to provide a theoretical throughput at the
larger scale, which should result in the maintenance
of critical scale-independent responses. Heat
and mass transfer limitations may exist, however,
particularly when the difference in scales is large.
When these limitations occur, it is necessary to
make adjustments to process parameters to main-
tain those scale independent responses that have
the greatest impact on CQAs of the final product.
References
1. J. Breitenbach, Eur. J. Pharm. Biopharm. 54: 107–117
(2002).
2. M. M. Crowley et al., Drug Dev. Ind. Pharm. 33:
909–926 (2007).
3. M. A. Repka et al., Drug Dev. Ind. Pharm. 33: 1043–
1057 (2007).
4. M. R. Thompson and J. Sun, J. Pharm. Sci. 99 (4),
2090–2103 (2010).
5. S. Weatherley et al., J. Pharm. Sci. 102 (12), 4330–
4336 (2013).
6. J. C. DiNunzio et al., Eur. J. Pharm. Biopharm. 74 (2)
340–351 (2010).
7. G. Van den Mooter, Drug Discovery Today: Technol-
ogies. 9 (2) e79-e85 (2012).
8. A. L. Sarode et al., Eur. J. Pharm. Sci. 48 (3) 371-384
(2013).
9. A. Dreiblatt, “Process Design” in Pharmaceutical
Extrusion Technology, I. Ghebre-Selassie and C.
Martin, Eds. (Marcel Dekker, New York, 2003), pp.
140–154.
10. C. McKelvey et al. “Applying Extrusion to Pharma-
ceutical Formulation Design,” Society of Plastics
Engineers Annual Technical Conference (2008).
11. L. Schenck, G. M. Troup, M. Lowinger, L. Li and C.
McKelvey, “Achieving a hot melt extrusion design
space for the production of solid solutions” in
Chemical Engineering in the Pharmaceutical Indus-
try: R&D to Manufacturing, D. J. a. Ende, Eds.
(Wiley, New York, NY, 2011), pp. 819–836.
12. A. Dreiblatt, “Technological Considerations Related
to Scale-Up of Hot-Melt Extrusion Processes” in
Hot-Melt Extrusion: Pharmaceutical Applications,
Eds. (John Wiley & Sons, Ltd, 2012), pp. 285–300.
13. C. Martin, “Twin Screw Extrusion for Pharmaceuti-
cal Processes” in Melt Extrusion, M. A. Repka, N.
Langley and J. DiNunzio, Eds. (Springer, New York,
2013), pp. 47–79.
14. J. C. DiNunzio, F. Zhang, C. Martin and J. W. Mc-
Ginity, “Melt Extrusion” in Formulating Poorly
Water Soluble Drugs, R. O. Williams III, A. B. Watts
and D. A. Miller, Eds. (Springer, New York, 2012),
pp. 311–362. PT
30 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Product Design
T
o err is human; but when it comes to medication errors,
patient safety is put at risk. It is estimated that each year,
approximately 7000 deaths in the United States are caused
by medication errors (1). The Division of Medication Error
Prevention and Analysis (DMEPA), which is part of FDA’s Center for
Drug Evaluation and Research (CDER), defines medication errors as
preventable events that may cause patient harm due to the inappropri-
ate use of medicines while in the control of healthcare providers or
consumers (2). The increasing prevalence and high cost of medication
errors have prompted both regulators and manufacturers to look more
closely into the role of product design in reducing the risk of medica-
tion errors. As noted by FDA, the goal is to design a drug product that
enables the safe and correct use of medicines and minimize the chances
of human errors. Kamlesh Oza, general manager of Colorcon’s Brand
Enhancement Services, and Perry Cozzone, president, North America,
share insights on how product appearance, such as size, shape, color,
and imprint can make a difference in mitigating medication errors.
A widespread problem
PharmTech: Medication errors are the most common preventable
cause of adverse events and deaths. How widespread is this problem?
Colorcon: Unfortunately, medication errors are widespread and have
been recognized as a global problem. Issues range from manufactur-
ing product mix-ups, dispensing, administration, and caregiver-to-
patient errors.
As noted in the New England Journal of Medicine, ‘Literature that
measures the magnitude of prescription error, medication adherence,
Safety by Design—Mitigating
the Risk of Medication Errors
Through Product Design
A Q&A moderated by Adeline Siew, PhD
The increasing prevalence
and high cost of
medication errors have
prompted regulators and
manufacturers to look into
the role of product design in
ensuring the safe and correct
use of medicines. Kamlesh
Oza and Perry Cozzone
from Colorcon share
insights on how product
appearance, such as size,
shape, color, and imprint
can make a difference in
reducing medication errors.
F
O
T
O
G
R
A
F
I
A
B
A
S
I
C
A
/
G
E
T
T
Y

I
M
A
G
E
S
32 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Product Design
and placebo effects attributable to generic or brand
pill appearance is limited; explicit outcomes research
in their area is still lacking. No one knows how many
medication errors are due to problems related to vi-
sual cues. Nonetheless, it is clear that the external
attributes of pills can have benefits separate from
the therapeutic effect of their active ingredients’ (3).
It is also clear that the problem is widespread
enough to spark FDA’s attention, resulting in the
publication of two draft guidance documents (4, 5)
recommending visual product design steps
that both innovator and generic oral solid-dose
producers should consider in the development of
their products.
Causes of medication errors
PharmTech: What are the common causes of
medication errors?
Colorcon: It appears that not much has changed
since a study by FDA, more than 10 years ago,
revealed that the most common error involving
medications was related to administration of an
improper dose of medicine, accounting for 41% of
fatal medication errors over the time studied (6).
We looked at the color and shape profiles of tablet
recalls in 2012 in the US. Forty-nine percent of the
tablets recalled were white and of those, 58% were
round. Over the past several years, most manu-
facturers have tried to make a distinction between
multiple dosages of the same product using
different colors. There are several documented
cases where a product recall was due to a mix-up in
production between plain white tablets that looked
alike. Obviously, just a single recall is costly and a
potential threat to patient safety.
