Journal of Pharmaceutical Sciences 107 (2018) 2653-2662
`
`Contents lists available at ScienceDirect
`
`Journal of Pharmaceutical Sciences
`
`j o u r n a l h o m e p a g e : w w w . j p h a r m s c i . o r g
`
`Pharmaceutics, Drug Delivery and Pharmaceutical Technology
`A Tutorial for Developing a Topical Cream Formulation Based on
`the Quality by Design Approach
`Ana Sim~oes 1, 2, Francisco Veiga 1, 2, Carla Vitorino 1, 2, 3, Ana Figueiras 1, 2, *
`1 Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
`2 LAQV. REQUIMTE, Group of Pharmaceutical Technology, Coimbra, Portugal
`3 Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
`
`a r t i c l e i n f o
`
`a b s t r a c t
`
`Article history:
`Received 9 April 2018
`Revised 7 June 2018
`Accepted 12 June 2018
`Available online 20 June 2018
`
`Keywords:
`quality by design
`quality target product profile
`critical quality attributes
`critical material attributes
`critical process parameters
`
`The pharmaceutical industry has entered in a new era, as there is a growing interest in increasing the
`quality standards of dosage forms, through the implementation of more structured development and
`manufacturing approaches. For many decades, the manufacturing of drug products was controlled by a
`regulatory framework to guarantee the quality of the final product through a fixed process and
`exhaustive testing. Limitations related to the Quality by Test system have been widely acknowledged. The
`emergence of Quality by Design (QbD) as a systematic and risk-based approach introduced a new quality
`concept based on a good understanding of how raw materials and process parameters influence the final
`quality profile. Although the QbD system has been recognized as a revolutionary approach to product
`development and manufacturing, its full implementation in the pharmaceutical field is still limited. This
`is particularly evident in the case of semisolid complex formulation development. The present review
`aims at establishing a practical QbD framework to describe all stages comprised in the pharmaceutical
`development of a conventional cream in a comprehensible manner.
`© 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
`
`Introduction
`
`Over the last decades, our understanding about physicochemical
`properties of topical formulations and their excipients, result in the
`ability to develop physical, chemical and biologically stable prod-
`ucts. To design and develop a successful pharmaceutical dosage form
`for skin delivery, preformulation and formulation studies require
`particular considerations. Moreover, the knowledge of skin barrier
`structure and drug permeation properties is essential for a rational
`progress in the development of topical formulations.
`Dosage forms for topical application are intended to produce the
`required therapeutic action at specific targets in the skin with the
`least probable adverse effects.1,2 Topical formulations can be easily
`administered and transported, and are used for the treatment of
`several disorders. For any topical formulation, the onset, rate, and
`extent of
`therapeutic response depend on the efficiency of
`sequential processes: release of the active substance from the
`dosage form, penetration/diffusion of the drug through the stratum
`corneum (SC), and other skin layers, before producing the
`
`* Correspondence to: Ana Figueiras (Telephone: þ351-239-488-431).
`E-mail address: rfigueiras@ff.uc.pt (A. Figueiras).
`
`pharmacological effect. These different processes are variables
`which result in formulation safety and efficacy differences.3 There
`are several topical formulations available in the market; however,
`semisolids (e.g., ointments, creams and gels) are the most
`commonly used for this purpose.4
`Included in the latter category, conventional creams/emulsions
`represent a promising pharmaceutical vehicle for skin drug
`delivery despite their thermodynamic instability and complex
`formulation remaining a challenge for pharmaceutical technology.5
`Depending on the physicochemical properties, desired site of
`action, and drug delivery strategies, drugs incorporated into
`semisolid products can be applied for different purposes. A cream is
`a semisolid emulsion containing one or more active substances,
`dissolved or dispersed, and may be defined as a biphasic system in
`which the dispersed or internal phase is finely and uniformly
`dispersed in the continuous or external phase. According to the
`dispersed phase nature, it is possible to acquire an oil-in-water
`cream (o/w) or a water-in-oil cream (w/o).4,6
`Besides the several aspects taken into account in cream product
`design, during the whole process, it is imperative to preserve a high
`quality level. Thereby, in cream research and development, the
`application of a systematic approach is demanded to avoid product
`rejections during manufacturing and to achieve regulatory approval.
