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Optimizing Topical

Semi-Solid Drug
Formulation and
Performance

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November 2016

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TOC
Table of contents
Optimizing Topical Semi-Solid
Drug Formulation and Performance

The Effect of Excipient Selection on the

3
Microstructure and Performance Attributes of
Topical Semi-solid Emulsion Creams
By Norman Richardson, Amy Ethier, and Frank Romanski, BASF

Common Deficiencies in ANDAs for

12
Dermatologic Drug Products
By Rong-Kun Chang, Pahala Simamora, Bing Cai,
Andre Raw, and Susan Rosencrance, FDA

Studying Microstructure in Topical Formulations


24 Q&A with Padam C. Bansal, Amneal Pharmaceuticals

27 Excipients: Anything but Inert


Q&A with Nigel A. Langley, BASF

The Relationship Between Critical Quality


Attributes and the Microstructure of Topical
31 Semi-Solid Formulations
Cover Image: phashinee/shutterstock.com

Highlights from a Webcast on Understanding the Relationship Between Critical


Quality Attributes and the Microstructure of Topical Semi-Solid Formulations

This custom ebook is sponsored by BASF and published by Pharmaceutical Technology.

2 | November 2016 | PharmTech/BASF eBook


The Effect of Excipient Selection on the
Microstructure and Performance Attributes
of Topical Semi-Solid Emulsion Creams
By Norman Richardson, Amy Ethier, and Frank Romanski

POSTER

Controlling the Physical Recently, regulators, formulators, and


Properties of Performance
of Semi-Solid Formulations product development scientists in the
Click to through Excipient Selection
view PDF pharmaceutical industry have begun
to pay more attention to excipients in
dermatological formulations, particularly
to the functional role of excipients, the
BROCHURE significance of excipient selection on
BASF Platform Solutions
the semi-solid microstructure, and the
influence of microstructure on product
Click to
view PDF
performance, critical quality attributes,
and potential failure modes.

During the design phase of topical semi-solid


PODCAST
product development at an innovator drug
company, the formulator decides which excipients
The Role of Semisolid
Microstructure in Topical
will be included in the formulation in order to
Formulation Performance accomplish specific functional endpoints such
phashinee/shutterstock.com

and Functionality
Click as: emulsification, consistency, and solubilization.
to hear
podcast Selecting and listing ingredients is the qualitative
element of design, and is designated as the Q1.
During formulation development, formulators

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Figure 1: The relationship between formulation inputs (including Q1 and Q2) and topical semi-solid performance attributes.

Formulation inputs Emulsion, cream, Performance


ointment, gel (Q3) Criteria
• List of excipients and API (Q1)
• Amount of each excipient and Viscosity
API (Q2)
Stability
• Processing
• Temperatures and ramp Sensory properties
rates Appearance
• Orders of addition API release
• Shear API absorption
• Packaging conditions
• Excipient source and grade
Heterogeneous
• Storage time System
(Non-Equilibrium System)

study product performance to determine two different topical cream products to


the optimal concentration of each look the same. At the microscopic level,
ingredient. At this stage, generic under higher magnifications, it becomes
pharmaceutical developers may use apparent that creams, lotions, gels,
reverse engineering to establish the and ointments are very heterogeneous,
concentration of excipients. This is the and populated with a great variety of
quantitative element of design and is different microstructures. As a result,
designated as the Q2. interest is turning toward understanding
In the case of generic formulations the complex milieu of mesophases, solid
filed with FDA’s Abbreviated New Drug states, solubilized API and excipients, and
Application (ANDA), developers may have colloidal structures that comprise the final
to match API dermal delivery profiles semi-solid. This complex arrangement of
and/or blood levels to get regulatory matter is designated as the Q3.
approval. In some cases, matching the Formulators and regulators have begun
Q1 and Q2 was not sufficient to replicate to realize that the characteristics and
drug delivery profiles. Furthermore, fundamental elements of Q3 are what
many dermatological formulations (e.g., drive the critical quality attributes and,
topical creams) look and behave very ultimately, the performance of semi-solid
similarly on a macro scale (i.e., during products. Figure 1 depicts a high-level
application to the skin surface). Under understanding of these relationships.
the microscope, however, it is rare for Excipients play a significant role in

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

formulation, so research is exploring the to negate the role of processing and


effect of excipient selection, excipient focus on the roles of excipients, which
source, and excipient grade on the Q3 were altered by one functional group at
and, ultimately, on product performance a time. Specifically, clotrimazole creams
attributes. were produced and studied by varying
Processing also plays a critical role the consistency factor or structure-
in the Q3; two formulations with the forming excipient (e.g., fatty alcohol) in
same Q1 and Q2 may end up with a the composition. Various measurement
different Q3 and performance due to techniques were then used to observe the
differences in processing. This initial effect on the formulation microstructure
study, conducted by BASF formulation and subsequent performance.
scientists, however, will focus entirely on
the role of excipients, leaving processing Preparation of formulations
issues to process equipment engineering Table 1 describes the composition of
experts. the experimental formulations. The
The authors have developed systematic only variable in these studies was the
methods for evaluating the effects of fatty alcohol in the cream formulation.
excipient on semi-solid compositions. The three different consistency factors
Their earliest work focused on simple were cetyl alcohol (Kolliwax® CA, BASF),
polyethylene glycol-based ointments, stearyl alcohol (Kolliwax® SA, BASF), or
as reported in a 2015 webcast (1) cetostearyl alcohol (Kolliwax® CSA 50,
and a presentation at the 2015 AAPS BASF). All excipients were compendial-
conference in Orlando (2). grade materials manufactured under
Since this time, more research has been current good manufacturing practice
done on excipients in cream formulations. (GMP) standards established by the
On May 24, 2016, BASF and the Center International Pharmaceutical Excipient
for Dermal Research at Rutgers University Council (IPEC).
hosted a full-day, multi-speaker event Semi-solid emulsions were prepared
(3) during which one of the authors using standard bench-scale, semi-solid
presented some of BASF’s findings to formulating methods. All lipophilic
date (4). ingredients were blended together in a
BASF’s efforts use a simple single vessel, melted at 80 °C in a hot
experimental design. Semi-solid cream water bath, and mixed using an overhead
emulsion formulations were created propeller mixer, until homogenous. The
under identical processing conditions aqueous phase was heated to 80 °C in

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ANDAs

Table I: Compositions of clotrimazole creams for systematic evaluation.

Function Chemical name BASF Trade Name Amount (w/w%)


Solvent DI Water 68.9
Solvent Propylene glycol Kollisolv PG
®
8.0
Emollient Octyldodecanol Kollicream OD®
12.0
Emulsifier Polyoxyl-20 cetostearyl ether Kolliphor® CS 20 3.0
Viscosity enhancer *Variable (see below) *Variable (see below) 7.0
Active Clotrimazole 1.0
Preservative Phenoxyethanol Euxyl 320 (Shülke)
®
~0.1
*Three different formulations were prepared at indicated levels. The three compositions had consistency factors as follows:
Kolliwax® CA (cetyl alcohol) or Kolliwax® SA (stearyl alcohol) or Kolliwax® CSA 50 (cetostearyl alcohol).

a separate vessel. The oil phase was Using these methods, three different
then poured into the water phase while formulations were prepared, each one
both were stirred at 500 rpm at constant differing only in the choice of the fatty
temperature. After 10 minutes of alcohol used as the consistency factor.
overhead mixing at 80 °C, the resulting The formulation compositions are
emulsion was homogenized with a described in Table 1.
Silverson homogenizer for 3 minutes at
5000 rpm. The API, clotrimazole, was Evaluation of formulations
added to propylene glycol, heated to Samples of the formulations were
80 °C, and stirred using an overhead examined at 100x magnification using
propeller mixer until dissolved. Next, the a Zeiss Axio Scope A1 microscope,
homogenized mixture was added to the with bright-field illumination and cross-
dissolved API in propylene glycol and polarized filters (Figure 2). In order to
allowed to cool to room temperature minimize artifacts and variability due to
while being stirred with a paddle blade varying thickness of product samples
at slow speed. Preservative was added, in the microscopical field of view, all
dropwise, at 45 °C, while the mixture samples were prepared for microscopy
remained at low viscosity. The batch by applying 3 mg of product onto a
was subsequently stirred until it reached microscope slide and pressing a cover-
30 °C, at which point it was transferred glass down onto the sample until the
to a sealed jar and allowed to rest at cream sample spread out to a circular
ambient conditions for a minimum of 24 diameter of 2 cm. In every case, the
hours before evaluation. optical settings were identical.

