The AAPS Journal, Vol. 15, No. 1, January 2013 ( # 2012)
`DOI: 10.1208/s12248-012-9411-0
`
`Regulatory Note
`
`Generic Development of Topical Dermatologic Products:
`Formulation Development, Process Development, and Testing
`of Topical Dermatologic Products
`
`Rong-Kun Chang,1 Andre Raw,1,2 Robert Lionberger,1 and Lawrence Yu1
`
`Received 25 July 2012; accepted 10 September 2012; published online 9 October 2012
`Abstract. This review presents considerations which can be employed during the development of a semi-
`solid topical generic product. This includes a discussion on the implementation of quality by design
`concepts during development to ensure the generic drug product has similar desired quality attributes to
`the reference-listed drug (RLD) and ensure batch to batch consistency through commercial production.
`This encompasses the concept of reverse-engineering to copy the RLD as a strategy during product
`development to ensure qualitative (Q1) and quantitative (Q2) formulation similarity, as well as similarity
`in formulation microstructure (Q3). The concept of utilizing in vitro skin permeation studies as a tool to
`justify formulation differences between the test generic product and the RLD to ensure a successful
`pharmacodynamic or clinical endpoint bioequivalence study is discussed. The review concludes with a
`discussion on drug product evaluation and quality tests as well as in vivo bioequivalence studies.
`
`KEY WORDS: dermatologic product; generic; semi-solid; topical product; quality by design.
`
`INTRODUCTION
`
`The skin is the largest organ of the integumentary system in
`humans. It covers the entire body and has a surface area of
`approximately 2 m2 with thickness ranging from 0.5 to 4 mm or
`more. The skin is involved in many functions, such as providing a
`
`The opinions expressed in this review by the authors do not
`necessarily reflect the views or policies of the Food and Drug
`Administration (FDA).
`
`1 Office of Generic Drugs, Center for Drug Evaluation and Research,
`U.S. Food and Drug Administration, 7500 Standish Place, Rockville,
`Maryland 20855, USA.
`2 To whom correspondence should be addressed. (e-mail:
`andre.raw@fda.hhs.gov)
`ABBREVIATIONS: Q1, Same components as the reference-listed
`drug; Q2, Same components in same concentration as the reference-
`listed drug; Q3, Same components in same concentration with the
`same arrangement of matter (microstructure) as the reference-
`listed drug; IIG, Inactive Ingredient Guide; RLD, Reference-
`listed drug; QbD, Quality by design; MDD, Maximum daily dose;
`SAR, Structure–activity relationship; NLT, No less than; NMT,
`No more than; API, Active pharmaceutical
`ingredient; ICH,
`International Conference on Harmonization; Q3A, Guidance for
`industry Q3A impurities in new drug substance; Q3B, Guidance
`for industry Q3B impurities in new drug product; Q3C, Guidance
`for industry Q3C impurities: residual solvents; Q1A, ICH topic
`Q1A stability testing of new drug substances and products; IT,
`Identification threshold; QT, Qualification threshold; ANDA,
`Abbreviated new drug application; FDA, Food and Drug
`Administration; USP, U.S. Pharmacopeia; CFR, Code of Federal
`Regulations.
`
`protective barrier from the external environment (e.g., defending
`against microbial infection, inhibiting the entry of chemicals and
`toxins, preventing dehydration), regulating body temperature,
`and producing vitamin D. The skin is also the most exposed
`organ and is subject to several physical and environmental
`stressors. Furthermore, autoimmunity, dysregulation of stratum
`corneum regeneration, drug-induced skin hypersensitivity, and
`many other reasons can result in skin disorders. As such, the skin
`is susceptible to various disorders and diseases. Topical
`dermatologic products, which can be administered easily and
`are convenient in terms of portability, are used in treating a
`variety of disorders. Topical preparations exist in many forms,
`such as ointments, gels, creams, lotions, solutions, suspensions,
`foams, and shampoos. The most commonly used topical
`preparations are semisolid dosage forms that include ointments,
`creams, lotions, and gels, which will be the main focus of this
`review. Table I shows common skin diseases along with some
`examples of topical drugs for their treatments.
