GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
RUPESH S. KOTWAL
The AAPS Journal, Vol. 15, No. 1, January 2013 2
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Introduction:➲ Dosage form applied on Skin to have therapeutic
effect on diseased Skin are termed as Topical dermatologic products.
➲ Topical products are ointments, creams, gels, lotions, solutions, suspensions, foams and shampoos.
➲ Skin, the major barrier consists of stratum corneum, epidermis and dermis layer.
➲ Transport routes are Transcellular, Intercellular, Hair follicles and sweat glands.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Formulation Design:Evaluation of Innovators Drug Product [RLD's]
● Literature, Patent, FOI, Patient Information.● RLD physicochemical parameters & pack evaluation.● Information on different grade of excipients and
finalization of excipient grade.● Reverse engineering of Innovators Drug Product.● IIG database evaluation for specific route and dosage
form.● Request for Patent landscape from IPR.● Q1/Q2 correspondence to USFDA.● API & Excipients vendor selection & procurement.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Formulation Design:Initiation of Generic Drug Product Development:
● Development with Q1/Q2 sameness.● Drug-Excipients compatibility studies.● Drug Solubility studies in different solvents used [If Drug
is in solubilized form].● Drug solution stability studies for atleast 24 hours.● Drug recrystallization/ precipitation studies.● Prototype formulation trials.● Evaluation of physicochemical parameters.● Viscosity method selection.● QTPP & CQA finalization
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Formulation Design:Initiation of Generic Drug Product Development:
● Temperature cycling studies for drug dispersion type formulations.
● Selection of type of emulsion (O/W or W/O).● Selection of type of emulsifier with similar HLB.● Selection of appropriate solvent to emulsifier ratio.● Selection of alternate excipient with proper justification
for its functionality and IIG database.● Excipient ≤ 0.1% of total product weight need not justified.● Microscopic evaluation of drug product throughout
stability.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Formulation Design:Stability of Generic Drug Product Development
● Stability inititiation in proposed Pack [same MOC].● IPR & IRA final clearance on proposed final formulation.
Development after finalization of Formula● Stability initiation (two reproducible) in final proposed
formulation and pack.● Hold time, contact part, freeze- thaw studies initiation.● Upright/ Inverted pack stability study.● Recrystallization study (topical solution) at 2°C to 8°C.● IVRT/ IVPT study initiation.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Process Development:Equipments/ Machines for Topical dosage forms
Mechanical stirrers.Homogenizers: Rotor/stator type (preferred).Vacuum pump.
Process Development Steps➔ Critical monitoring of individual process steps:a) homogenization speedb) homogenization timec) Microscopic observation of dispersed globules/particles.d) Hydration time for Carbomere) PH monitoring at intermediate stagesf) Cooling rate
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Formulation Design:Design of Experiment batches
● Identification of CMA (API), CMA (Excipients).● Identification of CPP.● Experiments initiation for Formulation/ process
optimization.● Initial evaluation for all identified CQA's.● Stability initiation of DOE batches.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Process Development:Process Parameters
● Individual process identification for initial risk assessment.● Individual process variability study.● Homogenization tip speed calculation for scalability at plant
level.● Finalization of individual process parameter with proper
optimization studies.● Risk mitigation and finalization of process steps.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Evaluation and Quality tests:Evaluation Parameters selection
● Topical drug products are analyzed at in-process, finished product and during stability.
● Topical products has in-process, finished product and stability release specifications.
● Parameters are included considering previous experience, RLD specifications and regulatory filing requirements to minimize regulatory deficiencies.
● Justifiable range is set for individual parameter.● Products official in USP are evaluated accordingly.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Evaluation and Quality tests:Evaluation Parameters
● Description: Description is an important parameter for Topical products.
● Identification: Drug specific test using IR or HPLC is preferred.
● pH: 10% aqueous solution at 25°C.● Product consistency: Viscosity in poise or centipoise is
preferred, with details of Instrument, model, spindle, rpm, time and temperature.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Evaluation and Quality tests:Evaluation Parameters
● Specific gravity: Though an important parameter it may not be the part of Finished product release parameter. However, it forms the basis for those product being filled as ml/ pack.
● Tube (content) uniformity: As per USP <3>● Water content (optional): Monitoring water content is an
important attribute in certain formulation having ristriction in water content.
● Excipient content: Certain formulations require critical monitoring of excipients viz. Ethanol, IPA, IPM etc.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Evaluation and Quality tests:Evaluation Parameters
● Weight loss/ gain: Performed in semi-permeable and/ or plastic containers.
● Microscopy: Can be the test to be included in release and stability specification, but need to be appropriately validated.
● Particle size distribution: As per USP <3>● Assay: A mandatory evaluation parameter to be included in
all product specifications.● Degradation Products/ Impurity: Limits are set as per ICH
Q3B guidelines using maximum daily dose calculation.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Evaluation and Quality tests:Evaluation Parameters
● Preservative/ Antioxidant content: A test to be included in release and stability specification.
● Formaldehyde or Benzaldehyde content for products having formaldehyde releasing preservatives or Benzyl alcohol respectively.
● Minimum fill: As per USP <755>● Residual solvents: Test as per USP <467>.● Microbial Limit Test: Test as per USP <61>, <62>and <1111>.● Package intergity: A visual test for package and label
evaluation ,ay be included in specification.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Evaluation and Quality tests:Evaluation Parameters for Special Product/ Pack
● Pump/ spray performance/ Dose Uniformity: A scientifically designed unique test for metered dose pack.
● Inverted pack studies: As required for specific products● Unit dose pack; weight variation studies: As per USP <905>● Invitro drug release studies: Q1/Q2/Q3 drug product
requesting for Biowaiver an In-vitro release studies forms a surrogate for comparison.
● Pack compatibility (contact parts)● In-Use studies
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Bioequivalence tests:Draft Guidance for Topical dosage forms
✔ Q1/Q2/ Q3 sameness for few products: BE Biowaiver.✔ Q1/Q2 sameness for Topical solution: BE not required.✔ Corticosteroid formulation: Vasoconstriction Assay.✔ Products with anti acne, psoriasis, NSAID etc activity:
Clinical end point study.✔ Biowaiver for DESI products.✔ Transdermal topical dosage form: BE with Pharmacokinetic
end point.
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS
Conclusions:➲ Reverse engineering to copy the RLD.➲ Q1/Q2/Q3 sameness to minimise BE failure.➲ Implementation of QbD to understand the product.➲ Satisfactory stability data of the test product.➲ In vitro skin permeation studies as a critical tool.➲ Drug-excipient compatibility data, Laboratory batch
stability profile and innovator's product impurity profile forms the basis for regulatory filing.
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THANK YOU
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