Appearance matters
PharmTech: Regulators have begun looking more
closely at the role of product appearance in en-
suring safe and correct use of medicines. Can you
describe how the appearance, such as shape, size
and color, of a tablet or capsule can help reduce
medication errors, enhance patient safety, and
improve treatment adherence/compliance?
Colorcon: The 2012 Draft Guidance on Safety Con-
siderations for Product Design to Minimize Medica-
tion Errors (4) is quite clear in its recommendations
regarding shape, size, and color.
Three key points in the guidance outline size,
shape, and color for the benefit of prescribers and
patients to identify the medication easily by:
t Avoiding multiple strengths that look the same
t Ensuring imprint codes are included, clearly
visible, and different based on strengths
t Ensuring that extended- or delayed-release
products are distinct from their immediate-
release counterparts.
PharmTech: The shape and size of a tablet or
capsule can cause swallowing difficulties. What
can/should manufacturers do to address this
issue? What guidance does FDA provide on
product shape and size?
Colorcon: In the December 2013 FDA Draft Guid-
ance for Industry on the Size, Shape, and other
Physical Attributes of Generic Tablets and Cap-
sules (5), the agency acknowledges that difficulty
swallowing tablets and capsules can be a problem
The goal is to design a
drug product that enables
the safe and correct
use of medicines.
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 33
for many individuals and can lead to a variety of
adverse events and patient noncompliance with
treatment regimens. In the draft guidance, FDA
stated that it is estimated that more than 15 million
people in the US have some difficulty swallowing,
also known as dysphagia. A survey of adults on
difficulties swallowing tablets and capsules
suggests that this problem goes well beyond the
patient population with clinically recognized dys-
phagia and may affect as many as 40% of Ameri-
cans. Individuals who find it difficult to swallow
tablets and capsules frequently blame the size.
Interestingly, Colorcon conducted a study
to examine the effect of tablet shape and the
influence of coating type on a patient’s ability to
swallow. The study showed that coated tablets were
easier to swallow (because of less sticking in the
esophagus) compared with uncoated tablets. Shape
was a key determinant for the transit time in the
study where oval tablets fared better than caplet
shapes. The Colorcon study demonstrated that
film coating and proper selection of tablet shape
will speed the transit time of tablets through the
esophagus.
At the time of this interview, we are preparing
our comments to FDA on their guidance docu-
ment for generic-drug manufacturers. In those
comments, we plan to request that FDA adds
that applying a coating to an uncoated reference
listed drug (RLD) should be encouraged since
coating will help patients with swallowing and
thereby provide improved compliance. A generic
should always be seen as having the same or better
attributes than the innovator product in the eyes of
the patient.
Key considerations in product design
PharmTech: What are the key considerations for
solid-dosage manufacturers in terms of drug prod-
uct design to minimize medication errors?
Colorcon: We believe the recent FDA guidance
documents address major considerations; however,
there is another key concern that brings together
big generic- and brand-drug manufacturers with
regulatory bodies worldwide and that is the issue
of counterfeit drugs. The pharmaceutical industry
is working closely with regulatory organizations
to combat growing concerns on counterfeit drugs
that do not contain the active ingredients. There
is no doubt that counterfeit drugs put patient lives
at risk. The World Health Organization estimates
that more than 200,000 deaths per year could be
prevented if patients did not use counterfeit medi-
cation (7). In this case, visual inspection is seen as
the first line of defense against drug counterfeiting.
Drug product design can be used to help mitigate
the threat of counterfeits with aspects such as color,
shape, and imprint codes.
PharmTech: Lastly, do you have any final thoughts
you wish to share on this subject?
Colorcon: Reducing medication errors should
be a unified goal for pharmaceutical companies.
For the patient population, pill differentiation can
positively influence patient compliance and result
in better health outcomes.
Differentiating medication does not have to be
costly. Simply adding pigmented coatings to tablets
Reducing medication
errors should be a unified
goal for pharmaceutical
companies.
34 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
provides differentiation, which improves brand
recognition and makes tablets easier to swallow.
Manufacturers can leverage a development
partner that can provide tablet-design options
based on research into currently marketed products
by therapeutic category, color, shape, logo, or special
coating options offers key advantages.
Colorcon provides a specialist tablet design
service to differentiate products while improving
decision making during product development
and accelerate development timelines for formu-
lators. In addition to researching color, shape, logo,
special coating options, Colorcon’s research and
regulatory assistance helps determine the regula-
tory acceptance for colorant materials used in the
final product design, as well as evaluate the designs
of currently marketed products by therapeutic
category. Data on consumer medication color
preferences for any region of the world are also
available to customers. The advantage is that it
significantly increases the likelihood that patients,
pharmacists, and caregivers can easily recognize
a prescription or over-the-counter medication
thereby mitigating the risk of medication errors.
References
1. D.P. Phillips, N. Christenfeld, and L.M. Glynn, The Lancet, 351
(9103) 643–644 (1998).
2. FDA, “Medication Errors,” www.fda.gov/drugs/drugsafety/medi-
cationerrors/default.htm, accessed Mar. 12, 2014.
3. J.A. Greene and A.S. Kesselheim, N Engl J Med, 365 (1) 83–89
(2011).
4. FDA, Guidance for Industry: Safety Consideration for Product De-
sign to Minimize Medication Errors, Draft Guidance (Rockville,
MD, December 2012).
5. FDA, Guidance for Industry: Size, Shape, and Other Physical Attri-
butes of Generic Tablets and Capsules, Draft Guidance (Rockville,
MD, December 2013).
6. M.C. Stoppler, “The Most Common Medication Errors,”
MedicineNet.com, www.medicinenet.com/script/main/art.
asp?articlekey=55234, accessed Mar. 12, 2014.
7. Visiongain, “Pharmaceutical Anti-counterfeiting Technologies
Market Analysis 2014–2024,” November 2013. PT
Product Design
Continuous Manufacturing in Solid-Dosage Drug Production
Continuous manufacturing offers the potential for improved quality, higher production efficiency, and smaller, more
flexible equipment. How is continuous manufacturing being used in solid-dosage drug production today, and what are
some of the next steps for further developing this technology? Doug Hausner, Associate Director for the Engineering
Research Center for Structured Organic Particulate Systems (C-SOPS) based at Rutgers University in New Jersey, USA,
speaks with Pharmaceutical Technology about the current and future use of continuous processes. Click on the player
to hear the interview.