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Figure 2: Microphotographs of clotrimazole cream containing formulations showed a few


formulations with different viscosity-enhancing
scattered, birefringent crystals, which,
excipients showed qualitative differences between
compositions. For reproducibility, 3-mg samples of due to their morphology, were assumed
cream were applied to a microscope slide, a cover glass to be associated with clotrimazole. In
was applied, and the sample was squeezed to a 2-cm
diameter to ensure the same sample thickness in the field contrast, the stearyl alcohol formulation
of view. Samples were evaluated and imaged at 100x showed numerous smaller crystals, the
magnification with a Zeiss Axio Scope A1 microscope,
with bright-field illumination and cross-polarized filters.
morphology of which suggested that they
might be related to the stearyl alcohol
Cetostearyl alcohol
100x
Cetostearyl alcohol
100x
rather than clotrimazole. Currently,
without additional data, it is assumed
Cetyl alcohol
100x
Cetyl alcohol
100x
that clotrimazole solubility is higher in the
Guerbet alcohol, octyldodecanol, and
Stearyl alcohol
100x
Stearyl alcohol
100x thus resides in this phase primarily. This
finding suggests that the stearyl alcohol is
less effectively mixing with the emulsifier
to form gel networks. This hypothesis
was further explored by X-ray diffraction
Under bright-field illumination, (XRD) analysis.
differences between the cream Previously published XRD studies have
microstructures are visibly present. Most resolved fatty-alcohol crystal structure
notable was that the stearyl alcohol and diffraction patterns; these are well
formulation illustrated very distinct characterized (5,6,7). When crystals of
oil drops, which tended to be larger. stearyl alcohol or cetyl alcohol are present
Also apparent was less widespread in semi-solid compositions, tell-tale
background texture that is typically diffraction patterns become visible. When
characteristic of extended gel or lamellar examined by XRD techniques, the three
phases that form when fatty alcohols formulations showed distinct differences
and emulsifiers mix together. In brief, (Figure 3). All of the formulations exhibited
the octyldodecanol in the stearyl alcohol a wide, broad peak spanning from about
formulation seemed to form larger, clearly 13° to about 45°. This is a characteristic of
distinguished droplets, and less of the amorphous, less-ordered structures that
background microstructure characteristic may be associated with the gel phases
of fatty acid-related lamellar gel phase. formed by mixing fatty alcohols and
Under cross-polarized filters, the emulsifier (e.g., Polyoxyl-20 cetostearyl
cetyl alcohol- and cetostearyl alcohol- ether [Kolliphor® CS-20]). Noted in the

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Figure 3: X-ray diffraction (XRD) studies of clotrimazole Figure 4: Rheological evaluation (parallel plate, shear
creams with different fatty alcohols as viscosity sweep protocol) of three clotrimazole creams differing
enhancers. Formulation with stearyl alcohol (Kolliwax only in fatty alcohol content. The stearyl alcohol
SA®) reveals more XRD peaks characteristic of fatty formulation shows a lower over-all viscosity. Shear
alcohols (Note especially peaks at 21° and 25°. In the viscosity of creams samples was measured on a TA
stearyl alcohol formulation, peaks are also evident at Instruments Discovery HR rheometer, with 40-mm
~5°, ~9°, and ~44°). Cetyl alcohol and cetostearyl alcohol diameter parallel plates with a 200-µm gap at 25 °C.
formulations show weaker and fewer peaks.
1.E+04
Cetostearyl alcohol
Cetyl alcohol
1.E+03
Stearyl alcohol Stearyl alcohol

Viscosity (Pa*s)
Cetyl alcohol
1500 1.E+02
Cetostearyl alcohol
Intensity(Counts)

1.E+01

1000 1.E+00

1.E-01
1.E-02 1.E-01 1.E+00 1.E+01 1.E+02 1.E+03
500 1.E-02
Shear Rate (s )
-1

0
10 20 30 40 50 60
2 (° )
If this hypothesis is correct, then these
effects would be expected to have an
stearyl alcohol- (Kolliwax® SA) containing impact on the rheology, namely that the
formulation, several sharp peaks are stearyl alcohol formulation, having less
evident; these are particularly notable at fatty alcohol engaged in gel network
approximately 5°, 9°, 21°, 25°, and 44°. formation, should have a lower viscosity
As previously studied, these peaks are than formulations containing cetyl and
characteristic of crystalline fatty alcohol. cetostearyl alcohol.
Except for a weak peak at ~21°, however, The rheological characteristics of the
they are not visible in the cetyl alcohol three formulations were evaluated by parallel
and cetostearyl alcohol formulations. plate shear sweep experiments, wherein the
Findings suggest that the presence viscosity of each formulation was measured
of these peaks in the stearyl alcohol at increments in a regime of increasing shear
formulation is indicative that the emulsifier rates (Figure 4). The resulting flow curves
and consistency factor has mixed less showed that the stearyl alcohol-containing
efficiently with the stearyl alcohol, forming formulation had a notably lower viscosity at
less of the gel network and allowing more all points throughout the increasing shear
of the stearyl alcohol to separate and rate regime, while the cetyl alcohol and
crystallize into homogeneous structures, cetostearyl alcohol formulations both had
particularly when compared with the cetyl significantly higher viscosity and analogous
alcohol and the cetostearyl alcohol. pattern of shear thinning behavior.

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Figure 5: Flow properties of two clotrimazole creams These rheological differences were
differing only in fatty alcohol content. Similar mass attributed to differences in the density
of two different formulations (as labeled) were placed
on a black panel. The panel was tilted at a 45-degree of extensive lamellar gel-network that
angle for 0, 1, and 5 sec. The stearyl alcohol-containing forms with the mixing of the polyoxyl-20
formulation demonstrated low stiffness and a fluid-like
behavior, while the cetyl alcohol cream showed higher
cetostearyl alcohol with fatty alcohols.
stiffenss and did not flow. As stated earlier, the presence of
Stearyl Alcohol Cetyl Alcohol more crystalline fatty alcohol in the
Cream Cream
stearyl alcohol formulation was noted,
t=0
suggesting that the distribution of
Flat polyoxyl-20 cetostearyl ether appears to
T=1s
be less efficient with stearyl alcohol than
with cetyl and stearyl alcohol. Therefore,
Held at 45° there is less of the viscosity-building gel
T=5s network present in the stearyl alcohol
formulation, resulting in lower viscosity.
Further investigations may disclose
Held at 45°
the optimal ratios of emulsifier and fatty
alcohol that are required to achieve an
ideal gel network formation and desirable
To further illustrate how this viscosity rheology; influence of emulsifier choice
difference would influence the aesthetic on ideal gel network formations; and, the
properties of the formulation in real influence of emulsifier grade and source.
time, the authors placed similar amounts Studies were also conducted to measure
of stearyl alcohol-containing and cetyl the drug flux through a Strat-M model skin
alcohol-containing formulations on a membrane and to ascertain the effect of
black panel and then tilted the panel fatty alcohol choice on the flux rate (Figure
for 15 seconds and photographed the 6). These studies showed a modest
samples at several time intervals (0, difference between the formulations. The
5, and 15 seconds). Figure 5 shows flux rate for the cetyl alcohol formulation
that the stearyl alcohol-containing was significantly lower than that for the
formulation flowed quite easily under stearyl alcohol formulation, possibly due
the influence of gravitational forces, to the higher mobility of the API molecules
while the cetyl alcohol formulation in the stearyl alcohol formulation where
remained undisturbed, due to its higher there was less networked microstructure to
yield stress. diffuse through.

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Figure 6: Clotrimazole cream compositions with different state (studied by XRD and microscopy),
fatty alcohol excipients demonstrated only slightly
formulation rheology, and API
different in-vitro API penetration rates through a skin
model membrane (Strat-M®). CA = Kolliwax® CA (Cetyl delivery through a skin model. Further
alcohol), CSA = Kolliwax® CSA50 (cetostearyl alcohol), investigations will seek to elucidate the
and SA = Kolliwax® SA (stearyl alcohol). Membrane
permeation studies were conducted with a Logan functional role that excipients play to
Instruments Franz cell system, with cell temperature set drive the observed phenomena.
to 37 °C, and infinite dosing of cream formulation.