`
`https://doi.org/10.1016/j.xphs.2018.06.010
`0022-3549/© 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
`
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`A. Sim~oes et al. / Journal of Pharmaceutical Sciences 107 (2018) 2653-2662
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`Over the years, pharmaceutical industries have spent significant
`efforts to ensure product quality, to achieve regulatory compliance,
`and to yield pharmaceuticals as cost efficient as possible. Therefore,
`they perform sophisticated processes and technologies that require
`steadiness among scientific progress and operational complexity.
`Nonetheless, such processes do not present a rational under-
`standing of critical variables and control strategies, which is
`imperative to ensure the product quality.7
`In this context, the U.S. Food and Drug Administration has
`highlighted Quality
`by Design (QbD)
`as
`current Good
`Manufacturing Practices initiative for the 21st century. The emer-
`gence of this approach has added a new dimension to pharma-
`ceutical development and manufacturing.8-10
`The implementation of the QbD approach includes the defini-
`tion of the quality target product profile (QTPP) and critical quality
`attributes (CQAs) of drug product, the accomplishment of risk
`assessment (International Conference on Harmonisation [ICH] Q9)
`to identify critical material attributes (CMAs) and critical process
`parameters (CPPs), the definition of a design space through design
`of experiments (DoEs), the establishment of a control strategy, and
`the continual improvement and innovation throughout the product
`life cycle.11
`As mentioned in the Q8 guideline, the aim of the pharmaceutical
`development based on a QbD approach is to design a successful
`product and its manufacturing process according to the intended
`quality performance. During product development, a detailed
`identification, understanding, and control of critical variables, with
`their optimal operating range definition, will enable to yield a
`product with the required quality profile. The information and
`knowledge gained from pharmaceutical development studies and
`manufacturing experience provide an enhancement of scientific
`understanding. Greater product and process understanding is also
`crucial for more flexible regulatory approaches. The degree of
`regulatory flexibility relies on the level of scientific knowledge
`provided in the registration dossier.
`Although the implementation of the QbD principles is one step
`forward for conventional solid form development, the case of
`conventional semisolid forms still remain largely unexplained. This
`review focuses on QbD approach for the development of semisolid
`dosage forms, particularly on cream formulations. Employing QbD
`principles to a complex formulation such as a cream, an effective
`product development, with an optimized formulation, and a
`continuous and robust manufacturing process, may be easily ach-
`ieved. Therefore, QbD approach will provide an opportunity for
`pharmaceutical
`companies
`to
`improve
`formulation
`and
`manufacturing efficiencies and productivity, with significant
`reduction in cost production, product variability, defects, and batch
`rejection, so as to get more flexible regulatory approvals, to
`decrease postapproval changes and to produce high-quality phar-
`maceuticals under real-time release.11-15 Thus, the predicted level
`established through this system is expected to be a scientific and
`technological progress for industries and regulatory authorities.
`
`QbD ApproacheCream Development Strategy
`
`Definition of Conventional Cream QTPP and CQAs
`
`The initial step when using QbD-based development is to pre-
`define the final quality profile. QTPP comprises cream quality
`parameters that should be ideally achieved at the final stage of the
`product development and production, considering its safety and
`efficacy.
`The second step of the QbD-based development is to identify the
`critical quality parameters. Derived from QTPP, CQAs are quality
`attributes that must be studied, controlled, and ensured during
`
`cream development and manufacturing to guarantee predefined
`product quality.7,11,16-18 An example of cream QTPP and its CQAs is
`provided in Table 1.
`
`Product Design and Development
`
`Once the dosage form is selected, the drug product development
`using the QbD approach is initiated. The main purpose of the
`product design is to develop a robust cream that can achieve the
`therapeutic objectives and quality attributes, remaining stable over
`the shelf life.
`
`Drug Substance
`The physicochemical and biological properties of the drug
`substance have a significant effect on drug product performance
`and manufacturability. Thereby, these properties must be identified
`to produce the right dosage form and to select the appropriate drug
`concentration, excipients, and process parameters.