877.503.8635 or pharmaceutcal@fedequip.com
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36 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Modular Systems
O
ver the past several years, there has been significant
interest in finding more efficient ways to design, build,
and operate pharmaceutical and biopharmaceutical
manufacturing processes and facilities. This interest
is driven by a combination of market needs and technical advance-
ments in bio/pharmaceutical processing. Much of the focus has been
on improving the production of biologic drug substances with higher
titers and an increasing use of single-use equipment and standard-
ized manufacturing suites. There has been less discussion on more
efficient ways to build processes and facilities for small molecule
API and oral solid-dosage (OSD) products. One reason for this is the
existing overcapacity for small molecule API and OSD production.
However, the same drivers for efficiency, combined with process
and technical advances, are now making inroads in small-molecule
product manufacturing.
Continuous processes, which offer a wide range of advantages, are
used in nearly every industry. An exception is the pharmaceutical in-
dustry, in which even large quantities are usually produced in a batch
manner. Recent developments, in particular FDA’s process analyti-
cal technology (PAT) initiative, are increasing the acceptance of the
excellence of continuous processes in pharmaceutical production.
Modularization offers several advantages in line with the market
trends and developments of processing technologies, including:
t Shorter time to market
t Higher quality and safety
t Quality-by-design aspects easily realized
t Higher level of predictability in quality, cost, and schedule
t Standardization of building blocks that, with limited con-
figuration, can be applied in different applications
Using Modular Systems in
Solid-Dosage Manufacturing
Pär Almhem, Reiner Lemperle, and Camilla Sivertsson
Modular systems offer a more
efficient way to design and
build manufacturing facilities.
Although recent focus in the
pharmaceutical industry
has been on using modular
systems in biopharmaceutical
processing, the same
advantages can be applied
to small-molecule API
and solid-dosage product
manufacturing. The authors
describe how modular
systems can be applied to
continuous solid-dosage and
nutraceutical manufacturing.
Pär Almhem* is president
of ModWave, par.almhem@
modwave.com, Reiner
Lemperle is director of sales at
Gebruder Lödige, and Camilla
Sivertsson is vice-president at
ModWave.
*To whom all correspondence
should be addressed.
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THE LEADER.
Natoli Engineering Company, Inc. • natoli.com • info@natoli.com • 636.926.8900 • 28 Research Park Circle, St. Charles, MO 63304
38 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
t Ability to test complete functions dur-
ing a factory acceptance test (FAT)
t Significant reduction in schedule and cost
t Intellectual-property protection
when processes are built in a well-
controlled factory environment.
Modular unit operations
The interest in continuous processing for small-
molecule products and the increasing production
of nutraceutical products meeting GMP standards
are drivers for increased use of modular solutions.
In both cases, modularizing the core process offers
a more robust and cost-effective way of implement-
ing new processing lines and facilities.
The compact nature of continuous lines makes
them ideal for modular implementation. A mod-
ular approach allows for completing and testing
the line before it is shipped to and installed at the
operator’s site. With the high level of integration
needed in a continuous line, being able to design,
build, and test the continuous line at the supplier’s
factory significantly reduces the time needed and
the risk exposure while implementing a continu-
ous line. It also offers full repeatability for multiple
deployments to different parts of the world with
the same quality and documentation.
Manufacturing of nutraceutical products often
involves the same process steps—weighing/dosing,
mixing, and packaging—often with a large number of
ingredients and in large volumes. Modular implemen-
tation with configurable systems offers ideal build-
ing blocks for nutraceutical manufacturing processes
and facilities. Also, the ability to build several identi-
cal instances of the same process and thus the ability
to re-use the same documentation offers significant
reduction in time, cost, and risk when multiple units
are built and deployed.
Continuous processes
Efficient production of larger product quantities has
traditionally been the main argument for continuous
processes. There is now an increasing awareness of
the advantages of continuous processing for smaller
production volumes. These advantages include:
t Product quality during production periods
is consistent.
t Production volume is defined by operating
time; a clinical line can be used for
commercial manufacturing.
t Smaller machines can be used
for the same capacity.
t Continuous machines that are integrated with
automatic feeding reduce manual product-
handling and thus the risk of contamination.
t Operators are less exposed to the product,
which increases employee health and safety.
t Fewer operators are required.
t Continuous units require less cleaning than
batch machines for the same application.
t Continuous processes reduce the produc-
tion cost while achieving the same or better
product quality compared to batch processes.
Continuous processes for tablet production can be
implemented in different ways. Typical alternatives are:
t Direct compression (mixing and tablet
compression)
A modular approach offers
repeatability for multiple
deployments to different
parts of the world.
Modular Systems
TO GO FROM
CONCEPT
TO CLINIC
TO MARKET
The COMMITMENT
The EXPERTISE
The EXPERIENCE
Potent Product Development.
Our state-of-the-art potent
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Our PhDs, Master and
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Chemists average 17 years
of professional experience.
4:1 Ratio.
We offer a healthy balance
of four analytical chemists
to every formulator to
keep your project on track.
What separates one CDMO from another? At Metrics, we believe it comes down to experience, expertise
and commitment. Like our formulators and analytical staff, who share decades of career experience
and expertise. Or our commitment to continually surpass our clients’ expectations by offering new
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Pharmaceutical Development

Analytical Testing

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Potent Products

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Metrics / Greenville, NC / 252-752-3800 / www.metricsinc.com
40 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Modular Systems
t Compression with granulation (mixing,
granulation, drying, and compression).
The process steps can be described as follows.
Mixing. A typical continuous mixer operates
with a mechanically generated f luid bed inside
the mixer. Ingredients are introduced at one end
of the mixer and conveyed, while being mixed, to
the other end where the mix is discharged at the
bottom of the mixer drum. The continuous mixer
achieves the same high mixing quality as the batch
mixer. Feeding of the mixer is performed using
gravimetric dosing (i.e., loss-in-weight) with one
dosing system for each component. Flexible inter-
mediate bulk-container (FIBC) stations or other
containers are installed upstream to feed the dosing
systems. Depending on the application, the product
is discharged in a wet granulator (wet granulation)
or in a compactor/tablet press (direct compression).