`Depending on the physicochemical properties, desired
`site of action, and formulation strategies for the drug, drugs
`incorporated into semisolids can show their activity on the
`surface layers of tissues or via penetration into deeper layers
`to reach the site of action or through systemic delivery. In
`some cases, some topical preparations may be designed to
`limit their activity on the surface of the skin with no stratum
`corneum penetration, for example repellents and chemical
`treatments for pediculosis. In such cases, excipients that
`inhibit skin penetration can be used to retain the drug on
`the surface layer of the skin. The barrier nature of the
`stratum corneum greatly limits the entry of drugs into the
`systemic circulation. Nonetheless if the drug is to act locally
`
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`1550-7416/13/0100-0041/0 # 2012 American Association of Pharmaceutical Scientists
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`Table I. Common Skin Diseases and Some Examples of Topical Drug Products for Their Treatments
`
`Disorders/diseases
`
`Pathogenic conditions/microorganisms
`
`Example of topical drug products
`
`Chang et al.
`
`42
`
`General
`category
`
`Bacterial
`infection
`
`Fungal/yeast
`infection
`
`Viral infection
`
`Inflammatory
`and pruritic
`manifestations
`
`Impetigo,
`forunculosis,
`cellulitis, folliculitis
`Tinea pedis, cruris,
`corporis, unguium
`Candidiasis
`
`External genital/
`perianal warts
`Cold sore
`
`Allergic contact
`dermatitis, atopic
`dermatitis,
`seborrheic
`dermatitis, eczema
`
`Staphyloccocus Aureus, Streptococcus
`pyogenes
`
`Tr i c h o p h y t o n r u b r u m, Tr i c h o p h y t o n
`mentagrophytes, Trichophyton tonsurans,
`Candida albicans
`
`Molluscam contagiosum virus
`
`Human papillomavirus
`Herpes Simplex virus
`The exact cause is unknown, but it is thought
`to be linked to an overactive response by the
`body’s immune system to external and/or
`internal triggers.
`
`Acne, Rosacea
`
`Acne vulgaris
`
`Psoriasis
`
`Psoriasis vulgaris
`
`Vitiligo
`
`Vitiligo
`
`Actinic/solar
`keratosis, skin
`cancer
`
`Actinic/solar
`keratosis
`
`Acne is caused by the stimulated sebaceous
`glands at the time of puberty, leading to the
`inflammation of skin surface.
`The exact cause of rosacea is still unknown,
`but many factors, such as genetic, emotional,
`and sun exposure may trigger and aggravate
`rosacea.
`The exact cause remains unknown. There may
`be a combination of factors, including genetic
`predisposition and environmental
`factors
`triggering cell proliferation out of control.
`A disorder that causes depigmentation of
`patches of skin
`Due to sun exposure and UV radiation and
`weakening of the immune system
`
`Mupirocin (Bactroban), Polymyxin B sulfate,
`Bacitracin zinc, Gentamicin sulfate, Neomycin,
`Silver sulfadiazine, Sulfanilamide, Nystatin
`Clotrimazole (Lotrimin, Mycelex), Terbinafine
`(Lamisil), Ketoconazole (Nizoral), Butoconazole
`Nitrate, Ciclopirox Olamine, Halobetasol
`Propionate, Econazole Nitrate, Terconazole
`Salicylic acid,
`Imiquimod (Aldara),
`Podophyllotoxin, Acyclovir, Docosanol
`
`Triamcinolone 0.1% (Triamcinolone),
`Fluocinonide (Lidex), Clobetasol (Temovate),
`Tacrolimus (Protopic), Pimecrolimus (Elidel),
`Desonide, Alclometasone dipropionate,
`Mometasone furoate, Desoximetasone,
`Prednicarbate, Diflorasone Diacetate,
`Amcinonide
`(Accutane),
`Isoretinol
`Metronidazole,
`Benzoyl peroxide, Dapsone, Azelaic acid,
`C l i n d a m y c i n , E r y t h o m y c i n , S o d i u m
`sulfacetamide, Adapalene, Tretinoin
`
`Hydrocortisone, Calcipotriene (Dovonex),
`Anthralin, Lactic acid (AmLactin, Lac-
`Hydrin), Tacrolimus (Protopic), Pimecrolimus
`(Elidel)
`Corticosteroid, Tacrolimus
`Pimecrolimus (Elidel)
`5-fluouracil (Efudex, Fluoroplex), Imiquimod
`(Aldara), Diclofenac (Voltaren, Solaraze)
`
`(Protopic),
`
`Loss of hair
`
`Damaged skin
`
`Local dermal
`anesthesia
`Pediculosis
`
`Squamous cell
`carcinoma
`Basal cell carcinoma
`Androgenic alopecia
`Cicatricial alopecia
`Alopecia areata
`
`Fine wrinkling,
`mottled
`hyperpigmentation,
`tactile, roughness
`of facial skin
`
`–
`
`inflammation
`Due to hormonal changes,
`damages/scars, autoimmune disease, and
`other reasons, hair follicles may have a
`shorter growth period and produce thinner
`and shorter hair shafts.