`During preformulation studies, drug properties such as solubi-
`lity, partition coefficient (log p), particle size, pKa, permeability,
`melting point, and molecular weight need to be identified because
`of their role on percutaneous permeation.8,11,19,20
`The quality attributes of drug substance will ensure that the
`drug product meets its CQAs and must be controlled within the
`defined specifications.21
`
`Excipient Selection
`Special consideration needs to be given to excipient selection
`because of their influence also on the final product performance,
`manufacturability, and stability. This selection is related to the
`intended dosage form, route of administration, safety profile,
`manufacturing process, and regulatory aspects. Excipient nature
`and concentration will determine drug release from the dosage
`form, skin barrier features and drug penetration/diffusion, affecting
`the duration and extent of the therapeutic action at the target skin
`layer.22
`In cream formulation, excipients are used to improve drug sol-
`ubility and to incorporate it at the target concentration (solvents),
`to control drug release and cream viscosity (thickeners), to improve
`drug skin permeability (chemical permeation enhancers),
`to
`enhance drug and formulation stability (antioxidants, emulsifiers
`and buffers), and to prevent microbial growth and contamination
`(preservatives).23 Acceptable pharmaceutical excipients are listed
`in international pharmacopoeias for pharmaceutical product
`development.4
`At this stage, special consideration must be given to drug solu-
`bility because it will dictate the excipient selection because of its
`impact on diffusion through each skin environment, as well as on
`release pattern from the dosage form vehicle, final cream unifor-
`mity, and stability. If a suitable solvent is selected, to comprise the
`solubilizing phase of the emulsion system, an excellent skin
`permeation rate of the drug substance will be provided. According
`to drug physicochemical properties and dosage form (aqueous or
`oily solubilizing phase nature), different solvents have to be wisely
`selected and tested. The equilibrium solubility is defined as the
`maximum quantity of a drug which can be completely dissolved, at
`a given temperature and pressure, in a specific amount of solvent.
`Therefore, for a specific drug substance in the solid form, it is
`imperative to perform a solvent screening to determine the active
`equilibrium solubility in each promising solvent and later in the
`solvent blend/solubilizing phase.24-26
`Another important parameter to be considered for drug
`release performance and percutaneous absorption rate assess-
`ment is the thermodynamic activity of the drug in the formula-
`tion. Once exceeded the solubility equilibrium, a supersaturated
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`2655
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`Table 1
`Example of General Elements of QTPP and CQAs for a Conventional Cream Formulation
`
`QTPP
`
`Target
`
`CQAs
`
`Justification
`
`Dosage form
`Route of administration
`Dosage strength
`Dosage design
`
`Appearance
`Identification
`Assay
`
`Impurities
`
`Uniformity
`API particle size
`API crystallization
`pH
`Viscosity
`
`Cream
`Topical
`% w/w
`Oil in water emulsion cream with API dispersed in
`the cream base
`White smooth cream with dispersed API
`USP <621>/Eur. Ph. 2.2.29
`80%-90% of the saturation concentration in the
`solubilizing phase
`USP <1086>/Eur. Ph. 5.20
`
`USP <905>/Eur. Ph. 2.9.40
`USP <429>/Eur. Ph. 2.9.31
`USP <854>/Eur. Ph. 2.2.24
`USP <791>/Eur. Ph. 2.2.3
`USP <911>/Eur. Ph. 2.2.9
`
`Oil droplet size
`In vitro release profile
`
`USP <776>/Eur. Ph. 2.9.37
`In vitro Release Testing Guidance
`
`Preservatives content
`Microbial limits
`
`Consult USP <51>/Eur. Ph. 5.1.3
`USP <61>/Eur. Ph. 2.6.12
`
`Residual solvents
`Stability
`Container closure system
`Package integrity
`
`USP <467>/Eur. Ph. 5.4
`ICH QI A
`Appropriate for the dosage form
`Compatible
`
`e
`e
`e
`e
`
`e
`e
`Yes
`
`Yes
`
`Yes
`Yes
`
`Yes
`Yes
`
`Yes
`Yes
`
`e
`Yes
`
`e
`Yes
`e
`e
`
`e
`Local administration avoiding systemic side effects
`e
`e
`
`e
`e
`To set up the dose that will ensure drug availability to promote
`therapeutic effect
`Should be maintained below set limits to ensure safety and efficacy of
`formulation
`To assure consistency of the delivery system performance
`Smaller size facilitates drug permeation
`Impact on formulation uniformity and stability
`Impact on physicochemical stability
`To increase drug residence time at the site of application and
`consequently its action duration/To ensure drug release
`Impact on release/permeation behavior
`To assess formulation delivery performance for enhanced therapeutic
`efficacy
`
`e
`Must be maintained below the specified limits to ensure formulation
`safety and stability
`
`e
`Quality requirement
`To ensure target shelf-life
`e
`
`API, active pharmaceutical ingredient; EE, encapsulation efficiency; Eur. Ph., European Pharmacopeia; PDI, polydispersity index; USP, United States Pharmacopeia.