Granulating. The continuous granulator—as
the continuous mixer—has a horizontal drum
equipped with a horizontal main shaft. The main
shaft is designed to ensure high-shear granulation
and is fitted with a number of mixing tools. The
granulation liquid is introduced into the machine
by a dosing pump. The intensive mixing and high
shear effect of the mixing tools create granules.
Feeding is carried out at the one end of the gran-
ulator and the product is conveyed, while being
granulated, to the other end where it is discharged.
The continuous process generates granules with a
uniform and consistent particle size distribution
and properties comparable with granules pro-
duced in a batch process. Granules are discharged
directly into a continuous dryer.
Drying. The continuous dryer operates accord-
ing to the fluid-bed technology. Wet granules are
introduced at one end and discharged at the other
end of the dryer. Heated air is introduced through
perforated-bottom plates keeping the product in
a f luidized state in which it is dried in a gentle
and effective manner during the product motion
through the machine. As the continuous fluid-bed
process is practically identical to the corresponding
batch process, the results are typically equivalent.
The mixer, granulator, and dryer can be arranged
in a vertical line, in which case the product trans-
port between the machines will be gravimetric. For
a horizontal arrangement of the line, product trans-
port will be pneumatic. The continuous machines
described are designed for throughputs of 5–500
kg/h and higher. This volume allows continuous
production of small quantities up to high-volume
drugs, as well as development of new recipes.
Control. The control system integrates operation
of the complete unit including process machines,
air handling system for the dryer, gravimetric dos-
ing stations, and material handling. Additional
process systems as well as PAT systems may be
included. The control system has to fulfill all re-
quirements of the pharmaceutical industry.
Integrating the continuous
process in a modular suite
A continuous processing line is inherently much
smaller than a batch line for the same capacity. It is
also more integrated, with more automation and less
operator intervention. These are two major reasons
why a modular implementation of a continuous line
has many advantages. There are two principally differ-
ent ways to implement a continuous line in modules:
t The process equipment itself and the mechanical
support for the equipment can be implemented
in separate modules that are installed in existing
cleanroom and mechanical areas, respectively.
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 41
t The line with all its support
functions is integrated in
modules that make up the
cleanroom suite and the
supporting mechanical
areas.
The second alternative is the
preferred method, which takes
full advantage of the benefits
of a modular implementation
and makes it possible to imple-
ment the continuous line as a
complete processing suite with
all necessary support functions.
Cleanrooms can be optimized for cleaning, ac-
cess to, and handling of the process equipment.
Mechanical areas are optimized for installation,
operational efficiency, and maintainability. Mod-
ule and equipment arrangements and adjacencies
are optimized to maximize installations within
the boundaries of each module, thus minimizing
the need for on-site connections between modules.
This also increases the ability to perform a site ac-
ceptance test (SAT) at the same time as the FAT.
By running the line in the modules, in not just the
same configuration but the exact same installa-
tion as on site, the testing at the owner/operator’s
site can be reduced to verification of connections
between modules before final qualification can be
performed.
The modular continuous suite typically includes:
material handling, dosing, mixing, granulation,
drying, and compression, all with integrated con-
trol. As discussed previously, the control system
must integrate the whole system while being able to
communicate with an overall supervisory-control
and data-acquisition system or a similar system.
Ideally, the control system should be modular as
well to simplify configuration of modes of opera-
tion of the continuous line.
Figure 1 shows an example of a modular con-
tinuous processing suite. This suite is designed to
allow for both modes of operation described previ-
ously. It is a three-story suite using eight modules,
with six oriented horizontally and two vertically
to allow for maximum integration of equipment
in the modules. Approximately one-third of each
floor is used for mechanical areas and the rest for
the cleanrooms needed to operate the process. The
floors contain the following process steps:
t Floor 3: material handling
t Floor 2: feeding of the continuous mixer,
feeding of the tablet press, and transfer of the
mixed product by vacuum to the tablet press
or the continuous granulator, depending on
the application.
t Floor 1: continuous wet granulation and
continuous fluid bed drying, vacuum feeding
of the tablet press from the dryer, and the
tablet press.
Figure 1: A modular suite for continuous processing of solid-dosage products.
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42 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Modular Systems
All process equipment is preinstalled in the
modules that also include architectural installa-
tions and finishes, electrical supply, wiring, piping,
ductworks and controls—everything that is needed
for a complete operational suite. The suite, or parts
thereof, can be pretested at the manufacturer’s site,
before it is delivered to the owner/operator for final
installation, startup, validation, and operation.
Example of a nutraceutical process
Nutraceutical products, such as vitamin prepara-
tions, mineral nutrients, or dairy products, are
enjoying increasing popularity as people tend
to consume additional nutrients or want to lose
weight or build-up muscle. The product variety is
large, ranging from vitamin and mineral nutrients
to sports nutrition and dietary beverages. Most of
these products are available in solid or semi-solid
form such as tablets, capsules, granules, or instant
powder shakes.
Most nutraceuticals have common characteris-
tics. They are composed of many single ingredients
and their structure and proportion can vary signifi-
cantly. Often, liquid components
are added to the mix.
The production requires mixes
of excellent homogeneity, and
manufacturing must comply
with pharmaceutical GMP stan-
dards. The process is mainly run
in batch operation. Machines can
range in sizes from 100-300 L for
small-scale production and up to
8000 L or even larger depending
on production capacity needs. In
addition to providing excellent
mixing quality, mixers must allow
for liquid addition, be easy to clean, and typically
be made of stainless steel with welded mixing el-
ements that have optimized clearance to the wall.
They should utilize low-maintenance, air-purge shaft
seals, large doors, and (optionally) automated wash-
in-place systems.
Process description. In a batch process, ingredi-
ents are added, either separately or preweighed
and added together, into the mixer. When mixing
is complete, often after several steps, the batch is
discharged in an intermediate container (IBC) or
flexible IBC (FIBC) installed downstream, or it is
pneumatically conveyed to the next process step.