160 References
140
y = 17.059x (1) N. Richardson, Controlling the Physical Properties and Performance
of Semisolid Formulations Through Excipient Selection, Pharmaceu-
Clotrimazole Release ug/cm2

y = 15.944x
120
y = 13.992x tical Technology webcast, June 10, 2015.
100
(2) AAPS 2015, BASF Pharma Ingredients and Services Technical Ses-
80 sions and Workshops.
60 (3) Center for Dermal Research, “Topical Semi-Solid Microstructure
40
Stearyl alcohol and its Significance in Product Performance and Functionality,”
Cetostearyl alcohol
Workshop (May 24, 2016, Rutgers University, Piscataway, NJ).
20 Cetyl alcohol
(4) N. Richardson, “The Influence of Excipient Choice on Topical Semi-
0 solid Microstructure and Performance,” Presentation, Center for Der-
0 1 2 3 4 5 6 7 8 9
Time (Hours)
mal Research (May 24, 2016, Rutgers University Piscataway, NJ).
(5) G. Eccleston, et al., Synchrotron X-ray Investigations into the Lamel-
lar Gel Phase Formed in Pharmaceutical Creams Prepared with Cet-
rimide and Fatty Alcohols. International Journal of Pharmaceutics,
In summary, these fundamental studies 203 (1-2) 127-139 (2000).
(6) T. Vringer, et al. A Study of the Gel Structure in a Nonionic O/W
have identified tools that can be used cream by X-ray Diffraction and Microscopic Methods, Colloid &
Polymer Sci Colloid and Polymer Science, 265 (2, 167-179 (1987).
to characterize semi-solid formulation (7) H. Junginger, Colloidal Structures of O/W Creams. Pharmaceutisch
microstructures both qualitatively and Weekblad Scientific Edition, 6 (4) 141-149 (1984).

quantitatively. It was observed that fatty


Norman Richardson is Global Technical Marketing Manager: Skin
alcohol selection had a notable effect on Delivery; Amy Ethier is Formulation Scientist Dermatology; and Frank
Romanski is account and business development manager, all at BASF.
formulation microscopy, fatty acid solid

10 | November 2016 | PharmTech/BASF eBook


Helping you to fine-tune
your ideal composition

Composing a skin delivery system is a process of fine-tuning. And we are here


to provide the tools you need to do just that. With a quality portfolio of excipients
and technical knowledge of product performance, mildness, and dermal drug
delivery, rely on us to help you refine and design your products to achieve the
highest level of efficacy.
www.pharma.basf.com

Instant & Modified Release | Solubilization | Skin Delivery | Softgels | Biologic Solutions
Common Deficiencies in
ANDAs for Dermatologic
Drug Products
By Rong-Kun Chang, Pahala Simamora,
Bing Cai, Andre Raw, and Susan Rosencrance

Related Content Companies may potentially accelerate


Optimizing Semisolid the approval of generic drugs by avoiding
Dosage Forms
deficiencies in ANDA submissions.
Click
to view
article
Approval of generic drugs can be slowed
down by deficiencies in abbreviated new drug
applications (ANDAs). Srinivasan et al. (1–4)
published a series of articles on common
deficiencies in ANDAs that provide clarification,
intention, and criticality of common deficiencies
found in the Chemistry, Manufacture, and
Controls (CMC) section of ANDAs. Liu et
al. (5) also published an article on common
deficiencies with “Bioequivalence Submissions
in Abbreviated New Drug Applications Assessed
by Food and Drug Administration (FDA)”. All
the authors, including Srinivasan et al. and Liu et
al. hope that the generic-drug companies take
steps toward eliminating recurring deficiencies.
porcorex/E+/getty images

In their articles, they offer opportunities for


Editor’s Note: The opinions expressed in this
generic-drug firms to look into FDA’s mindset
commentary by the authors do not necessarily reflect for regulatory considerations. Advice from FDA
the views or policies of the United States Food and Drug
Administration. can help companies overcome common pitfalls

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

in research stages, development steps, topical dermatologic products cannot


and document filing. The approval of be estimated in a plain, straightforward
generic drugs can be accelerated for way. Because of this difficulty, sponsors
the companies that pay special attention often disregard MDD intentionally in
to these common deficiencies and their applications. If the sponsor does
consistently submit high-quality ANDAs not provide an estimated MDD, it
(see Sidebar). may force reviewers to over-estimate
In general, the deficiencies discussed MDD. For example, the MDD may be
in these articles can be applied to estimated using the largest pack size
generic topical dermatologic products. (if the treatment duration is not in the
Because of the uniqueness and potential package insert) or using the largest pack
complexity of topical products, however, size divided by the treatment duration
it is required to focus on additional areas (if the treatment duration is available
to ensure their regulatory success for in the package insert). A reviewer may
ANDA filing. This article is an addendum also assume the entire body surface as
to the aforementioned articles. Because affected area to calculate the initial MDD.
a detailed and thorough discussion on Forty finger-tip units (approximately
regulatory filing pitfalls for each section 0.5 g/finger-tip unit) are required to cover
of modules was given in the preceding the entire body surface (6), and MDD is
publications, a review focusing on calculated as 40 fingertip units x
section-by-section of ANDAs again 0.5 g/finger-tip unit x 0.01 (drug
would be redundant. The shortcomings concentration of the formula).
for ANDAs specifically for topical It is advantageous for the applicant
dermatologic products are the main focus to provide their estimated MDD with an
of this article. estimating equation, which will assist in
justifying proposed impurity limits upon
Shortcomings in ANDAs of review of the ANDA.
topical dermatologic drug products
Maximum daily dose. It is important for Quality attributes related to
the sponsor to provide the maximum microstructure and arrangement
daily dose (MDD) for their drug product. of matters (Q3 properties)
Without an estimated MDD, FDA cannot Because there are many risks associated
judge the appropriateness of any impurity with changes in formulation, FDA
specification limits proposed by the encourages that generic-drug companies
sponsor. In many cases, the MDD for submitting ANDAs match the reference-

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

listed drug (RLD) both qualitatively (Q1) physicochemical properties, skin


and quantitatively (Q2). This can be permeability properties, and solubility
done through reverse engineering the and thermodynamic activity of the
formulation of the RLD. The generic drug formulation. In other words, some
topical product is not required to be excipients themselves can penetrate skin
Q1/Q2 the same as the RLD, but non- and act as a drug solubility modifier to
Q1/Q2 products will face more regulatory alter the solubility of the API, as a lipid
scrutiny. This is because composition mobilizer to alter the ordered intercellular
differences in excipients could change lipid structure, and as a tight junction

Commonly Cited Deficiencies for Topical Dermatologic Drug Products in ANDAs


The authors paraphrase deficiencies commonly cited by FDA in the past four years.
■■ “We note that you have not provided the appropriate. Please show us your corrected
maximum daily dose (MDD) for your drug calculation for the MDD to justify, or tighten,
product. In the absence of such information, we the specification limits.”   
have used the largest tube (60 g) to calculate the
■■ “Because your test formula contains
MDD. Based on an MDD of 60 mg of the active,
many ingredients and you did not provide
the ICH [International Council for Harmonization]
information regarding your understanding of
Q3B guidelines allow an Identification Threshold
the critical material attributes that may affect
of 0.2% and a Quantitation Threshold of 0.33%.
your drug product quality, please discuss
Your limit for any unidentified impurity in your
critical material attributes and their impact on
drug product release and stability specifications
the drug product quality, if there are high-risk
is set at 0.5%. Please show us your calculation
excipients used in your formula. Because your
for the MDD to justify your proposed limit
manufacturing process is a complicate one,
or tighten the specification for any unknown
please discuss your understanding of critical
impurities to Not More Than 0.2%.”
process parameters that may affect your drug
■■ “We acknowledge that you attempt to use the product quality attributes. In addition, we
finger-tip unit to estimate the maximum daily notice that you incorporated water soluble
dose (MDD) for your drug product. However, surfactant into the lipid phase and you added
because you did not provide the maximum aqueous phase to the lipid phase to form an
possible affected area for your drug product emulsion. Please discuss the effect of the
and your estimating equation is not correct, order of addition (e.g., adding the surfactant
we have used the entire body surface as the to aqueous phase and adding lipid phase to
affected area (40 finger-tip units x 0.5 g/finger- aqueous phase) on Q3 attributes of your drug
tip unit) to calculate the MDD. Based on an product. Also, we encourage that the generic
MDD of 200 mg and the ICH Q3B guidelines, companies adopt the QbD concept in their
your limits for any individual unknown impurity drug product development. Please comment
and identified impurity in your drug product on your rationale not to apply QbD in your
release and stability specifications are not drug product development.”  