`
`solution is yielded and a higher thermodynamic activity is ach-
`ieved,
`increasing the driving force drug diffusion from the
`formulation.27-32
`Compatibility among excipients and drug(s) must be evaluated
`to anticipate any stability failures and possible incompatibilities in
`the final formulation.19 These studies are imperative in the drug
`product development process because the acquired information
`from compatibility data is applied to select the suitable excipients,
`to ensure active substance stability, to understand degradation
`products and its formation pathway, and to investigate reaction
`mechanisms, which help to prevent unexpected hurdles and
`identify stable storage conditions.33
`In the pharmaceutical technological field, there are different
`accepted methods for drug and excipients compatibility analysis.
`The accelerated stability test is the most common to evaluate
`chemical compatibility for topical formulation development.34
`In the sections that follow, the choice of excipients, their con-
`centration, and characteristics that can influence the drug product
`performance are discussed as well as their corresponding functions.
`
`Choice of the Oily Phase
`External emulsions comprise oily compounds as active sub-
`stance carriers. There are different oily excipients suitable to use in
`cream formulations. Saturated and unsaturated fatty acids/fatty
`acid esters,35 hydrocarbons, and polyols can constitute the oily
`phase, also functioning as penetration enhancers, and consistency
`or viscosity modifiers. Therefore, the selected oily excipients may
`also influence cream viscosity, drug solubility, physical stability,
`drug release performance and transport into the skin. Controlling
`emulsion consistency will ensure cream spreadability, but it needs
`to be slimy enough to form a continuous film over the skin.36
`
`Thickeners and Emulsifying Agents
`The physicochemical principles underlying emulsion formula-
`tion and stabilization are extremely complex. When 2 immiscible
`
`liquids are mechanically mixable without any interfacial stabiliza-
`tion, both liquids will form droplets, which rapidly flocculate
`(aggregation of dispersed droplets), coalesce (aggregation of floc-
`culated droplets with possible oily and water phases separation),
`and form a creamy layer (dispersed phase droplets on the top of the
`continuous phase).37,38 Physical stability is determined by the
`ability to mitigate these physical instability phenomena, and it may
`be accomplished by increasing the viscosity of the continuous
`phase, reducing the droplet movement rate of the dispersed phase,
`or decreasing interfacial tension between both phases by an
`emulsifier addition.
`It has been described a direct relationship among cream
`viscosity and the viscosity of its continuous phase, but it is also
`possible to improve its apparent viscosity by increasing the con-
`centration of the dispersed phase or reducing mean droplet size
`during homogenization process. A high apparent viscosity is
`imperative to retard the movement of dispersed phase droplets,
`keeping an emulsion physically stable.36
`Thickeners are important excipients with impact on cream
`viscosity and, consequently, on skin retention of the topical dosage
`form and on drug penetration. Thereby, it is crucial to carry out
`in vitro skin permeation studies to assess formulation release
`behavior. For example, the inclusion of methylcellulose and paraffin
`reduces dispersed droplets mobility in an o/w emulsion and in a w/
`o emulsion, respectively.
`Apparent viscosity can be also controlled by the homogeniza-
`tion process. This unit operation allows the reduction of droplet
`size and thus increases their number and surface area, increasing
`cream viscosity.
`The inclusion of emulsifying agent(s) is also imperative to assist
`the emulsification process during cream manufacturing and to
`ensure emulsion physical stability during the product shelf life.
`When an emulsion formulation is developed, the type of emulsi-
`fying agent (anionic, cationic or nonionic), hydrophilic-lipophilic
`balance (HLB), log p, and concentration are fundamental aspects
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`to be considered in the emulsifier selection. Although this task
`seems to be limitless, there are some guidelines that may help in
`their correct choice. First of all, the use of pharmaceutically
`approved excipients will reduce regulatory justification periods.