`Photo-damaged skin
`
`Minoxidil, Anthralin, Cyclosporine
`
`Tretinoin
`
`Dermal anesthetic product to numb the skin
`
`Benzocaine, Lidocaine, Tetracaine, Prilocaine
`
`Head lice
`
`Chemical treatment of pediculosis
`
`Lindane, Permethrin, Pyrethrin, Piperonyl
`Butoxide, Malathion
`
`or systemically, it must first penetrate the stratum corneum.
`Most topical dermatologic preparations are meant to be
`locally active, but some preparations have local action as
`well as a minor/negligible systemic effect, as a small amount
`of the drug is absorbed systemically. In some cases, drug
`accumulation in the dermal
`layer is critical and the drug
`transport via hair follicles (e.g.,
`liposome) is a potential
`
`approach. On the other hand, because of the excellent
`transdermal permeability of certain drugs and/or suitable
`formulation modifications, semisolids (e.g., 2% nitroglycerin
`in a lanolin–petrolatum base, 10% oxybutynin chloride in an
`alcohol-based gel, 1% or 1.62% testosterone in a clear gel)
`have been used to deliver the drug systemically, bypassing the
`destructive hepatic first-pass metabolism. To promote the
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`Generic Development of Topical Dermatologic Products
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`43
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`systemic availability, penetration enhancers may be used to
`enhance the drug transport through skin. However, systemic
`delivery of drugs from topical dosage forms has several
`problems, including inconvenience of administration, inaccuracy
`of administered dose, difficulties in removing the residual
`formulation from the skin, and aesthetic reasons. Owing
`to these drawbacks, bandage-type transdermal patches
`have to a large extent replaced the semisolid preparations
`intended for systemic effect. Transdermal patches and
`semi-solid products for systemic use, however, are not
`considered typical
`topical products and are outside the
`scope of this article.
`
`Topical Drug Delivery
`
`The major barrier layer of skin, the stratum corneum,
`consists of an interstitial lipid pathway and a proteinaceous
`cellular compartment. Drug molecules penetrate the skin
`primarily through the tortuous and continuous intercellular
`path. Transport of topical drugs, especially with the aid of
`solvents and enhancers used in the formulation, may also
`occur through a transcellular route, the hair follicles, or sweat
`ducts. Only the drug in the molecular state can penetrate
`through the skin. Occluded skin, e.g., the application of
`ointment on the skin, may retain significant amounts of the
`transepidermal water and facilitate drug transport through
`the hydrated skin. States with diseased skin, such as atopic
`dermatitis, psoriasis, and warts, may have effects on the
`barrier property of skin, which must be considered for the
`drugs geared toward these skin diseases. From a drug
`delivery perspective the concentration gradient between the
`formulation and site of action provides the driving force for
`penetration of drug through the skin. Thus saturation of the
`drug in the vehicle having a thermodynamic activity of unity
`provides a larger driving force for transporting through the
`skin than a formulation at a lower fraction of saturation (e.g.,
`highly solubilized system). Super-saturated conditions having
`a thermodynamic activity greater than unity, can further
`enhance the drug delivery through skin. However, a drug in a
`super-saturated solution is in a metastable state and, hence,
`may convert back to its stable form, thus changing the flux of
`the drug through skin.