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

modulator to affect the intercellular gaps drug product quality. In addition, the
of skin barrier. In turn, these changes drug product equivalence and similarity in
can influence diffusion and permeability terms of the microstructure/arrangement
properties of the drug. of matters quality attributes (Q3)
Topical dermatologic drug products from exhibit batch to commercial batch
generally tend to be complex dosage are not certain. In view of this, it is
forms that require complex manufacturing logical that FDA strongly encourages
processes. Because of this complexity, pharmaceutical companies to adopt a
one cannot solely rely on traditional quality-by-design (QbD) concept for
quality batch release testing to ensure their development and manufacturing

Commonly Cited Deficiencies for Topical Dermatologic Drug Products in ANDAs (Cont.)
The authors paraphrase deficiencies commonly cited by FDA in the past four years.
■■ “Because pH, viscosity, particle size, and of experiment (DoE) in their drug product
globule size are potential critical quality development, partly because we would like the
attributes for your drug product, we request applicant to elucidate the interaction between
you include these tests in your drug product variables. Also, we initiated risk-based review
release and stability specifications.” in which we view a drastic interaction between
two quality attributes as an increased risk.
■■ “Please also include description test for your
Hence, we request you to provide pH effect on
drug product in the proposed container
viscosity of your drug product to demonstrate
closure system to evaluate packaging
your understanding of your drug product
components (i.e., label condition, container
and to mitigate this risk.  Please conduct a
product interaction, container integrity, etc.).” 
viscosity-pH study for your test product to
■■ “Because your drug substance has ionizable show understanding of your drug product and
functional groups and ionized/unionized ratio to justify the limits of viscosity based upon
is an important factor for drug performance, viscosity-pH relationship, if feasible.”
pH specification limits should be in line
■■ “The gelling agent used in your ANDA product
with the RLD [reference listed drug]. We
is known to be pH dependent, and viscosity
recommend you to tighten the upper limit for
decreases while pH decreases. In addition,
your in-process, drug product release and
the acidic degradative product from active
stability specifications to be in line with that of
pharmaceutical ingredient can significantly
the RLD. In addition, we recommend that the
lower pH and then viscosity of your product.
pH be characterized by preparing a dilution
In order to mitigate the risks of pH and
of the drug product (e.g., 1:10 dilution with
viscosity downward trend, we recommend
distilled, deionized, CO2-free water).”
you to provide pH effect on viscosity of your
■■ “We encourage the generic companies to drug product to justify your drug product
adopt quality by design (QbD) and design specification limits of viscosity, if feasible.”

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Excipient Analyzing Excipient Form CQAs and
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of topical dermatologic drug products. the applicant of the importance of QbD


Q3 attributes are emphasized as part of and Q3 attributes as well as the need to
quality target product profile (QTPP) and adequately characterize the parameters
critical quality attributes (CQA) due to this of semisolid drug products (7, 8). The
paradigm shift from the “equivalence- agency remains cautious to adopt an
by-testing” traditional approach to the approach for the thorough evaluation of
“equivalence-by-design” QbD approach. all quality attributes (Q1/Q2/Q3) as well
If the applicant did not adopt the current as surrogate markers (i.e., in-vitro release,
regulatory trend, significant numbers in-vitro permeation, and/or in-vitro dermal
of deficiencies may be issued to alert distribution) for which there was known

Commonly Cited Deficiencies for Topical Dermatologic Drug Products in ANDAs (Cont.)
The authors paraphrase deficiencies commonly cited by FDA in the past four years.
■■ “Because semisolid preparations commonly estimation of the particle size distribution, it is
have a non-Newtonian flow behavior, recommended that you report the average of
please provide comparative rheological ~300 particles. To alleviate this slow and tedious
characteristics (i.e., upward and downward manual procedure, a computerized image analysis
flow curve of shearing stress vs. shearing rate method or other appropriate test method can be
along with yield value) for both your drug adopted for particle size measurements.”
product and the RLD to demonstrate the
■■ “We notice that you have proposed one tier
appropriateness of your selected viscometer.”
particle size specification limit in your drug
■■ “We notice that your temperature condition product release and stability specifications. It
for viscosity measurement is excessively is recommended that you establish a three-tier
higher than that of the storage condition. particle size distribution for your proposed
Please revise your test condition to be drug product.”
ambient to avoid any microstructural change
■■ “Your drug product is an oil-in-water cream.
(e.g., melting down of excipient(s)).”
The globule size is a potential critical quality
■■ “Drug substance polymorphism can be the attribute. Please include globule size test in your
critical attribute to ensure drug performance. drug product release and stability specifications
Please demonstrate the drug form for API is the with appropriate limits, based on the test results
same as that in the RLD [reference listed drug] or of your test products and the RLD.”
discuss the polymorphism form issue following
■■ “We recommend that comparative in-vitro
the ICH [International Council for Harmonization]
release test for your drug product and the
Q6A decision tree for #4 polymorphic form.”
RLD be conducted using a validated test
■■ “Your procedure for analyzing drug product method, and the data generated can be used
particle size reports an average of very limited as a baseline for future potential formulation
crystalline particles. In order to define a better and process changes for your drug product.” 

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or suspected bioequivalence problem, should be noted that in some occasions,


such as in Acyclovir cream and ointment to measure bioavailability or establish
cases. For the drug product with no bioequivalence for certain topical drug
known or suspected bioequivalence products, the agency recommends
problem (e.g., AT-rated drug products), in-vitro or in-vivo study option. This
the agency focuses on Q3 attributes information is available on FDA’s
demonstrating pharmaceutical website (9). Acceptable comparative
equivalence and patient acceptability physicochemical characterization and/or
(e.g., guidance on Triamcinolone in-vitro drug release rates of the generic
Acetonide Cream and Ointment). It and RLD products is of importance to be

Commonly Cited Deficiencies for Topical Dermatologic Drug Products in ANDAs (Cont.)
The authors paraphrase deficiencies commonly cited by FDA in the past four years.
■■ “We notice that you only test top, middle, and release and stability specifications to include
bottom (three samples), which is not sufficient ethyl alcohol assay, isopropyl myristate assay,
to demonstrate the homogeneity of bulk and edetate disodium content.”
product. Please acknowledge this inadequate
■■ “Please include weight loss test in your drug
sample number for bulk content uniformity
product stability specification with a footnote
test and commit to increase the sample
to reflect such a test for developmental
number (at least 10 samples) collected from
batches (exhibit and validation batches) only
appropriately spaced locations for your future
to qualify the proposed container closure
batches to attain statistically meaningful
system.”
results.”
■■ “Because your test formula contains large
■■ “What additional in-process controls and
amount of ethyl alcohol and the solvent has
tests are in place during filling and packaging?
powerful extraction ability, we request you
Specifically, provide specific details on the
conduct the extractables/leachables studies
controls in place for fill weight, sealing and
for your container closure system. Please
capping of the tubes. Also, seal integrity or
investigate and demonstrate the absence of
tube leaking test should be performed to
benzophenone in the drug product stability
ensure adequate protection for the drug
samples using an established analytical
product.”
method. In case benzophenone is detected in
■■ “Your drug product contains the solvent (ethyl the drug product, we recommend including
alcohol), penetration enhancer (isopropyl a leachable specification to limit its amount
myristate), and chelating agent (edetate in your drug product release and stability
disodium); however, your drug product release specifications. Also, note that benzophenones
and stability specifications do not include have been named the American Contact
assay tests for these important components Dermatitis Society’s 2014 Contact Allergen of
of your formulation. Please modify your DP the year.”