`Emulsifier agent nature is extremely important for emulsion
`stabilization and generalization; ionic surfactants are used in o/w
`emulsions, whereas nonionic surfactants can be used in both o/w
`and w/o formulations. Essential information is provided by HLB
`system, a useful method for calculating the relative emulsifier
`amounts necessary to produce the most physically stable emulsion.
`Each surfactant is associated to an HLB number (usually between
`0 and 20), representing the relative ratio of surfactant lipophilic and
`hydrophilic proportions. Emulsifiers with high HLB values (hydro-
`philic or polar proprieties) enable to develop o/w emulsions,
`whereas surfactants with low HLB values (lipophilic or nonpolar
`characteristics) allow to formulate w/o emulsions.36
`Physical stability of semisolid formulations can be assessed
`through different analytical methodologies. Microscopic examina-
`tion, centrifugation tests, and viscosity analysis are essential tech-
`niques performed for this purpose.36,39,40
`
`Preservatives and Antioxidants
`Oils and fats used in emulsion formulation are susceptible to
`oxidation by atmospheric oxygen or the action of microorganisms.
`The atmosphere oxidation results in degradation products which
`confer unpleasant cream characteristics. The resulting instability
`can be prevented by introduction of excipients with antioxidant
`properties. The selection of the antioxidant and its concentration
`can only be determined by testing its effectiveness on the final
`product, according to pharmacopoeial information. Their efficiency
`depends on its compatibility with other excipients and on its oil/
`water partition coefficient.
`Oxidation from microbiological source influences the physico-
`chemical properties of the emulsion, such as color and odor
`changes, hydrolysis of fats and oils, pH changes in the aqueous
`phase, and breaking of emulsion. Emulsions with aqueous contin-
`uous phase nature are more susceptible to microbial contamina-
`tion. Therefore,
`it is required to include antimicrobial agents
`(preservatives) to prevent any microorganism growth. A preser-
`vative suitable for an emulsion must present wide spectrum of
`bactericidal activity, low log p, compatibility with other excipients,
`stability, and effectiveness over a wide range of pH and
`temperatures.
`
`Buffer Agents
`To provide chemical stability and to ensure physical compati-
`bility, it is necessary to include buffer agents, but these electrolytes
`have to be carefully added to avoid undesirable effects on physical
`stability (e.g., rheological behavior).36,40
`All components are related to the requirement that formulation
`must be capable of delivering the correct amount of drug to the
`therapeutic application site, be free from microbial contamination,
`and physically unchanged since the manufacturing day.
`
`Process Design and Development
`
`Since a formulation cannot become a product without a process,
`process and product design and development cannot be separated.
`Process design is an initial phase of the process development and
`should include all factors that need to be considered in cream
`production,
`such
`as
`equipment, material
`transfer,
`and
`manufacturing variables. Therefore, process selection depends on
`the product design and material properties. Once process design
`and development has been concluded, preliminary studies are
`
`conducted in accordance to the cream QTPP, product, and process
`knowledge.
`To produce the intended quality product, a series of unit oper-
`ations are accomplished throughout the cream manufacturing
`process. A unit operation involves physical or chemical changes
`while process parameters are referred to the input operating
`parameters (e.g., speed) or variables associated with a specific
`operation (e.g., temperature).
`
`Manufacturing Process
`In cream formulation production, the first mechanical process
`carried out is the mixture of both the aqueous and oily phases by
`adding the dispersed to the continuous phase or of the continuous
`to the dispersed phase. Sometimes, o/w emulsions are prepared
`through the phase inversion technique, in which the aqueous phase
`is slowly added to the oily phase. Initially, a w/o emulsion is formed,
`but as further aqueous phase is added, the emulsion inverts to form
`an o/w emulsion. It should be evaluated the effect of the order of
`addition and the rate of addition on the drug product quality
`attributes.
`Prior to mixing, different excipients are dissolved in the phase in
`which they are soluble. The initial mixing temperature of both
`phases should be high enough to ensure intimate liquid mixing and
`avoid premature solidification of the oily phase by the colder water.
`Aqueous phase should be warmed to a temperature slightly higher
`than the oily phase.