Feeding is usually carried out from the top of the
mixer. Automated production units are equipped
with hoppers, weighing other appropriate dosing
systems installed upstream enabling product feed
into one or several inlets on top of the mixer. Dis-
charge is made at the bottom of the mixer.
A mixing cycle is often the result of a combina-
tion of several process steps, each 1–3 minutes for a
total mixing time of 5–6 minutes. Fragile or sensitive
components are usually added towards the end, and
Figure 2: A typical line for manufacturing nutraceutical products.
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Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 43
if deemed necessary, the batch can
be processed using different shaft
speeds in different steps. Most nu-
traceuticals contain a small quan-
tity of liquid ingredients (e.g., leci-
thin, oils, flavors, and colorants).
As an example, a mix can be
composed of more than 50 dry
ingredients with proportions
ranging from 0.001% to 50%
and a liquid fraction of 2-3%.
Depending on the degree of au-
tomation, the mixer can achieve
4–5 batches per hour. In a 2000-L
mixer as shown in Figures 2 and 3, this rate would
result in production of around 3–4 tons per hour.
Integrating a batch nutraceutical process into a modular
unit operation. A typical (batch) processing line for
nutraceutical products lends itself well to integra-
tion into complete process modules. These mod-
ules will, in most cases, be installed in convention-
ally built rooms.
Figure 2 illustrates a nutraceutical process with
the addition of a downstream tablet-compression
machine or a filling machine for filling of powder
products in bottles. The process uses a combina-
tion of gravity feed and vacuum conveying between
process steps. The process steps are weighing, dis-
pensing, and buffering (per batch) of ingredients;
charging of the mixer in one or several steps; liquid
injection; mixing in several steps; discharging; and
either filling of IBCs or FIBCs, or as in Figure 2,
buffering and vacuum feeding to a tablet press or
a filling machine.
The process is integrated in four vertical mod-
ules as illustrated in Figure 3. The vertical modules
allow for the installation and integration of IBC or
FIBC unloading, dosing, and product transport in
one module. The next module receives the ingre-
dients for a batch, charges into the mixer, mixes
the product, discharges into a hopper, and vacuum
conveys to the next module containing the tablet
compressor or the powder-filling line. Controls
and other support functions are integrated in the
modules, allowing for near complete testing in the
factory, with minimal disassembly for transporta-
tion and reassembly on the owner/operator’s site.
Conclusion
Modular implementation of processes for the pro-
duction of solid-dosage and powder products of-
fers significant advantages that amplify the benefits
offered by new process technologies such as con-
tinuous processing. In the near to mid-term future,
these designs will be further refined and optimized,
and additional building blocks and applications will
be added to the portfolio. Over time, these types of
modular applications have the potential to become
a preferred way of implementing new process lines
and facilities. PT
Figure 3: A modular system for manufacturing nutraceutical products.
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44 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Granulation
C
ontinuous dry granulation is a well-established process in
the pharmaceutical industry. It is used primarily for mois-
ture- and temperature-sensitive materials, but it is also
commonly applied to large-volume and herbal products.
Unlike traditional wet granulation, drying systems for dry granula-
tion need not be overly sophisticated, which eliminates the need for
large investments in dryer equipment and space. Dry-granulation
systems are also comparatively inexpensive to operate. Furthermore,
the fast roller-compaction process can be used in high-material-
throughput operations, enabling the production of different products
and batch sizes with a single machine (1).
The market already offers various dry granulators that can be de-
scribed by the arrangement of the two compaction rollers, which are
mounted horizontally, vertically, or on an incline. Depending on the
supplier, the rollers differ in width, diameter, and surface properties.
Roller compactors are further distinguished as either fixed-gap or
moveable-gap compactors.
Moveable roller compactors are newer technology and still con-
sidered state of the art. Only moveable-gap compactors assure ho-
mogeneous ribbon porosity at constant compaction pressure. The
granulation step where the ribbons are transferred into final gran-
ules is usually integrated in the roller-compactor equipment and is
performed in one or two steps (2, 3).
A dry granulator (BRC 100, L.B. Bohle) uses an electromechanical
roller drive and massive roller shafts to allow greater control over
granule size and fines distribution. The granulation step is achieved
using a conical sieve (Bohle Turbo Sieve 200, L.B. Bohle), which
Obtaining User-Defined
Particle Size Distribution
Using Dry Granulation
Dejan Djuric
Users can define a desired
particle-size distribution
using continuous dry
granulation. The author
examines the effect of
compaction force, gap
width, and sieve setup
on granule size.
Dejan Djuric, PhD,
is manager of scientific
operations at L.B. Bohle,
granulation@lbbohle.com,
www.bohle-tablet-coater.com.
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Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 45
transforms the ribbons
into final granules. User-
defined particle-size dis-
tribution can be obtained
using variable sieve set-
ups. The effect of com-
paction force, gap width,
and sieve setup on gran-
ule size was measured for
this equipment setup.
Materials and methods
A powder mixture (1:1
ratio) consisting of lactose
(Granulac 200, Meggle,
Germany) and micro-
crystalline cellulose (Avi-
cel PH 101, FMC, USA)
was used for roller com-
paction. For lubrication,
0.5% magnesium stearate
(Pharma VEG, Baerlocher,
Germany) was added.
The excipients were pre-
mixed in a bin blender
(PM 600, L.B. Bohle).
The homogeneous
blend was then rol ler
compacted using a vari-
ety of different compac-
tion forces and sieve setups. A smooth master roll
and a 100-mm-wide grooved slave roll were used
for the trials. Sampling was performed after the
process startup when steady state was reached.
Final granules were manually subsampled and an-
alyzed in duplicate by mechanical sieving (Haver
EML 200 digital, Haver & Boecker, Germany).
Results
Compaction force. The impact of the compaction force
on the final granule particle size was analyzed at 2
rpm roller speed, 300 rpm for the 1.5-mm rasp sieve,
and gap width of 2.5 mm. An activated proportional-
integral-derivative (PID) loop control was used for the
feeding system. Steady state was achieved within 40 s
Figure 1: During granulation (Bohle Turbo Sieve 200, L.B. Bohle), steady state of the gap width
and compaction force was achieved within 40 s.