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ANDAs

considered as qualified for the in-vitro rheological behavior, drug polymorphic


option. form, and in-vitro release rate. Some
The applicant should include a common concerns regarding Q3
comprehensive, comparative quality attributes are discussed in the following
attribute evaluation of both the RLD sections.
and the generic-drug candidate. Ideally, Appearance descriptions. Some
an evaluation of three separate lots of applicants offer incomplete appearance
the RLD with different expiry dates (i.e., descriptions. More detailed descriptions
a fresh lot and lots close to expiry) is (e.g., free of lumps, free of foreign matter,
recommended to provide a complete homogeneous consistency, no phase
understanding of the variability of each separation, etc.) should be included in
quality attributes for the RLD. These Q3 the drug product specification. Also,
attributes may include the following: the description for the drug product in
pH, globule size, drug particle size, its container closure system should be

Commonly Cited Deficiencies for Topical Dermatologic Drug Products in ANDAs (Cont.)
The authors paraphrase deficiencies commonly cited by FDA in the past four years.
■■ “The thermal cycling studies you conducted (May 2014), specifically to Section E Q2
are not acceptable in their current forms. One and A2, for FDA’s recommendations on
of the purposes to a conduct thermal cycling the storage positions for stability samples
(freeze-thaw) study is to assess the effects in the stability program. Please note that
of transportation on the quality of the drug we recommend that for semi-solid drug
product. The temperature range you selected product the stability samples should be
does not adequately simulate the actual placed into two orientations: an inverted
transportation conditions, which routinely (or horizontal) position and an upright (or
span a temperature range of 40 °C to -20 °C. vertical) position. We ask that you comply
Please also note that the thermal cycling study with our recommendation in any future
is part of the stability studies. Therefore, all ANDA submissions. For your current ANDA
quality attributes of the stability specifications application, we recommend that you adopt
should be evaluated and the results reported. the required two (2) sample orientations for
Please revise your thermal cycling study at least one of the validation batches. Once
protocol and provide all relevant data you demonstrate that the products in one
according to your stability specifications.” orientation do not have significant greater
impact on stability over the other, you may
■■ “Please refer to FDA Guidance for Industry:
discontinue the testing with samples stored
ANDAs: Stability Testing of Drug Substances
in upright orientation for routine stability
and Products Questions and Answers
studies.”

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ANDAs

included as part of appearance test (e.g., be generated to demonstrate that the


package appearance [inner and outer selected viscometer is appropriate for
wall]) to check for seal integrity and any semi-solid texture material analysis.
discoloring of inner wall as well as label If the material tested has plastic flow
evaluation. behavior, it is important to report yield
pH. pH can affect many parameters, value. The flow curve should consist of
such as: ionization state of the drug multiple data points. The number of
substance, solubility of the drug data points for the flow curve depends
substance, drug-product stability, on the selected viscometer’s capability,
viscosity, preservative efficacy, but should be comprehensive enough
performance, etc. Generally, conventional to characterize the flow curve. Viscosity
pH meters are designed to measure values at specific test conditions for
the pH of aqueous solutions. Topical multiple lots of the test product and the
dermatologic drug products, however, RLD should be generated as a foundation
may contain limited quantities of aqueous to set the viscosity acceptance criteria
phase and may instead contain solvents for the generic-drug product. In special
and lipoidic materials in larger quantities. cases, apparent viscosity specifications
Dilution of the preparation using an at more than one set of conditions may
appropriate medium may be necessary be required to monitor product viscosity
to keep the pH sensor in an aqueous properly. Also, note that viscosity
phase and measure pH accurately. It is measurement of the molten state of the
recommended to use a 1:10 dilution with product under an elevated temperature is
distilled, deionized, CO2-free water for pH not acceptable as a drug product quality
determination, when direct measurement attribute.
is not feasible. Polymorph equivalence. Polymorphs
Viscosity. Rheological behavior of the can vary in their physicochemical
test drug product and the RLD needs to properties, which may in turn affect the
be characterized using an appropriate quality, safety, and efficacy of the final
viscometer/rheometer for semisolid product. Demonstrating the equivalence
texture material. Because semi-solid of polymorphic form of a generic
dosage forms usually display non- product to that of the RLD is critical, if
Newtonian flow behavior, it is prudent applicable. Identification of the specific
that the upward and downward flow polymorph of drug substance in the
curve (shear rate vs. stress plot) for the generic drug may be performed through
test drug product and RLD product x-ray diffraction, Raman spectroscopy,

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ANDAs

or other appropriate techniques. In include a particle size distribution test


these cases, it is necessary to compare with three-tier specification limits (e.g.,
analyses of the drug substance in the D10%, D50%, and D90%). To avoid this
semi-solid product for both the RLD slow and tedious manual procedure,
and generic products with the aid of computerized image analysis methods or
drug substance polymorphic standards other validated methods are permitted
and placebo matrix. This direct analysis for particle size measurements. If the drug
of the drug product is the preferred product contains the drug in a molecular
method to identify and quantify the state, it is prudent to microscopically
polymorphic form. It can be technically ensure lack of crystallization of the active
challenging to measure polymorphic ingredient during the drug product
changes in drug products. However, development stage. If the drug product
the applicant needs to show their is emulsion-type cream, the apparent
proper due diligence in analyzing the distribution of particles between aqueous
polymorphic form of the drug substance phase and oil phase should be evaluated
in dermatologic products, either by microscopically.
analysis of drug products or isolated Globule size. Topical preparations
drug particles. In addition, the applicant in the form of either oil-in-water cream
should refer to the #4 Polymorphic Forms (vanishing cream) or water-in-oil cream
section of the International Council for (cold cream) are commonly used to
Harmonization’s (ICH) Q6A decision tree deliver APIs to the epidermis or upper
to discuss their drug substance and drug dermis to elicit their pharmacological
product situation to alleviate regulatory effects. Globule size can influence the
polymorphic form concern (10). drug product quality and performance.
API particle size. If the drug product Because emulsions are inherently
contains a dispersion of drug substance, thermodynamically unstable, the
then the particle size of the active measurement of globule size and size
ingredient in the drug product base distribution is a crucial test item for
needs to be monitored. In general, the monitoring the stability of emulsion type
particle size of the active ingredient in products.
a drug product should be generated Drug release tests. Currently, in-
by microscopic measurement of at least vitro drug release tests (IVRT) are rarely
300 particles to obtain an accurate included in finished drug product
estimate of particle size distribution. release and stability specifications
The drug product specifications should for generic dermatologic products.

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ANDAs

If the drug product is a complex and NDA supplements of dermatologic


semisolid preparation (e.g., emulsion drug products, this trend also applies to
type cream), however, it is imperative ANDA products. Currently, the authors
to submit comparative IVRT data in encourage that comparative in-vitro
the application. In specific cases (e.g., release test for generic drug product and
the formula containing microsphere, a the RLD be conducted particularly during
novel excipient), IVRT was included in product development and the data can
the drug product specifications. FDA be used as a baseline for future potential
has several reasons to implement the formulation and process changes for a
inclusion of the in-vitro drug release drug product
test as a required drug product release Permeation tests. In-vitro permeation
and stability specifications in the future. test (IVPT) across human skin is perhaps
The main reason is that the IVRT can the most useful, versatile and insightful
reflect the combined effect of several in-vitro information in development of
physicochemical characteristics (e.g., a topical drug product. The authors
solubility of API, pH, particle size, encourage generic-drug applicants to
globule size, viscosity, and diffusion adopt this technique in their drug product
resistance of the vehicle). Recently, FDA development; the knowledge gained can
has recommended that IVRT method give better understanding of impact of
development be started early in the any difference in the Q3 attributes.
drug product development  phase for all
topical drug products, if applicable. For Specific tests
new drug applications (NDAs), Ghosh (11) In the ANDA pharmaceutical
pointed out that FDA is facing challenges development stage, it is important
in bringing discontinued products back to have complete documentation for
to the market in the absence of current all stages of drug development and
reference products; an established IVRT production. This documentation includes
method and specification could alleviate complete batteries of quality testing in
this problem. Likewise, in ANDAs, the the drug substance, as well as complete
authors have concerns that there is examinations of in-process and drug
no historical IVRT data as a baseline product specifications as described in this
to assess product “sameness” during section. This thorough investigation will
scale-up and post-approval changes for ensure the quality, safety, and efficacy
dermatologic drug products. As FDA of the generic topical-drug product.
continues to request IVRT data for NDAs Through this extensive testing, it will be