`Some active pharmaceutical ingredients can be dissolved at high
`temperature and recrystallized during the cooling stage. In this
`case, the active substance can be carried to the cooled down cream
`base via a powder eduction system or through a slurry addition and
`simultaneously mixed into the cream base, thus preventing the
`recrystallization problem. The stage to introduce the active sub-
`stance into the semisolid mixture may be critical and should be
`identified.20,39
`The next step in cream production is the homogenization stage.
`Agitators, mechanical mixers, rotor stators, homogenizers, or
`ultrasonic devices could be employed to ensure uniform excipient
`dispersion and droplet size reduction. To remove cream air pockets,
`a deaeration via vacuum with low-speed mixing may be turned on
`to the system. Homogenization time and vacuum pressure are
`significant process variables that can affect physical stability (e.g.,
`coalescence of droplets, phase separation) and homogeneity.
`During cream process development and manufacturing, time,
`temperature, and mechanical energy are high-risk variables of the
`homogenization equipment that must be controlled to produce
`consistent quality.
`Furthermore, as cooling rate can influence the final product
`quality, different cooling rates after melting, mixing, and homog-
`enization steps should be additionally investigated as process
`variables.
`Visual inspection is a useful and simple confirmatory test to
`ensure solid dissolution or uniformity system before proceeding to
`the next step. Microscopic visualizations should be also performed
`to select homogenization speed and time, so as to enable proper
`incorporation of the active substance into the base and conform the
`microscopic appearance, including drug particle size and droplet
`size.14,41
`
`Risk Assessment
`
`Based on prior knowledge, an initial risk assessment is per-
`formed to identify and prioritize potential high-risk variables that
`may influence identified cream CQAs. The outcome of this pro-
`cedure is to determine which material attributes and process pa-
`rameters are critical and which ones need to be experimentally
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`2657
`
`Figure 1. Ishikawa diagram showing critical parameters of a conventional cream pharmaceutical development. Log p, octanol-water partition coefficient.
`
`investigated and controlled within appropriate ranges to ensure
`cream quality.
`Using a risk approach, the starting point must be the identifi-
`cation of all material attributes and process parameters that can
`influence product CQAs and hence generate quality failure. To
`ascertain which of these parameters need to be further studied and
`controlled, an Ishikawa diagram is constructed (Fig. 1).42,43 In
`addition, a risk estimation matrix (REM) is carried out to prioritize
`material attributes and process parameters that were demon-
`strated to be a potential risk factor for cream CQAs (Fig. 2).44-46
`In pharmaceutical development, risk assessment analysis must
`be accomplished in early phases, but it is important to be updated
`at different development stages as further information becomes
`available and greater knowledge is obtained.47,48 After risk assess-
`ment data analysis, specific parameters are, then, selected for
`subsequent screening studies (DoEs).
`
`Formulation Optimization
`
`After performing screening experiments, variables that show
`criticality in the previous phase are also optimized through a DoEs.
`The optimization stage aids to specify CMAs and CPPs optimal
`settings, and, ultimately, the definition of design space. Note that
`any manufacturing process developed within the design space will
`be regulatory acceptable.
`Response surface designs, such as Central Composite Design and
`Box Behnken are the most usual models to predict the optimal
`CMAs and CPPs ranges. Currently, some software packages are
`available to simplify experimental design procedure and assist in
`results interpretation: MODDE, Design Expert Design-Ease, and
`JMP.52-56 The application of the QbD concepts to optimize formu-
`lation, single-unit operation, or to the entire manufacturing pro-
`cess, is intended to support end-product quality and real-time
`release.11,14
`
`Identification of CMAs and CPPs
`
`Formulation Performance Testing
`
`In cream development, several variables need to be considered
`and investigated to reach predefined QTPP. CMAs and CPPs that
`may specifically influence one or more cream CQAs must be iden-
`tified to develop an adequate cream formulation (Tables 2 and 3).
`Critical variable identification is the preliminary step in the
`optimization methodology, which is established through a
`screening process. A screening design is an experimental planning
`where a relatively large number of
`factors is simultaneously
`evaluated using a small number of experiments. During the
`screening phase, all factors are tested to indicate the most critical
`ones. These designs enable to detect which variables are respon-
`sible for the final product quality to eliminate all those ones which
`do not play an important role in ensuring quality constancy.