`
`Formulation Design of Generic Topical Drug Products
`
`Definitions of semisolid preparations, such as ointments,
`lotions, gels, etc. vary and are ill-defined and
`creams,
`imprecise in some cases. Based on rheological behavior,
`water and volatiles, composition, and thermal behavior,
`Buhse et al. [1] devised new definitions and a system for
`determination of the appropriate nomenclature for a topical
`dosage form. Osborne [2] further summarized the topical
`drug product classification system and discussed the impor-
`tance of accurately labeling a topical dosage form. It should
`be pointed out that there are some older topical products
`described in Pharmacopeia based on imprecise nomenclature
`to name the drug products. As a result, the labeling for
`approved topical drug products may not be accurate or
`commensurate with the current classification. For these
`reasons, it is important to evaluate the reference-listed drug
`(RLD) critically based upon its physical chemical character-
`
`istics and not rely solely upon labeling for dosage form
`selection in generic drug development [3, 4].
`To ensure pharmaceutical and therapeutic equivalency,
`generic drug formulas often tend to mainly mimic those of the
`RLDs. It is prudent to use the drug product information
`appearing in the packaging insert, patents, and published
`literature for the RLD, along with data generated by reverse
`engineering efforts to come up with the initial generic
`formula. If feasible, the major formulation goal for a generic
`topical drug product is quantitative sameness (Q1, same
`components as the RLD) and qualitative sameness (Q2, same
`components in same concentration as the RLD, i.e., within
`±5%) to the RLD [5, 6]. However, even with Q1/Q2
`sameness, special attention needs to be directed toward the
`grade of the excipient, because different grades of excipient
`can have a significant
`impact on drug product quality
`attributes. For example, a low-melting-grade material may
`melt under accelerated stability conditions and a high-
`melting-grade excipient can withstand higher storage temper-
`atures; conversely a high-viscosity-grade excipient has a
`better ability to impart the consistency to semisolid prepara-
`tions, compared to a low-viscosity-grade material. Another
`advantage of developing a formulation with Q1/Q2 sameness,
`is that although topical dosage forms (other than solutions)
`often require in vivo bioequivalence studies, in some instan-
`ces a biowaiver (for a non-solution product) may be granted
`with supporting data to demonstrate Q1/Q2 sameness and
`similar physicochemical characteristics as in the case of
`topical solutions. Thus, by reverse engineering the RLD, all
`the potential
`issues such as critical product attributes,
`stability, and efficacy for a test generic product may be
`minimized.
`In some cases, due to patent protection or to undesirable
`product attribute(s) of the RLD formulation, the generic drug
`firm may choose not to match the RLD formula. The generic
`firm may choose to reformulate to improve certain product
`attributes. During generic product development, modifica-
`tions of the RLD formula in terms of excipient replacement,
`grade of excipient, or amount of excipient used in the
`formula, etc. needs to be justified by its functionality, the
`FDA Inactive Ingredient Guide (IIG) [7], pharmacology/
`toxicology data, and bioequivalence/clinical data. Each inac-
`tive ingredient must be justified unless it is ≤0.1% of the total
`drug product weight.
`it is reasonable to
`When developing a formulation,
`keep the type of emulsifier, hydrophilic–lipophilic balance
`value, and solvent to emulsifier ratio similar to those of
`the RLD. An appropriate emulsifier system is needed for
`emulsion-type topical drugs to disperse the drug contain-
`ing solvent phase and to produce the desired type of
`emulsion (O/W or W/O) with satisfactory appearance and
`consistency for the final product. To avoid regulatory
`classification issues, pharmaceutical
`formulators need to
`avoid the replacement of water with polar solvents in
`preparation of emulsion-type semisolids.