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ANDAs

possible to work backwards to pinpoint temperature conditions on the quality of


any manufacturing steps for trouble dermatologic drug products. The authors
shooting, if necessary. The proposed also recommend two storage orientations
in-process tests should render adequate (i.e., horizontal or inverted vertical and
monitoring and control of the high risk upright vertical) for the exhibit batches to
attributes (e.g., assay, impurities, blend support the ANDA filing (13).
uniformity, pH, viscosity, globule size, and
particle size distribution), if applicable. Extractables and leachables studies
For the blend uniformity test, the authors Leachables/extractables studies are
recommended that the sample size required for injectables, inhalation
should be at least 10 to attain statistically products, and ophthalmic products.
meaningful results. In-process controls They are, however, not required for
and tests during filling and packaging are dermatologic drug products in most
frequently missing in submissions. cases (14). When a dermatologic drug
All topical semi-solid drug products, product contains significant amounts
if applicable, should be monitored of solvents, reviewers tend to inquire
for, but not limited to the following about leachables/extractables studies
characteristics: description, identification, due to the high extractability of the
assay, impurities (known impurities, solvents in the formula, which is
individual unknown impurity, and total supported by a published article (15).
impurities), pH, viscosity, API particle size The applicant should refer to USP
distribution, globule size, minimum fill, chapters <1663> and <1664> for further
microbial limits, uniformity in container, guidance (16, 17).
non-aqueous solvent assay, anti-oxidant Furthermore, benzophenones
assay, antimicrobial preservative assay, are given more attention because
penetration enhancer assay, water they have been named the Contact
content, weight loss, and leachables. The Allergen of 2014 by the American
applicant should refer to United States Contact Dermatitis Society (18–20).
Pharmacopeia (USP) chapter <3> Topical In addition, benzophenones are used
and Transdermal Drug Products–Product in many industries, ranging from UV
Quality Tests to meet compendial light absorber, adhesives, and plastics.
requirements (12). Hence, reviewers often ask applicants
It is essential to include thermal cycling to demonstrate the absence of
studies as a part of stability studies benzophenones in the drug product.
to assess the effects of transportation

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Excipient Analyzing Excipient Form CQAs and
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ANDAs

Conclusion (10) ICH, Q6A Specifications: Test Procedure and Acceptance Criteria for
New Drug Substances and New Drug Products, Chemical Substances
Increased sharing of internal policy (ICH, 1999).
(11) T.K. Ghosh, “Topical Drug Delivery: U.S. Regulatory Perspectives
assists in increasing FDA’s transparency, from Biopharmaceutics and Related Disciplines,” presented in USP
Workshop on Quality Attributes of Drug Products Applied to the
which is crucial to minimize the problems Skin, Sept. 21–22, 2015.
(12) USP, Chapter <3> Topical and Transdermal Drug Products–Product
and pitfalls in ANDAs. Hopefully, Quality Tests, USP 39-NF 34 Vol. 1, page 81-86 and Official from
increased transparency and clarity August 1, 2016.
(13) FDA, Guidance for Industry, ANDAs: Stability Testing of Drug Sub-
about FDA’s internal review processes stances and Products, Questions and Answers (CDER, May 2014).
(14) FDA, Guidance for Industry, Container Closure Systems for Packaging
will help generic-drug companies Human Drugs and Biologics, Chemistry, Manufacturing and Controls
avoid the aforementioned pitfalls. For Documents (CDER, CBER, May 1999).
(15) J.B. Haverkamp et al., Eur. J. Phrm.Biopharm. 70 (3), 921-8 (2008).
ANDA sponsors, careful attention to (16) USP, Chapter <1663> Assessment of Extractables Associated with
Pharmaceutical Packaging/Delivery Systems, USP 39-NF 34, Vol 1,
these insights will improve quality of page 1835-1848, Official from August 1, 2016.
ANDA documents, increase chances (17) USP, <1664> Assessment of Drug Product Leachables Associated
with Pharmaceutical Packaging Delivery Systems USP 39-NF 34,
of regulatory success, and benefit in Vol. 1, page 1850, Official from August 1, 2016.
(18) A. Heurung, S. Raju, and E. Warshaw, Dermatitis 25 (1): 3–10,
expediting approval of their dermatologic (2014), DOI:10.1097/DER.0000000000000025.
(19) D. Brunk, “Benzophenones Named 2014 Contact Allergen of the Year,”
drug products. Dermatology News Digital Network (March 14, 2014), www.skinan-
dallergynews.com/single-view/benzophenones-named-2014-contact-
allergen-of-the-year/cb086f7e351cccbcfd9dbf5fa806762b.html.
References (20) A. Vazirnia and S.E. Jacob, “Review ACDS’ Allergen of the Year 2000-
(1) A. Srinivasan and R. Iser, Pharm. Technol. 34 (1), 50-59 (January 2010). 2015,” The Dermatologist, 22 (11), (2014), www.the-dermatologist.
(2) A. Srinivasan, R. Iser, and D. Gill, Pharm. Technol. 34 (8), 45-51 com/content/review-acds’-allergen-od-year-2000-2015.
(August 2010).
(3) A. Srinivasan, R. Iser, and D. Gill, Pharm. Technol. 35 (2), 58-67
(February 2011).
(4) A. Srinivasan and R. Iser, Pharm. Technol. 35 (4), 62-68 (April 2011). Rong-Kun Chang is master chemistry reviewer, Division of Liquid-
(5) Q. Liu et al., AAPS Journal 14 (1), 19-22 (2012), DOI: 10.1208/ Based Products; Pahala Simamora is acting branch chief, Division of
s12248-011-9312-7. Liquid-Based Products; Bing Cai is acting director, Division of Liquid-
(6) C.C. Long and A.Y. Finlay, Clin. Exp. Dermatol. 16 (6), 444-7 (1991). Based Products; Andre Raw is senior scientific and policy advisor,
(7) R.K. Chang et al., AAPS Journal, 16 (1), 41-52 (2013), DOI: 10.1208/ Office of Lifecycle Drug Products; and Susan Rosencrance is direc-
s12248-012-9411-0. tor, Office of Lifecycle Drug Products, all at FDA’s Office of Life Cycle
(8) R.K. Chang et al., AAPS Journal, 15 (3), 674-83 (2013), DOI: Products, Office of Pharmaceutical Quality, Center of Drug Evaluation
10.1208/s12248-013-9472-8. and Research.
(9) FDA, “Product-Specific Recommendations for Generic Drug Devel-
opment,” FDA.gov, www.fda.gov/Drugs/GuidanceComplianceReg- This article originally appeared in Pharmaceutical Technology, Vol.
ulatoryInformation/Guidance/ucm075207. 40, No. 9, pp 68-76 (September 2016).

23 | November 2016 | PharmTech/BASF eBook


Studying Microstructure in Topical
Formulations
Q&A with Padam C. Bansal, Amneal Pharmaceuticals

Video Interview Probing microstructure requires smart use


The Importance of
of analytics, guided by the principles of
Microstructure of Q3
quality by design.
Click to
launch
video The Q3 microstructure of any topical drug
formulation is complex. Structured studies are
required in order to understand the composition
and behavior of components of the formulation.
In an interview with Pharmaceutical Technology,
Padam C. Bansal, senior vice president of research
and development at Amneal Pharmaceuticals,
explains best practices for studying the Q3
microstructure and applying quality-by-design
(QbD) principles to topical drug formulation.

Pharmaceutical Technology: What


analytical and testing methods are becoming
more important today in studying the Q3
roger ashford/shutterstock.com

microstructure of topical formulations?


Bansal: Depending on the complexity of
the given formulation and product, a variety of
testing methods may be used to study the Q3
microstructure of semi-solid dosage forms. The

24 | November 2016 | PharmTech/BASF eBook


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ANDAs

most commonly used is microscopy, On the other hand, for local


which allows one to see the structure application, generally, only minimal
of the matrix under the microscope and penetration through the skin is required.
identify distinct particulates in the semi- In that case, it is important to look at
solid matrix. For extensive evaluation, the drug distribution into the skin layer,
electron microscopy may be used. whether the drug is in the stratum
Studies pertaining to rheological corneum, epidermis, or dermis, whereby
behavior are also critical. These studies the penetration through skin is minimized.
utilize a rheometer to determine the For membrane diffusion, one can
effects of shear rates and temperature on develop methods that discriminate
the structure of a semi-solid mass. This between formulations, or one can use
information helps one study the behavior methods that compare the formulation
of a semi-solid mass at different shear rates with a reference product, and match
and temperatures. Such microstructure its Q3 microstructure properties.
studies are helpful to understand the Determining the soluble fraction of the
physical stability of the semi-solid matrix at API in the product matrix is a very critical
different temperatures. step at this stage.
Additionally, spreadability and texture Microscopy and X-ray diffraction can
testing can be used to help determine be used to determine the particle size of
how acceptable any given topical product the dispersed API and its polymorphic
will be to the consumer. These tests are form. If a drug is present in very low
also indicative of the semi-solid matrix concentrations, Raman spectroscopy may
microstructure. be utilized.
In a skin flux study, a drug is applied to By using these tests and equipment,
the skin (human cadaver skin membrane), one can gain a clear understanding of
and its diffusion through this membrane the Q3 microstructure of any semi-solid
is examined to determine how much of dosage from.
the drug is actually penetrating through
the skin. When conducting this test, it is Pharmaceutical Technology: Is it
very important to know whether the drug difficult to apply QbD principles in
is meant for local or systemic use. If it is any consistent way to optimize the
for systemic application, then it is crucial formulation of topical products? If it
to see how fast the drug will penetrate is, what will be needed to change the
and what kind of blood level you’re going situation?
to get after a certain length of time. Bansal: QbD principles must always

