generic development of topical products

GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS

RUPESH S. KOTWAL

The AAPS Journal, Vol. 15, No. 1, January 2013 2


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.



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.



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



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.



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.



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



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.



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.



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.



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.




● 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.




● 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.




● 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.



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



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.



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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generic development of topical products

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topical solution

finished product

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