`Also, formulators should be certain that the excipients
`and quantity used in the drug product are in IIG list with the
`same route of administration and no more than the amount
`listed in the IIG. In case a novel excipient is essential to
`achieve the desired physicochemical properties and perfor-
`mance characteristics for the drug product, appropriate
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`44
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`Chang et al.
`
`toxicological and pharmacological data need to be generated
`to support its use in drug product formulation. In general,
`pharmaceutical formulators avoid this costly approach.
`Overage is not normally allowed unless it is due to
`manufacturing losses. The use of a “stability overage” should
`only be a last resort, and is strongly discouraged. However, some
`RLDs contain significant amount of overage to compensate for
`the loss of drug due to its degradation. In such cases, an overage
`can be allowed up to the overage present in the RLD and the
`importance of thorough investigation of product attributes for
`the RLD cannot be over-emphasized.
`For formulation design, simplicity is the basis of good
`formulation design and the shorter the ingredient list, the
`better. Good formulators eliminate redundant elements and
`integrate components when possible [8]. Formulation compo-
`nents for topical drug products are briefly summarized in
`Table II. However, to achieve the delivery of the drug and the
`consumer’s acceptance, a complex combination of excipients is
`often required for topical drug product formulations. Given the
`numerous excipients used, it is important to avoid unwanted
`interactions among the ingredients used in the formula. For
`example, an anionic surfactant may react with a positively
`charged drug or vice versa; an anionic emulsifier with
`
`monovalent salt may be inactivated by multivalent counter ions
`(e.g., Ca++, Mg++). If the formulation requires solvent(s) to
`dissolve the API in the manufacturing process, it is prudent to
`have solvent screening studies to determine the solubility of the
`drug in the potential solvent systems and to generate the short-
`term accelerated stability data (e.g., 4 weeks at 40°C) of the
`drug in the potential solvent system to justify the selection
`of the solvent system. The amount of the solvent system
`used in the formula should be cautiously selected to
`ensure that solubility is below 90% of
`the saturation
`solubility of
`the drug in the solvent system at room
`temperature to eliminate the drug re-crystallization issue.
`Furthermore,
`solvent-screening experiments can be
`performed using an additional cold condition, e.g.,
`refrigerated temperature,
`to detect
`the undesired
`precipitation.
`Gels are relatively easier to prepare compared to
`emulsion-type creams and lotions. In general, a selected
`gelling agent, such as Carbomers and xanthan gum, can be
`dispersed in purified water or hydroalcoholic medium to form
`uniform lump-free dispersion and subsequently, an active and
`preservative phase can be added to the gel phase to form a
`medicated gel.
`
`Table II. Formulation Components for Topical Drug Products
`
`Component description
`
`Example
`
`Main structure-forming materials for semisolid dosage form
`Based on their composition and physical characteristics, the
`USP classifies ointment bases as hydrocarbon bases
`(oleaginous bases), absorption bases, water-removable
`bases, and water-soluble bases.