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ANDAs

be applied scientifically, if one is to By utilizing QbD in development, one


develop an optimal formulation and can derive the desired Q3 characteristics
process. Sometimes, we really need to of the drug product.
think outside of the box and find ways QbD principles are used to match
to apply QbD principles. Initially, this Q3 characteristics by studying the
could mean optimizing the product’s microstructure. In this case, QbD
composition in the early R&D stages by is derived from the process design
conducting a literature search, and by through DOE, which renders consistent
reverse engineering of the reference and reproducible Q3 properties. In
product. These steps will generally result addition, QbD experiments that use
in a qualitatively and quantitatively similar DOE to confirm the parameters will not
composition. only result in consistent Q3 properties,
The next step is designing the process, but also create a more consistent and
which also plays a very important role in reproducible process.
achieving the microstructure. One should
design experiments based on process
parameters, and optimize the process by Padam C. Bansal received his
doctorate in pharmaceutics
applying QbD principles. In this way, a and has worked at Pfizer, Ortho
Pharmaceuticals, and Berlex
reproducible process can be developed Laboratories, where he was
resulting in a drug product with desired director of pharmaceutical
development. At present,
Q3 properties. Dr. Bansal is the senior vice
president of research and
development at Amneal
Pharmaceutical Technology: How can Pharmaceuticals where he
Q3 and QbD principles be used together directs his team toward topical
product development. So far,
to optimize design of experiments (DOE) the company has developed
and streamline product development? a wide variety of products,
and submitted more than
Bansal: QbD is the principle and Q3 is 50 abbreviated new drug
the endpoint or the characteristic of the applications (ANDAs).

product that one must achieve. Thus, Q3


is the response factor.

26 | November 2016 | PharmTech/BASF eBook


Excipient Form and FunctionExcipients:
Anything but Inert
Q&A with Nigel A. Langley, BASF Pharma Solutions

Manufacturers, especially some generics


companies, may still take excipients for
granted in topical formulations.

Optimizing topical drug formulations requires


understanding how each component may interact
with other ingredients and how it will react on
the skin. Nigel A. Langley, director of global
technical marketing and technical service at BASF
Pharma Solutions, discussed the importance of
excipient form and function in an interview with
Pharmaceutical Technology.

Pharmaceutical Technology: Do pharma


companies—especially generics firms—still tend
to take excipients for granted? Why would this be
a problem for topical formulations?
Langley: Some companies are more advanced
in their understanding of excipients than others,
Artenex/shutterstock.com

especially in topical pharmaceutical drug


formulation and development. The importance of
using pharma-grade excipients when developing
formulations is sometimes overlooked. The

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ANDAs

use of non-pharma, non-compendial Langley: It should play very important


excipients can lead to product quality roles in both QbD and Q3 microstructure.
and safety issues, as well as drug One way to develop this knowledge
degradation and product instability. is to have a close understanding and
Non-pharma-grade excipients are not relationship between excipient suppliers
necessarily manufactured under cGMPs and pharmaceutical companies within the
and may lack the required full regulatory industry.
documentation to support their use. Certainly, the concept of microstructure
It is only recently that the role and is a new topic for many companies
functionality of excipients, especially in and suppliers. At BASF, we are taking
topical dosage forms, are being more a proactive role to help support the
widely considered. The FDA Inactive pharmaceutical industry in this area.
Ingredients database (IID) implies that We, ourselves, are doing work in the
the listed ingredients (i.e., excipients) are laboratory to understand how excipients
inactive or inert. This is a little misleading can affect formulation characteristics, and
because in reality, excipients have how they can help provide a more stable
functionality and can play critical roles in and robust product.
both the efficacy and stability of a given Excipient choice and quality
drug product. are important in both QbD and
In the case of topical drug products, microstructure. Some topical formulations
there can be a much larger number are complex, consisting of many different
of excipients in the drug formulation excipients. It will be critical for companies
compared with other dosage forms such to better understand each excipient’s role
as tablets, capsules, and others. Each and function. Only by formulating with
excipient will have its own function; for pharma-grade excipients of a consistent
example, one may provide emolliency quality will they be successful in both
or skin feel, while another may help the QbD and in satisfying the critical quality
API penetrate the skin, and yet another attributes, Q3, for microstructure.
can build the viscosity required to form a
cream. Pharmaceutical Technology: Will
consolidation occur in the pharma
Pharmaceutical Technology: What excipient market with few companies
role should excipient understanding specializing in this area, which is a
play in quality by design (QbD) and Q3 relatively small portion of the overall
microstructure analysis? ingredients market?

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Langley: I think this will not only Langley: Some companies are
depend on economics, but also on extremely sophisticated, while others are
what regulators do in the future. With not. It generally depends on the size of
respect to topical drug products, once the company.
the FDA defines and publishes its I would anticipate that for some
industry guidelines for microstructure/ companies, the analytical testing and
critical quality attributes, pharmaceutical the material science knowledge that will
companies may require a greater level be required to gain a comprehensive
of information and documentation from understanding of a topical product’s
excipient suppliers. Initially, this would microstructure would be conducted in-
probably come from generic topical house. For other companies with fewer
pharmaceutical companies, but later, it analytical capabilities, this activity would
may also come from innovator companies need to be outsourced.
as well. There will also be a role for where
Some excipient suppliers may be more the scale-up and manufacturing takes
willing to do this than others and I think place. How the generic topical product
this will depend on how important their is manufactured compared with the
pharmaceutical excipient portfolio is to originator will also play a very important
their overall business. For some suppliers, role in the microstructure and the
the pharmaceutical excipient area is a associated analytical testing. Differences
very minor part of their business. in product rheology, for example, from
At this time, I think it is too early to say small-scale to large-scale production,
what the future may bring and whether may have a dramatic effect on product
increased consolidation within excipient quality, stability, efficacy, and batch-to-
suppliers will occur. batch consistency.

Pharmaceutical Technology: How


sophisticated are your customers getting
in terms of being able to use analytics
and in their knowledge of material
science?

29 | November 2016 | PharmTech/BASF eBook


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The Relationship Between Critical Quality
Attributes and the Microstructure of
Topical Semi-Solid Formulations

WEBCAST Researchers developing topical semi-solid


Understanding the Rela-
products must understand the factors that
tionship Between Critical
Quality Attributes and the
influence the formation of the complex
Click
to view
Microstructure of Topical
Semi-Solid Formulations microstructures that compose the Q3, how
webcast
the microstructure influences the critical
quality and performance attributes of the
drug product, and how analytical studies
can reveal vital information to improve a
drug’s quality and performance.

Microscopy, image analysis, x-ray diffraction,


and other methods can be used to evaluate and
quantify the microstructure of cream formulations
and show how excipient selection can influence
product stability, rheology, drug delivery, and
other performance factors.
WilleeCole Photography/shutterstock.com

Norman Richardson, global technical marketing


manager of skin delivery at BASF, explained
the challenges of formulating semi-solid
drug products for skin delivery in a webcast,
Understanding the Relationship Between Critical
Quality Attributes and the Microstructure of

31 | November 2016 | PharmTech/BASF eBook


Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Figure 1: Two creams with same API (1%) macroscopically appear to be the same, feel and behave the same, but
microscopically look very different.