Figure 2: Particle-size distribution was measured for a powder mixture of lactose and
microcrystalline cellulose compacted with a 1.5-mm rasp sieve at 5, 10, and 15 kN/cm specific
compaction force.
16
14
12
10
8
6
4
2
0
10:30 10:33 10:36 10:39 10:42 10:45
Specifc compaction force (kN/cm)
Gap width (mm)
10:48 10:50
Time (min.)
0
20
40
60
80
100
0 500 1000 1500 2000 2500
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5 kN
10 kN
15 kN
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46 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Granulation
with a constant specific compaction force and a con-
stant gap width (see Figure 1). Minimal material loss
was detected due to the quick loop control. During
processing, the compaction force was gradually in-
creased, and the next force level was achieved within
seconds. Deviations were below ±0.1 kN/cm for the
specific compaction force
and ±0.1 mm for the gap,
respectively. Thus, both
parameters could be con-
sidered constant during
the whole process.
Granule particle size in-
creased with higher com-
paction force levels (4).
After granulation through
a 1.5-mm rasp sieve, the
amount of fines (particle
size <100 μm) ranged
from 39% for the gran-
ules compacted at 5 kN/
cm down to 11% for gran-
ules prepared at 15 kN/cm
compaction force (Figure 2).
Compaction at such a high
force level led to a higher
amount of coarse (>2000
μm) granules. Therefore,
a smaller screen size, be-
tween 1.0 and 1.5 mm, is
recommended in order to
minimize this large gran-
ule fraction.
Gap width. Material
throughput during roller
compaction can be in-
creased with a larger gap
width. It was reported in literature that a larger gap
width at a constant compaction force level leads to finer
granules (4). This effect could not be observed when
compacting the powder mixture at 10 kN/cm (Figure
3). At 2 rpm roller speed and 300 rpm sieve speed (1.5-
mm rasp sieve), comparable granule particle size dis-
Figure 4: Particle-size distribution was measured for a powder mixture of lactose and
microcrystalline cellulose compacted at 10 kN/cm specific compaction force and 300-rpm sieve
speed with varying screen size of the granulation unit (1.0, 1.5, or 2.0 mm).
100
80
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0 500 1000 1500 2000 2500
1.0mm
1.5mm
2.0mm
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Figure 3: Particle-size distributions for a powder mixture of lactose and microcrystalline
cellulose compacted with a force of 10 kN/cm and 2 rpm roller speed with increasing gap widths.
100
80
60
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0 500 1000 1500 2000 2500
1.5mm gap
2.5mm gap
3.5mm gap
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Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 47
tributions were obtained,
although the gap width
was increased from 1.5
mm to 3.5 mm. A ho-
mogeneous application
of the compaction force
over the whole roller
width could be one rea-
son for the similar gran-
ule size. Thus, material
throughput could be
easily increased with-
out a change in granule
properties.
Sieve setup. The ap-
plied compaction force mainly affects granule par-
ticle size. The setup of the integrated granulation unit
(Bohle Turbo Sieve 200) also determines the final
particle size distribution. Increasing the screen size
yields coarser granules (Figure 4). The rasp sieves with
1.5- and 2.0-mm screen size led to similar granule
particle size distributions at 300-rpm sieve speed. By
comparison, the 1.0-mm rasp sieve led to granules
with higher amount of fines. Finally all three screen
types led to acceptable amounts of fines generated by
the gentle cutting behavior of the rasp sieve during
granulation.
The choice of the right screen size makes it pos-
sible to influence the final granule particle size dis-
tribution. A further variant test was performed by
altering the sieve rotor speed. In contrast to tradi-
tional rotating sieve systems, conical sieves produce
high material throughput at low sieve speeds. To
evaluate the impact of sieve speed on final granule
size, compaction was performed at 10 kN/cm spe-
cific compaction force, 2 rpm roller speed with in-
creased sieve speed for the 1.5-mm rasp sieve. With
higher sieve speed the amount of fines decreased
(Figure 5). This decrease can be explained by the fact
that at higher rotor speeds, the ribbons need less
time to pass the screen. Less friction occurs during
granulation and leads to lower amounts of fines.
Thus, altering the sieve speed is another possibility
to adjust the desired particle size distribution of the
final granules.
Conclusion
By altering screen size and sieve speed, operators
can control granule size and fines to optimize
compactibility and thus processability in down-
stream processing after granulation.
References
1. R.W. Miller, Pharm. Tech. 18 (3) 154-162 (1994).
2. P. Kleinebudde, Eur. J. Pharm. Biopharm. 58 (2) 317-
326 (2004).
3. Y. Teng, Z. Qiu, and H. Wen, Eur. J. Pharm. Bio-
pharm. 73 (2) 219-229 (2009).
4. P. Serno, P. Kleinebudde, and K. Knop,
Granulieren, apv-basics (Editio Can-
tor Verlag, Aulendorf, 2007). PT
Figure 5: Particle-size distribution was measured for a powder mixture of lactose and
microcrystalline cellulose compacted at 10 kN/cm specific compaction force and 2 rpm roller speed
with a 1.5-mm rasp sieve at increasing sieve speeds.
100
80
60
40
20
0
0 500 1000 1500 2000 2500
100rpm
200rpm
300rpm
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48 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Quality by Design
T
he quality-by-design (QbD) guidelines Q8, Q9, and Q11, as
established by the International Conference on Harmoni-
zation (ICH) of Technical Requirements for Registration
of Pharmaceuticals for Human Use, clearly state the intent
of the QbD initiative (1–3). The key elements named therein are: risk
management, scientific knowledge, and process understanding. FDA
advises the use of these elements to reach the desired condition of “a
maximally efficient, agile, flexible pharmaceutical manufacturing
sector that reliably produces high-quality drug products without
extensive regulatory oversight” (4).
QbD principles are crucial as they help ensure the quality of products.
In the following case study, the application of QbD principles
to process optimization is presented. As a model, f luid-bed
coating and subsequent in-process curing of a sustained-release
coating with a copolymer of methylacrylate and ethylacrylate
(EUDRAGIT NM 30 D, Evonik Industries) were chosen.