`Surfactants used to reduce the interfacial tension to stabilize
`emulsions and to improve the wetting and solubility of
`hydrophobic materials
`
`Promotes the retention of water in the system
`
`Increases viscosity
`Main structure-forming materials for gels
`
`Carnauba wax, Cetyl alcohol, Cetyl ester wax, Emulsifying
`wax, Hydrous lanolin, Lanolin, Lanolin alcohols,
`Microcrystalline wax, Paraffin, Petrolatum, Polyethylene
`glycol, Stearic acid, Stearyl alcohol, White wax, Yellow wax
`
`Polysorbate 20, Polysorbate 80, Polysorbate 60, Poloxamer,
`Emulsifying wax, Sorbitan monostearate, Sorbitan
`monooleate, Sodium lauryl sulfate, Propylene glycol
`monostearate, Diethylene glycol monoethyl ether,
`Docusate sodium
`Glycerin, Propylene glycol, Polyethylene glycol, Sorbitol
`solution, 1,2,6 Hexanetriol
`Carbomer, Methyl cellulose, Sodium carboxyl methyl
`cellulose, Carrageenan, Colloidal silicon dioxide, Guar
`gum, Hydroxypropyl cellulose, Hydroxypropyl methyl
`cellulose, Gelatin, Polyethylene oxide, Alginic acid,
`Sodium alginate, Fumed silica
`Benzoic acid, Propyl paraben, Methyl paraben, Imidurea,
`Sorbic acid, Potassium sorbate, Benzalkonium chloride,
`Phenyl mercuric acetate, Chlorobutanol, Phenoxyethanol
`Propylene glycol, Ethanol, Isopropyl Alcohol, Oleic acid,
`Polyethylene glycol
`
`Ethylene diamine tetraacetate
`
`Butylated hydroxyanisole, Butylated hydroxytoluene
`Citric acid, Phosphoric acid, Sodium hydroxide, Monobasic
`sodium Phosphate, T`rolamine
`
`Component
`functionality
`
`Emollient/
`stiffening
`agent/
`ointment
`base
`Emulsifying
`agent/
`solubilizing
`agent
`
`Humectant
`(polyols)
`Thickening/
`gelling
`agent
`
`Permeation
`enhancer
`
`Chelating
`agent
`Antioxidant
`Acidifying/
`alkalizing/
`buffering
`agent
`Vehicle/
`solvent
`
`Preservative
`
`Prevents microbial growth
`
`Increases the permeation by promoting the diffusion,
`partitioning, or the drug solubility of an active ingredient
`through the stratum corneum
`Binds metal ions to minimize metal-catalyzed degradation
`and to enhance the preservative effect
`To minimize oxidative deterioration
`Maintain a proper pH for the dosage form
`
`Facilitate the dispersion and/or dissolution of API
`
`Purified water, Hexylene glycol, Propylene glycol, Oleyl
`alcohol, Propylene carbonate, Mineral oil
`
`Many excipients used in topical drug products have dual or multiple functionalities
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`Generic Development of Topical Dermatologic Products
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`45
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`Viscosity modification is an important part of semi-solid
`formulations. However, viscosity of the test drug product is not
`required to be identical to that of the RLD, provided that
`viscosity of the drug product is not a critical quality attribute.
`Theoretically, viscosity may impact skin retention of the dosage
`form and drug delivery/penetration via the skin. Therefore, it
`is prudent to provide data from a well-designed in vitro
`skin permeation study demonstrating that flux is similar
`between the test product and the RLD. Furthermore, the
`retentive properties on the skin and patient acceptability
`need to be evaluated to assess whether the test product
`with a different viscosity from the RLD has a negative
`impact on these attributes. Because its effect is multidi-
`mensional and not easily predictable, viscosity and spread-
`ability are regarded as critical quality attributes in the
`initial product development stage.
`For drug-dispersion-type semisolid products, small drug
`particles may dissolve in the continuous phase and deposit onto
`the larger particles (i.e., Ostwald ripening). A temperature
`cycling study with cycles from room temperature to 40°C may be
`used to evaluate the tendency of Ostwald ripening during the
`product development stage. For emulsion-type semisolid drug
`products, typically the test products are subjected to alternate
`freeze–thaw cycles as follows: 24 h at −20°C followed by a
`24-h thaw at room temperature, 24 h at −20°C followed by a
`24-h thaw at room temperature, and 72 h at −20°C followed by a
`24-h thaw at room temperature. The drug products should
`remain stable with respect to physical appearance, absence of
`drug crystals (solubilized-type product), particle size of drug
`crystals, and package integrity following these cycles.