400x 400x

Components Branded Generic


Consistency   cetyl alcohol, stearyl stearic  acid,  stearyl
Factor   alcohol alcohol
Emulsifier polysorbate 60,  sorbitan polysorbate 60,  sorbitan
monostearate monostearate
Emollient octyldodecanol,  cetyl isopropyl  myristate,  
esters  wax liquid  paraffin
Solvent   water,  benzyl  alcohol water,  benzyl  alcohol,
propylene  glycol 1

Topical Semi-Solid Formulation. This 1% API concentration feel the same. A


summary highlights key points of that microscopic analysis of the two samples
presentation. shows different crystal morphologies
Microscopic analysis of over-the- (Figure 1). Both creams use the same
counter creams for different medical emulsifier, but other excipients used
applications reveals, as expected, as emollients, as solvents, and for
differences in API morphologies, oil consistency may contribute to the
droplet distribution, and excipient and difference in the crystal morphology, said
wax crystals. A comparison of branded Richardson.
and generic products with the same API The complex formulation of a
and concentration, however, also reveals generic semi-solid cream is determined
differences in formulation that could qualitatively by the selection of API and
impact product performance and patient excipients (Q1) and quantitatively by the
response. amount of excipients (Q2). Formulators
When rubbed on the skin, a branded must assess how various excipients can
cream and a generic equivalent with a interact with the API, and determine the

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Figure 2: The performance of semi-solid formulations is determined by the Q3, and the Q3 is determined by the formulation
inputs (including Q1 and Q2).

Formulation  inputs Emulsion,  cream,   Performance


ointment,  gel  (Q3) Criteria
• List  of  excipients  and  API  (Q1)
• Amount  of  each  excipient  and   Viscosity
API  (Q2)
Stability
• Processing  
• Temperatures  and  ramp   Sensory  properties
rates Appearance
• Orders  of  addition API  release
• Shear API  absorption
• Packaging  conditions
Heterogeneous  
• Excipient  source  and  grade
• Storage  time System  
(Non-­‐Equilibrium  System)

best approach to optimize the stability, Understanding the


release of the drug, and the delivery of Role of Excipients
the API through the skin. In addition, To understand the actions of various
manufacturing and packaging conditions, excipients in a branded formulation,
excipient sources and grades, and shelf experts at the BASF dermatology
life must be evaluated. laboratory examined and estimated the
All of these inputs result in a ingredients in a brand-name clotrimazole
complex, heterogeneous system, cream. Using this product as a model,
the Q3, composed of complexes they systematically changed individual
and colloidal structures that result excipients to evaluate the impact on
from the self-assembly of the various product microstructure, rheology, and
ingredients that go into the formulation state of matter.
(Figure 2). “When we look under the In one study, the emollient
microscope, we’re actually visualizing octyldodecanol was changed in different
some of these structures, these entities samples to isopropyl myristate, mineral
that have formed by the mixing of oil, and cocoyl caprylocaprate; all other
the excipients,” said Richardson. A ingredients stayed the same. Similar
variety of analytical techniques reveal systematic studies were conducted
the effects of various excipients and on other parts of the formulation
the interactions in a formulation’s using microscopy and other analytical
microstructure. techniques to evaluate what occurs in

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Figure 3: Emollient variations are shown in microscopic images of different excipients (octyldodecanol, isopropyl myristate,
mineral oil, and cocoyl caprylocaprate) tested in a clotrimazole formulation. Consistency factor (wax) = Kolliwax CSA 50
(cetostearyl alcohol); Emulsifier = Kolliphor CS 20 (Polyoxyl 20 cetostearyl ether); Emollient (oil) selected from Kollicream
series (i.e., Kollicream OD, IPM, 3C).

the formulation microstructure and its structures are the wax phases, which have
performance based on changing a single mixed with the emulsifier and are forming
excipient. layered shells around the oil droplets or
Comparing a formulation at varying extending through the spaces between
magnifications using a Zeiss Axio bright- the oil droplets as a gel network,
field microscope revealed different levels explained Richardson.
of detail for the crystals and emulsion A visual comparison of the four
and provided information about the oil formulations, octyldodecanol, isopropyl
droplets. The 40x magnification shows myristate, mineral oil, and cocoyl
a fairly homogenous distribution of caprylocaprate, are shown in Figure 3.
oil droplets with some air bubbles. At The oil droplet sizes and distribution of
100x, individual droplets can be seen. populations of oil droplets are different in
At 400x, multiple emulsion droplets are each formulation.
visible, including some that appear to be Next, the laboratory quantified the oil
droplets within droplets and some folded droplet distributions using the ImageJ
structures between the droplets. These software, an open-source imaging

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Figure 4: Microscopy and image analysis provides information about excipient impact on droplet size distribution. MO is
mineral oil. IPM is isopropyl myristate.

program available through the National the distribution for the oil droplet size
Institutes of Health. Using 3 mg of is quite wide with some measuring up
product, they examined each formulation to 500-square pixels. For the isopropyl
in a 2-cm diameter sample under the myristate, a majority of the oil droplets
microscope. The ImageJ software are less than 80-square pixels in the
identified all the droplets, measured area with few droplets above 210-square
each as an area measurement in square pixels.
pixels, and then it plotted a histogram An analysis of the data showed a
that shows the distribution of these oil correlation between the physical stability
droplets. at 40 °C and the average oil droplet sizes
Figure 4 compares a formulation for 10 formulations. Formulations with
with mineral oil and a formulation with an average oil droplet size of 127-square
isopropyl myristate; all other ingredients pixels or less remained stable for four
are the same. The microscopic images weeks. Those with oil droplets more than
show great differences, confirmed 135-square pixels failed after one week.
by the histograms, that show the oil This comparison was limited to the oil
droplet distribution. For the mineral oil, droplet sizes and the stability, and did

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Figure 5: X-ray diffraction (XRD) analysis of the effect of fatty alcohol selection on crystalline/gel network state in
Clotrimazole cream model system. Formulation with stearyl alcohol (Kolliwax SA, BASF) reveals more XRD peaks
characteristic of fatty alcohols.

θ°

not consider other variables, explained In a typical structure using polyoxyl 20


Richardson. He hypothesized that the cetostearyl ether as an emulsifier along
narrow difference in the oil droplet size with fatty alcohols, stiffer regions layer
of 127-square pixels versus 135-square with fluid regions to create a gel network.
pixels indicates that other factors need to Analysis of the gel network by x-ray
be considered, including the status of the diffraction (XRD) yielded the three curves
matter between the oil droplets. in Figure 5, separated from each other
to show the details. In this study, only
Evaluating Gel Networks one component, the fatty alcohol, was
High melting point lipophiles—such as changed in each formulation.
fatty alcohols, and emulsifiers—mix to For each formulation’s curve, the large,
form structured gel networks that can broad peak extending from approximately
influence physical stability, rheological 10 degrees to approximately 40 degrees
properties, the API solubilization capacity, represents amorphous structures that
the API release, and product aesthetics could be related to the gel network, but
during application. is not pure crystalline matter, explained

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Common
Excipient Analyzing Excipient Form CQAs and
Deficiencies in
Selection Microstructure and Function Microstructure
ANDAs

Richardson. The blue curve represents effective rheology and consistency in the
the formulation with stearyl alcohol; the formulation,” said Richardson.
distinct peaks show that crystalline stearyl To evaluate drug delivery, an in-
alcohol separated out of the formulation vitro diffusion study using a skin model
to form crystals. The green curve, which demonstrated differences in diffusion
represents the cetyl alcohol formulation, of the API, clotrimazole, for the different
indicates a small amount of crystallinity, formulations. Isopropyl myristate had the
but much less than the stearyl alcohol. highest flux rate; cocoyl caprylocaprate
The red curve for the cetyl stearyl had the lowest diffusion rate. For
alcohol cream formulation shows a more treatments with clotrimazole, where
pronounced peak than the cetyl alcohol the API should stay on the surface
formulation, but much less crystallinity of the mucosal membrane, a cocoyl
than the stearyl alcohol formulation. All of caprylocaprate may be the better choice
the stearyl alcohol is not being effectively for the formulation.
incorporated into the gel network that
builds rheology and consistency. Figures courtesy of BASF.
Rheology studies showed that the
cetostearyl alcohol and the cetyl alcohol
formulation were similar; however, the
stearyl alcohol had significantly lower
viscosity. “We can hypothesize that the Norman Richardson
good mixing of the emulsifier and the Global Technical Marketing
Manager – Skin Delivery at BASF
wax, where you have less crystalline wax
and more of the gel network, is building
up the rheology and that you get a more

37 | November 2016 | PharmTech/BASF eBook