EUDRAGIT NM 30 D in sustained-release coatings
EUDRAGIT NM 30 D is a highly flexible EUDRAGIT polymer that
shows an elongation at break of approximately 600%. It can be used to
apply diffusion-controlled coatings for extended drug release multi-
particulates on almost any substrate, no matter how the pellets,
crystals, or granules are shaped. To ensure stable functional-
ity throughout the shelf life of the coated dosage form, the co-
alescence of the polymer latex particles must be completed. This
coalescence can be realized by an in-process curing step directly
after the coating.
A Quality-by-Design Approach
to Optimize In-Process Curing
of EUDRAGIT NM 30 D
Thomas Dassinger, Jessica Müller-Albers, and Sascha Jautze
Previous studies with
EUDRAGIT NM 30 D showed
that storage stability can
be achieved with in-process
curing at specific conditions.
The aim of this study was to
identify and investigate the
influence and correlation of
critical process parameters
for the optimization of
in-process curing.
Thomas Dassinger* is
senior scientist, formulation
development, at Evonik
Industries AG, Pharma
Polymers & Services,
Darmstadt, Germany,
thomas.dassinger@evonik.com;
Jessica Müller-Albers is head
of discovery and development
at Evonik Industries AG,
Pharma Polymers & Services,
Darmstadt, Germany; and
Sascha Jautze is project
manager at Evonik Corporation
Tippecanoe Laboratories,
Lafayette, IN, USA.
*To whom all correspondance
should be addressed.
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Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 49
Quality target product profile
As the first step of a pharmaceutical development,
quality, safety, and efficacy of the product have
to be defined in a quality target product profile
(QTPP) (see Table I). QTPP forms the basis for the
development of the product, where drug release
and stability are important drug product quality
criteria. For functional coatings with EUDRAGIT
NM 30 D, these criteria are mainly defined by the
film formation.
Physics of film formation
The formation of a film from any aqueous polymer
dispersion can be described in the following
four steps:
t Step one: Evaporation of water and
densification of latex particles
t Step two: Deformation of latex particles
t Step three: Fragmentation and segregation
of hydrophilic shells
t Step four: Interdiffusion of latex particles.
Step two happens under the condition of T>MFT,
where T is the product temperature and MFT is
the minimum film-forming temperature.
Step four happens under the condition of T>Tg,
where Tg is the glass transition temperature of the
polymer. In step four, the appearance of the film
does not change, but elongation at break, dielec-
trical resistance, and diffusability properties do
change. With the application of a sustained-release
coating, step four has a major impact on the qual-
ity of the coated drug product, especially because
the Tg of EUDRAGIT NM 30 D is only 9 °C.
To control this step, a thermal treatment (cur-
ing) is done after coating, conventionally con-
ducted on trays in a circulating air cabin at
40 °C over 24 h. As an efficient alternative and
more adequately suited for production, the cur-
ing can be performed in the coating equipment.
Relative humidity, temperature, and curing
time have been identified as factors inf luenc-
ing the curing process (5). Prior studies on the A
L
L

F
I
G
U
R
E
S

A
R
E

C
O
U
R
T
E
S
Y

O
F

T
H
E

A
U
T
H
O
R
S
.
Table I: Quality target product profile (QTPP).
Product attribute Target Implications
Dosage form and route of administration Oral modified-release pellets Coated pellets
Dose strength 80 mg propranolol Twice a day
Identity
Meeting compendial or other applicable
quality standards
Pharmacopoeial methods
Assay
Content uniformity
Degradation products
Drug release Sustained release Dissolution over 12 h (> 80%)
Storage stability Drug release unchanged Dissolution testing
Figure 1: Contour plot for all responses at 15 min curing time.
Dissolution 3 hours
T
e
m
p
e
r
a
t
u
r
e
Relative humidity [%]
30 35 40 45
35
40
45
50
18
20
22
24
26
28
30
Dissolution 6 hours
Relative humidity [%]
30 35 40 45
35
40
45
50
50
52
54
56
58
60
2
64
Dissolution 10 hours
Relative humidity [%]
30 35 40 45
35
40
45
50
74
76
78
80
82
84
T
e
m
p
e
r
a
t
u
r
e
T
e
m
p
e
r
a
t
u
r
e
M
O
D
D
E

9
.
1
50 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Quality by Design
curing behavior of sustained-release formula-
tions have shown an operating range of 40–45
°C product temperature and 45–50% relative
exhaust air humidity for 30 min to be ideal for
EUDRAGIT NE and NM coatings (6, 7).
Risk assessment
A risk assessment begins with a review of the en-
tire process. For each step the possible modes of fail-
ure are considered. Therefore, prior knowledge and
expertise are of great importance. To ensure the best
Table II: Risk analysis. S is severity, O is occurance, D is detectability, RPN is risk priority number.
Process
step
Failure mode Failure effects
Causes of
failure
Controls S O D RPN Actions
Preheating
Abrasion of
pellets
Drug release out of
specification due
to incorporation of
drug particles in
sustained-release
coating
Preheating
time too long
None 8 1 1 8
Preheat coater
without pellets
Preheating time set
to 2 min
Abrasion of
pellets
Drug release out of
specification due
to incorporation of
drug particles in
sustained-release
coating
Inlet air
volume too
high
None 8 1 1 8
Inlet air volume
set to
300 m
3
/h
Coating
Pellets
sticking
Drug release out
of specification; if
pellets stick together,
surface area will
change, and hence,
affect release rate
Inlet air
temperature
too high
Product
temperature
sensor
9 3 2 54
Product
temperatureset to
20–23
o
C
Pellets
sticking
Drug release out
of specification; if
pellets stick together,
surface area will
change, and hence,
affect release rate
Process
humidity too
high
Humidity
sensor
9 3 2 54
Inlet air volume
set to exhaust
air humidity of
maximum
60% relative
humidity
No spraying No coating
Nozzles
blocked
Spraying
suspension
weight control
6 1 9 54
Stirring of coating
suspension to avoid
sedimentation of
talc
Production of
fine parts
No coating
Spray drying
due to too
high inlet air
tempeature
Product
temperature
sensor
4 1 1 4
Product
temperature set to
20–23
o
C
Preheating
Filter
clogging
Interruption of batch Filter clogging
Pressure
difference
0 1 1 0
Change filter to
rougher type
Curing
Incomplete
coalescence
Instable release
profile over time
Inlet air
temperature
too low
Product
temperature
sensor
10 1 10 100
Inlet air/product
temperature
Incomplete
coalescence
Instable release
profile over time
Process
humidity too
low
Exhaust air
humidity
sensor
10 2 10 200 Spray rate for water
Incomplete
coalescence
Instable release
profile over time
Curing time
too short
None 10 1 10 100 Time
Drying
None N/A N/A N/A 0 0 0 0 None
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 51
possible outcome, it is vital that a cross-functional
team of experts with product knowledge, formulation
expertise, and process know-how performs the re-
view. This risk assessment helps in identifying material
attributes and process parameters that have an im-
pact on critical quality attributes (CQAs) of the
product. Table II shows the risk assessment for the
sustained-release product using failure mode effects
analysis as a tool. Curing has been identified as a
significant parameter and was studied through
design of experiments (DoE) to achieve a higher level of
process understanding.