`Different experimental designs, such as, full factorial, fractional
`factorial, and Placket-Burman designs are usually used for
`screening purposes.18,49-51
`
`According to the predefined QTPP, cream performance needs to
`be assessed. There are 3 important CQAs to consider in topical
`formulation development: formulation stability, drug release pro-
`file, and skin permeation behavior.11,33,57
`
`Stability Testing
`To identify formulation stability issues, formulation stability
`studies must be performed.34 This stage aims at developing a sta-
`bility screen of prototype formulations to select the most promising
`ones for in vitro drug release and permeation testing.
`
`In Vitro Release Studies
`The release rate of an active substance from a dosage form is a
`critical feature for semisolid dermatological products because the
`active must be released from the vehicle and diffused through the
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`A. Sim~oes et al. / Journal of Pharmaceutical Sciences 107 (2018) 2653-2662
`
`Figure 2. Risk estimation matrix presenting initial risk assessment levels of individual formulation and manufacturing parameters: Low, low risk parameter; Medium, medium risk
`parameter; High, high-risk parameter; Log p, Octanol-water partition coefficient.
`
`skin. When a topical formulation is applied to the skin, drug ther-
`modynamic activity must be suitable to ensure an adequate release
`rate from the final topical dosage form. To characterize and
`
`optimize formulation release performance, in vitro release tests are
`performed. In QbD context, it is imperative to select a suitable
`release study to discriminate differences on cream release rate
`FlatWing Ex. 1049, p. 6
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`

`

`A. Sim~oes et al. / Journal of Pharmaceutical Sciences 107 (2018) 2653-2662
`
`2659
`
`Table 2
`CMAs of a Cream Formulation
`
`Formulation
`Components
`
`Parameter
`Type
`
`CQAs
`
`Table 3
`CPPs of a Cream Formulation
`
`Risk Assessment
`
`Parameter
`Type
`
`CQAs
`
`Drug substance
`Physical attributes
`Log p
`Molecular weight
`Melting point
`
`Equilibrium
`Solubility and
`Concentration
`Assay
`Related substances
`Excipients
`Compatibility
`Viscosity
`Concentration
`Melting point
`Oil/water ratio
`Emulsifying agent
`Type
`Log p
`HLB
`Concentration
`Melting point
`Preservatives
`Log p
`Concentration
`Melting point
`Antioxidants
`Log p
`Concentration
`Melting point
`
`e
`CMA
`CMA
`CMA
`
`CMA
`
`CMA
`CMA
`
`CMA
`CMA
`CMA
`CMA
`CMA
`
`CMA
`CMA
`CMA
`CMA
`CMA
`
`CMA
`CMA
`CMA
`
`CMA
`CMA
`CMA
`
`e
`Drug release/permeation, stability
`Permeation
`Drug release/permeation, viscosity,
`stability
`Drug release/permeation, uniformity,
`viscosity, stability
`
`Content uniformity, drug release
`Degradation products
`
`Stability
`Viscosity, stability
`Uniformity, viscosity, stability
`Viscosity, stability
`Stability
`
`Droplet size, uniformity, stability
`Stability
`Droplet size, uniformity, stability
`Droplet size, uniformity, stability
`Viscosity, stability
`
`Stability
`Stability
`Viscosity, stability
`
`Stability
`Stability
`Viscosity, stability
`
`Log p, octanol-water partition coefficient.
`
`when variations in formulation and manufacturing parameters of
`the drug product are applied and assessed.3,58-62
`commonly
`Topical
`formulations
`release performance is
`performed by Franz diffusion cells, where synthetic membranes
`(silicone, polycarbonate, or cellulose) have received distinct
`attention because of their ability to mimic physiological and
`anatomical skin conditions. This is a well-established method
`where a specific dose of formulation is applied on a membrane
`surface in the open donor chamber of the cell. The diffusion of
`drug from the topical product across the membrane is monitored
`by assay of sequentially collected samples from the receptor
`chamber. The receptor compartment of the Franz cells is filled
`with a suitable receiver fluid to maintain sink conditions
`embedded in a water bath at 37C, so as to ensure a temperature of
`32C at the surface. The receptor chamber content is agitated by