`Most topical preparations, especially those with emulsion
`formulations have a potential for contamination by various
`bacteria. Hence, antimicrobial preservatives are used to
`inhibit the growth of bacteria, fungi, and mold. The selection
`of preservative for a generic semi-solid product is typically
`based on the RLD. A combination of methylparaben and
`propylparaben is the most commonly used preservative at
`levels typically ranging from 0.01% to 0.3%. In some instances
`there may be concerns about the use of some preservatives in
`topical drug products. For example, formaldehyde-releasing
`preservatives like imidurea and hydantoin are known to have a
`tendency of causing allergic contact dermatitis. Furthermore,
`formaldehyde is also a human carcinogen and a known
`sensitizing agent, and in these cases it is necessary to demon-
`strate that the observed level of free formaldehyde for the drug
`product is within an acceptable threshold. Benzyl alcohol may
`degrade to benzaldehyde, and when used in the formulation
`it is important to include benzaldehyde as part of a related
`substances test in the drug product release stability testing
`specifications as a precaution.
`Antioxidants, alone or in combination with a chelating
`agent, are added to semi-solid preparations to prevent oxidative
`degradation. Addition of a chelating agent and incorporation of
`an antioxidant for the RLD give a hint of instability of the drug
`in the formulation matrix. Some excipients, such as white
`petrolatum also may oxidize at high temperatures during
`manufacturing of the drug product, and may result in different
`by-products in addition to the potential oxidative degradants
`from the pharmaceutical active ingredient.
`In developing generic formulations of topical dermatologic
`preparations that require repeated and long-term use, ultrapure
`
`and hypoallergenic ingredients may sometimes be warranted to
`minimize sensitization and contact dermatitis in patients. Special
`attention should be paid to the use of fragrance in the
`formulation, because 1% of the general population suffers from
`fragrance allergies [9]. Omission of the fragrance components
`from the RLD may be justified by the SUPAC-SS Guidance,
`which states that deletion of an ingredient intended to affect
`fragrance is unlikely to have any detectable impact on formula-
`tion quality and performance and is considered as a Level 1
`change and no bioequivalence testing would be necessary [10]. If
`possible, formulators should consider hypoallergenic, fragrance-
`free, artificial color-free, gluten-free, peanut-free, alcohol-free,
`preservative-free, latex-free, or ethoxylate surfactant-free com-
`ponents for drug products to make them less harsh on the skin
`and less concern for end users with ingredient anxiety. Also some
`emulsifiers, especially when used in large amounts, may cause
`skin irritation. If in doubt, dermal irritation, corrosivity, and
`sensitization potential need to be evaluated for ingredients and
`test drug product using an animal model or in vitro model
`(human epidermal tissue constructs and biobarrier membrane).
`In addition to the aforementioned considerations, many other
`points listed in Table III need to be contemplated thoroughly.
`Also during development, the volatility and penetra-
`tion rate of the ingredients in the formula are additional
`important factors to be considered. As a result of solvent
`evaporation, skin absorption of the vehicle and interaction
`among drug substance, changes to the residual formula
`and skin components may occur after application altering
`drug properties. For example, due to solvent evaporation,
`the physical state of drug substance may change (crystal-
`lization, dissolution, or polymorph) resulting in a change
`in the skin drug permeation and retention. Therefore, the
`proportion of volatile and non-volatile excipients used in
`the test and RLD formulations and their effects need to
`be carefully evaluated.
`For semi-solid preparations, Q1/Q2 is not a must for
`generic products to be acceptable by the agency. However, the
`generic firm will face more regulatory scrutiny for a non-Q1/Q2
`formula and need to demonstrate that the physicochemical
`characteristics, critical quality attributes, and in vitro flux rate of
`its drug products are in line with the RLD, especially
`considering the insensitivity of clinical endpoint bioequivalence
`studies. In this respect, two studies for topical drug product
`development that are considered as the most powerful to
`ascertain drug flux in dermatologic and transdermal product
`development include in vitro human skin permeation and in vivo
`percutaneous absorption in animal models:
`
`& Flux measurement across human skin is perhaps the
`most useful and insightful in vitro information in
`development of a topical drug product. Based on the
`physical design of a diffusion cell, they can be classified
`as horizontal, vertical, or flow-through diffusion cells
`along with several adaptations to the basic design. The
`vertical type Franz diffusion cell is the most widely
`accepted for in vitro percutaneous absorption studies.
