Quality by design approaches for topical dermatological dosage forms

Figures & data

Table 1 Quality by testing versus quality by design in pharmaceutical development

Quality by testing	Quality by design
Quality targeted by setting tight specifications from manufactured batches	Quality targeted based on scientific understanding of critical attributes and design space
Rigid process avoids any changes; if changes required, supplements are added, causing burden to FDA	Flexible process accepts changes within design space; not required to add supplements to FDA
Targeted toward repeated reproducibility with zero space for variations	Targeted toward robustness of the methodology with enough space for acceptable variations

Abbreviation: FDA, US Food and Drug Administration.

Figure 1 General quality by design approach for development of a pharmaceutical drug product.

Table 2 Critical criteria for development of a topical dermatological dosage form

Critical attributes during TDDF development	Critical criteria
Active pharmaceutical ingredient	Solubility, melting point, salt or base form, particle size, polymorph, liquid or solid form
Excipients	Solubility, polymorphs, melting point, liquid or solid form, compatibility, certificate of analysis specifications, particle size, National Formulary status
Physical and chemical stability	Crystallization, phase separation, sedimentation, rheology/viscosity change, color change, volatility
Processing conditions (especially important for Q3 products as they can influence the microstructure arrangement)	Mixing time, mixing type (high or low shear homogenizing), mixing speed, temperature range, physical observation, insolubility of ingredients
Preservatives	Level and type of antimicrobial or antioxidant or chelating agents, endogenous preservative (some preparations may contain sufficient volume of alcohol which may not need separate preservative)
Packaging	Container and closure material (coated with plastic or aluminum or other) type, glass or plastic storage, amber or transparent, loss of solvent/ volatility, leachable

Abbreviations: TDDF, topical dermatological dosage form; Q3, same components in same concentration with same arrangement.

Table 3 General elements of a QTPP for a TDDF

Dosage form Route of administration Stability Drug product quality attributes Physical attributes: rheology, particle size, globule size of dispersed droplet Assay Homogeneity/uniformity pH Degradation products/residual solvent Preservatives Microbial limits In vitro release Container closure system Package integrity

Note: The QTPP elements represented above are not specific to a particular TDDF.

Abbreviations: QTPP, quality target product profile; TDDF, topical dermatological dosage form.

Table 4 Hypothetical risk assessment using failure mode effects and criticality analysis for lack of viscosity and particle size analysis

Processing parameters	Failure modes	Causes of failure	Effect of failure	S^a (1–5)*	P^b(1–5)*	D^c(1–5)*	RPN^d (S×P×D)	C^arank
Raw material weighing	Error in weighing	Lack of monitoring or lack of guidance or lack of GMP training or lack of proper labeling	Over or insufficient material which can adversly impact the viscosity or the particle size of the final product	3	1	1	3	5
Mixing Speed	Out of specification	Lack of process monitoring or lack of scientific knowledge/detailed understanding	Low speed: incompleted mixing components precipitation, clumps formation, lack of homogenization causing viscosity and particle size changes High speed: polymer structure/ network breakdown causing viscosity breakdown, too low particle size	5	2	2	20	1
Duration	Out of specification	Lack of process monitoring or lack of scientific knowledge/detailed understanding, malfunction of the equipment	Low duration: lack of homogenized product or lack of optimized particle size product, clumps formation, uneven blend or content uniformity High duration: viscosity breakdown or too low particle sizes, excess heat generation leading a threat to volatile components and charring resulting indirect changes to viscosity or particle size aggregation	5	1	2	10	2
Method	Out of specification	Lack of process monitoring or lack of scientific knowledge/detailed understanding, malfunction of the equipment, lack of proper alignment of the mixer	Variation in particle size, viscosity homogeneity, content and blend uniformity, stability	5	2	2	20	1
Temperature	Out of specification	Lack of process monitoring, malfunction of the equipment	Low temperature causes clumps formation, non-homogenous mixure, excess heat generation causes batch failure, and enhances impurities and chemical degradation	3	2	1	6	4
Flow rate of the powder or solvent	Out of specification	Lack of process monitoring, powder aggregation (hygroscopicity), low weight of fulffy powder, uneven geometric addition of powder or solvent	excess or low wetting causes viscosity variation and particle aggregation	4	2	1	8	3
Order of addition	Out of specification	Lack of process monitoring	Rheologh variation, clumping of particle aggregation	2	1	1	2	6

