2. 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.
3. The AAPS Journal, Vol. 15, No. 1, January 2013 3
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.
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Request for Patent landscape from IPR.
●
Q1/Q2 correspondence to USFDA.
●
API & Excipients vendor selection & procurement.
4. The AAPS Journal, Vol. 15, No. 1, January 2013 4
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.
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Drug recrystallization/ precipitation studies.
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Prototype formulation trials.
●
Evaluation of physicochemical parameters.
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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.
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Selection of type of emulsion (O/W or W/O).
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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.
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Upright/ Inverted pack stability study.
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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 speed
b) homogenization time
c) Microscopic observation of dispersed globules/particles.
d) Hydration time for Carbomer
e) PH monitoring at intermediate stages
f) Cooling rate
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GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Formulation Design:
Design of Experiment batches
●
Identification of CMA (API), CMA (Excipients).
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Identification of CPP.
●
Experiments initiation for Formulation/ process
optimization.
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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.
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Individual process variability study.
●
Homogenization tip speed calculation for scalability at plant
level.
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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
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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.
17. The AAPS Journal, Vol. 15, No. 1, January 2013 17
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.