`Other than the design of the diffusion cell, a finite dose
`technique (i.e., ~3 to 5 mg/cm2) is considered more
`relevant than infinite dose design as it better represents
`the clinical situation for topical drug products. The skin
`obtained from surgery and cadavers can be excised
`
`5 of 12
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`

`Table III. Various Points to Be Considered in Topical Formulation Design
`
`Consideration
`
`Comment
`
`Chang et al.
`
`46
`
`Area
`
`• Drug substance
`
`• Excipients
`
`• Quality of API and adequate DMF
`• Residual solvents
`• Physical state of API, e.g., melting point
`(liquid, low melting point, or high
`melting drug), micronized drug,
`polymorphs, etc.
`• Solubility of API in hydrophobic and
`hydrophilic vehicles
`• Cost and availability issue
`• Compendial material vs.
`non-compendial material
`• Residual solvents
`
`• Physical state of excipients, e.g., melting point
`(liquid, low melting point, or high melting
`excipient)
`
`• Excipient compatibility
`
`• Hydrophilic–lipophilic balance (HLB)
`and type of emulsifier
`
`• Functionality
`
`• Physicochemical
`properties of
`drug product
`
`• Target product profile such as dosage form,
`viscosity, pH, strength, release profile, in vitro
`permeation rate, homogeneity, etc.
`
`• Container
`closure system
`
`• Selection of container closure system
`as close to that of the RLD as possible.
`• Package compatibility
`
`• Chemical stability
`
`• Consistency for chemical properties
`of the drug product over time
`
`• Physical stability
`
`• Consistency for physical properties
`of the drug product over time
`
`• Manufacturability
`and scalability
`
`• Process equipment
`• Process parameters, such as agitation
`rate, mixing time, temperature, etc.
`
`• Preservative efficacy • Selection of preservatives
`• Optimization of
`preservative concentration
`• Minimum acceptable limit
`of preservatives
`• Patient’s acceptance • Consistency of the preparation
`• Sensory perception before, during
`and after application
`
`• The selection of an API source is a central part
`of generic drug formulation development. Pay attention
`to the impurities which are not present in the RLD and
`residual solvents which are not listed in the ICH Q3C.
`• Preformulation data are critical for generic formulation and
`process development. This data may include API’s physical
`state, particle size, morphic form, solubility properties, sensitivity
`to light, moisture or air, and degradation pathway.
`
`• Compendial excipients usually are preferred; non-compendial
`materials are acceptable with justifications.
`• The firm is required to provide residual solvent data and
`test specifications to demonstrate that its drug product is
`in compliance with USP <467> requirements.
`• Excipient compatibility study using a binary mixture is
`desired to ensure the drug product stability prior to the drug
`product development. However, in many cases, homogenous
`mixing of the selected excipient and the API is impossible.
`Different excipient compatibility study design can be used.
`• Generally, the excipients used in the RLD are presumed compatible
`with the drug substance. The formulator should be aware that
`different vendors or grades may contain different impurities, which
`in turn may trigger the drug degradation.
`• It is prudent to keep the type of emulsifier(s), hydrophilic–lipophilic
`balance (HLB) of emulsifier and solvent to emulsifier ratio similar
`to those of the RLD, if the test formula is different from the RLD.
`• Excipients used in topical formulation can have emollient and
`hydrating effects and make the skin softer, smoother, and firmer.
`• Characterization of the RLD in terms of product attributes
`and stability profile is essential for the generic drug development.
`• Quality target product profile and critical quality attributes need
`to be identified as a part of quality by design.
`• Material of construct for the selected container closure system
`should be similar to that of the RLD. It is prudent to conduct
`a preliminary stability study using the final formula to
`demonstrate package compatibility in the formulation
`development stage.
`• The goal, if possible is to maintain assay value as close
`to 100% label claim and impurity level as close to 0%
`throughout the shelf-life period.
`• The goal, if possible is to maintain physical properties of
`the drug product throughout the shelf-life period. Potential
`problems include separation of phases, syneresis, pH change,
`specific gravity change, viscosity change, homogeneity of d