Design of experiments
As part of the control strategy, DoE was used to gain
knowledge on the curing process. Batches of 3 kg pel-
lets were coated in a fluid-bed coater (Unilab, Hüttlin
GmbH, Bosch Packaging Group, Schopfheim, Ger-
many) in bottom spray mode with a sustained-release
coating formulation based on EUDRAGIT NM 30 D.
The coated pellets were then cured at different con-
ditions in the fluid-bed coater. For this in-process
curing, product temperature, exhaust air humidity,
and curing time were investigated as factors in the
DoE. Drug releases after 3, 6, and 10 hours were es-
tablished as responses. MODDE software (MODDE
v. 9.1, MKS Umetrics AB, Sweden) was used to esti-
mate a design space, and thus, a safe region of oper-
ability in which the desired response profile could
be realistically met. With this software, it was pos-
sible to display the estimated probability of failure at
the specified risk level. The limits of the DoE design
were set according to prior knowledge (8, 9). Product
temperature was set between 32 and 54 °C. Relative
exhaust air humidity ranged from 28 to 54%. Reflect-
ing the heating capacity of common fluid-bed coaters,
the design had to be limited to an enthalpy of 140 kJ/
kg. The design plan resulted in 11 trials.
As the actual curing process parameters
differed slightly from the designed factor levels, the
Figure 2: Design-space plot.
T
e
m
p
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r
a
t
u
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[
°
C
]
T
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p
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a
t
u
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e

[
°
C
]
T
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m
p
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r
a
t
u
r
e

[
°
C
]
Humidity [% r. h.]
CuringTime = 7
Humidity [% r. h.]
CuringTime = 26
Humidity [% r. h.]
CuringTime = 45
Risk of failure [%]
MODDE 9.1
52 Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2014 Phar mTech. com
Quality by Design
experimental process parameters were used for the
interpretation of the data with MODDE 9.1.
Results and discussion
The software predicted a robust model over the full
area, which is visualized for three time points (see
Figures 1 and 2). The contour plots show the influence
of temperature and humidity (see Figure 1). Entering
the criteria for dissolution time points into the opti-
mizer function of MODDE 9.1 allows a risk of failure
estimation utilizing a Monte Carlo simulation. This
method results in a design space as required in an en-
hanced QbD approach for an abbreviated new drug
application (ANDA) registration. The plot can be
used as a forward loop control, contrary to standard
contour plots, which reflect a backward loop control.
It also shows how the working range increases with
prolonged curing time (see Figure 2).
The conditions of in-process curing mainly de-
pend on the polymer and its formulation. Different
pieces of equipment, however, will have different
heat loss through the product container, and the
sensors for product temperature and exhaust air hu-
midity will need to be placed in different locations.
By doing this, any curing design space is dedicated
to the equipment. Previous transfers have, nonethe-
less, shown that the ranges overlap almost entirely
between different equipment.
Conclusion
The principles of QbD delivered a reliable model ex-
plaining the correlation of the carefully selected pa-
rameters at a reasonable number of trials. Enhanced
knowledge regarding the process was obtained and al-
lowed for control of the parameters during production.
Operating within the design space results in higher
process safety and a product that meets the defined
quality. The size of the design space depends on the
risk one is willing to take. A smaller risk gives a smaller
design space. As an element of the proposed manufac-
turing process, it can be included in the submission.
Acknowledgment
The authors would like to thank to Erik Johansson,
senior application scientist from MKS Umetrics AB,
for his insights and support with this study.
EUDRAGIT is a registered trademark of Evonik
Industries.
References
1. ICH, Q8 Pharmaceutical Development, Step 4 version (August 2009).
2. ICH, Q9 Quality Risk Management, Step 4 version (November 2005).
3. ICH, Q11 Development and Manufacture of Drug Substances, Step 4
version (May 2012).
4. J. Woodcock, “The Desired State: A Mutual Goal of Industry and Regu-
lators,” presentation at ISPE Annual Meeting (November 2005).
5. K. Amighi et al., STP Pharma Sciences 7 (2) 141–147 (1997).
6. T. Dassinger et al., “Scale-up Study of Propranolol Sustained Release
Pellets Coated with EUDRAGIT NE 30 D,” poster at 7th PBP World
Meeting (Valletta, Malta, March 2010).
7. J. Albers et al., “Storage Stable, In-process Cured Sustained-Release
Coatings Based on EUDRAGIT NM 30 D,” poster at AAPS Annual
Meeting and Exposition (Washington, D.C., October 2011).
8. H. Bär, Untersuchung des Curings- und Alterungsverhaltens von
EUDRAGIT NM 30 D Filmüberzügen auf Metoprololtartrat Pellets
(Bachelor Thesis) University of Applied Science (Bingen, 2009).
9. O. Hensel et al., “Development of Storage Stable, Sustained-Release
Coatings Based on EUDRAGIT NM 30 D,” poster at 8th PBP World
Meeting (Istanbul, March 2012). PT
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