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:
➲ Dosa...
The AAPS Journal, Vol. 15, No. 1, January 2013 3
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Formulation Design:
...
The AAPS Journal, Vol. 15, No. 1, January 2013 4
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Formulation Design:
...
The AAPS Journal, Vol. 15, No. 1, January 2013 5
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Formulation Design:
...
The AAPS Journal, Vol. 15, No. 1, January 2013 6
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Formulation Design:
...
The AAPS Journal, Vol. 15, No. 1, January 2013 7
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Process Development:...
The AAPS Journal, Vol. 15, No. 1, January 2013 8
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Formulation Design:
...
The AAPS Journal, Vol. 15, No. 1, January 2013 9
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Process Development:...
The AAPS Journal, Vol. 15, No. 1, January 2013 10
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Evaluation and Qual...
The AAPS Journal, Vol. 15, No. 1, January 2013 11
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Evaluation and Qual...
The AAPS Journal, Vol. 15, No. 1, January 2013 12
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Evaluation and Qual...
The AAPS Journal, Vol. 15, No. 1, January 2013 13
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Evaluation and Qual...
The AAPS Journal, Vol. 15, No. 1, January 2013 14
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Evaluation and Qual...
The AAPS Journal, Vol. 15, No. 1, January 2013 15
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Evaluation and Qual...
The AAPS Journal, Vol. 15, No. 1, January 2013 16
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Bioequivalence test...
The AAPS Journal, Vol. 15, No. 1, January 2013 17
GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC
PRODUCTS
Conclusions:
➲ Reve...
The AAPS Journal, Vol. 15, No. 1, January 2013 18
THANK YOU
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Generic development of topical products

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Generic development of topical products

  1. 1. GENERIC DEVELOPMENT OF TOPICAL DERMATOLOGIC PRODUCTS RUPESH S. KOTWAL
  2. 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. 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. ● Request for Patent landscape from IPR. ● Q1/Q2 correspondence to USFDA. ● API & Excipients vendor selection & procurement.
  4. 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. ● Drug recrystallization/ precipitation studies. ● Prototype formulation trials. ● Evaluation of physicochemical parameters. ● Viscosity method selection. ● QTPP & CQA finalization
  5. 5. The AAPS Journal, Vol. 15, No. 1, January 2013 5 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.
  6. 6. The AAPS Journal, Vol. 15, No. 1, January 2013 6 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.
  7. 7. The AAPS Journal, Vol. 15, No. 1, January 2013 7 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
  8. 8. The AAPS Journal, Vol. 15, No. 1, January 2013 8 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.
  9. 9. The AAPS Journal, Vol. 15, No. 1, January 2013 9 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.
  10. 10. The AAPS Journal, Vol. 15, No. 1, January 2013 10 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.
  11. 11. The AAPS Journal, Vol. 15, No. 1, January 2013 11 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.
  12. 12. The AAPS Journal, Vol. 15, No. 1, January 2013 12 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.
  13. 13. The AAPS Journal, Vol. 15, No. 1, January 2013 13 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.
  14. 14. The AAPS Journal, Vol. 15, No. 1, January 2013 14 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.
  15. 15. The AAPS Journal, Vol. 15, No. 1, January 2013 15 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
  16. 16. The AAPS Journal, Vol. 15, No. 1, January 2013 16 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.
  17. 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.
  18. 18. The AAPS Journal, Vol. 15, No. 1, January 2013 18 THANK YOU

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