Notes: ^aSeverity; ^bprobability; ^cdetectability; ^drisk priority number; ^ccriticality rank; *scale from 1 to 5 where 1 is lowest and 5 is highest. Springer and the AAPS Journal, 15(3), 2013, 674–683, Generic development of topical dermatologic products. Part II: quality by design for topical semisolid products, Chang R-K, Raw A, Lionberger R, Yu L, Table IV, with kind permission from Springer Science and Business Media.¹⁷

Abbreviation: GMP, good manufacturing Practice.

Figure 2 General quality by design approach for development of a topical dermatological dosage form.²⁵

Notes: Q1, same components or qualitatively; Q2, same components with same concentration or quantitatively; Q3, same components in same concentration with same arrangement.

Table 5 Commonly used excipients and their challenges during development of a topical dermatological dosage form

Functional category of the excipient	Commonly used dosage forms	Purpose of excipient	Examples	Issues during processing or development
Solvent/vehicle	Topical solution, gel, cream, paste, lotion, suspension	Solvation, solubility enhancer, penetration enhancers	water, ethyl alcohol, isopropyl alcohol, mineral oil, hexylene glycol	volatility
Suspending/gelling agents	Gel, cream, paste	Viscosity modifiers, matrix formers	Carbomer, cellulose derivatives, hydrophilic or hydrophobic silica, gelatin, carrageenan, sodium alginate, polyethylene oxides, magnesium aluminum silicate	Poor or over wetting, fish eyes, agglomeration or clump formation, adherence of aggregates to mixers, rheology change during storage
Emulsifiers	Cream	Interfacial tension reducers, impart both hydrophobic and hydrophobic characteristics, thereby reducing phase separation, stabilizers	Sodium lauryl sulfate, isostearic acid, white soft paraffin, glycol stearate, glyceryl palmitate, dimethyl isosorbide, acrylate copolymer, oleyl alcohol, ceto stearyl ether	Agglomeration or clump formation
Stiffening agents	Ointment, paste, cream	Viscosity modifiers, matrix formers	Petrolatum, polyethylene glycol, triglycerides, paraffin, anhydrous or hydrogenated lanolin, microcrystalline wax, coconut oil, beeswax, stearic acid, stearyl alcohol, cetyl alcohol, fatty alcohols	Agglomeration or clump formation, adherence of aggregates to the mixers, requires a robust cleaning validation procedure
Permeation enhancers	Topical solution, cream, paste, lotion, suspension, ointment	Solubilizing agent, drug partition, or diffusion enhancers	Propylene glycol, oleic acid, alcohols like ethyl and isopropyl alcohols	Discoloration, physical incompatability
Preservatives	Topical solution, cream, paste, lotion, suspension, ointment	Microbial growth reducer, product stabilizer	Methylparaben, propylparaben, beonzoic acid, benzyl alcohol	Discoloration, adsorption to the containers
Antioxidants	Topical solution, cream, paste, lotion, suspension, ointment	Oxidation reducer, product stabilizer	Butylated hydroxy toluene, butylated hydroxy anisole	Discoloration
Neutralizer	Gel	Ion stabilizer	Sodium hydroxide	Precipitation
Chelating agents	Topical solution, cream, paste, lotion, suspension	Product stabilizer	Ethylene diamine tetra acetate	Discoloration

Table 6 Types of levels and descriptions

Level	Definition and required actions
1	Unlikely to have an impact on formulation quality and performance; these types of changes require only annual reporting
2	Could have a significant impact on formulation quality and performance; these types of changes require in vitro release rate data for both prechange and postchange formulations
3	Likely to have a significant impact on formulation quality and performance; these types of changes, which include changes in formulation composition and category of components, require documentation of bioequivalence between the prechange and postchange formulation or between the postchange test and reference product

Note: Data from Shah et al.²²

Buhse L, Kolinski R, Westenberger B, et al. Topical drug classification. Int J Pharm. 2005;295(1–2):101–112.

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