This section contains only new information from FY2016. For background scientific information and outcomes from previous years on this research topic, please refer to the FY15 Regulatory Science Research Report on Topical Dermatological Drug Products.

Introduction

To ensure that high quality topical dermatological generic drug products can be made available to the American public, multiple research initiatives are underway to evaluate the feasibility of alternative, scientifically valid methods for evaluating the therapeutic equivalence for these topical drug products. These research projects are exploring the development of appropriate in vitro and in vivo approaches that have the potential to support an evaluation of BE based upon cutaneous PK approaches. Such approaches might be utilized to compare the rate and extent to which a drug becomes available at or near the site of action in the skin when applied topically in semisolid dosage forms like creams, ointments and gels, or even in topical patches. In the cases where the influence of manufacturing process variables on the physical, chemical, and microstructural critical product quality attributes are well characterized and found to be equivalent for generics compared with their corresponding RLD products, we are exploring whether BE may be established by integrating collective evidence related to product quality and performance from multiple, rationally selected, in vitro and/or in vivo approaches.

Research

One research initiative evaluates the comparative bioavailability from topical dermatological drug products through dermal PK sampling, using in vivo techniques known as microdialysis or open flow microperfusion. These are conducted by inserting a fine, semi-permeable tube, called a probe, into the dermis layer of the skin. As a physiological buffer solution flows through the probe, the concentration of drug in the dermis equilibrates with the solution inside the probe, and that concentration can thereby be monitored/measured over time as the solution is collected (Figure 1). This approach would facilitate the in situ measurement of drug concentrations in the dermis at different sampling time points, which can be compared between generic drug products and their corresponding RLDs (Figure 2).

Figure 1: Schematic diagram illustrating an open flow microperfusion probe in the skin, utilized to continually sample the concentration of a drug in the dermis: Source: Bodenlenz M, Tiffner K, Raml R, Augustin T, Dragatin C, Birngruber T, Schimek D, Schwagerle G, Pieber TR, Raney, SG, Kanfer I, Sinner F (2016) Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. Clinical Pharmacokinetics. DOI 10.1007/s40262-016-0442-z.

Figure 2: Dermal pharmacokinetics of acyclovir in vivo in human subjects from Test and Reference Acyclovir 5% Creams: Dermal open flow microperfusion (dOFM) acyclovir concentration profiles for the test product (T) site and the two reference (R1 and R2) sites (mean ± standard error of the mean, n = 40 test triads in 20 subjects). Acyclovir was analyzed from one pre-dose sample (spanning -1 to 0 h) and nine pooled post-dose samples (spanning 0–4, 4–8 … 32–36 h). The post-dose concentrations are plotted at the mid-point of the time intervals (2, 6 … 34 h). Adapted from Bodenlenz M, Tiffner K, Raml R, Augustin T, Dragatin C, Birngruber T, Schimek D, Schwagerle G, Pieber TR, Raney, SG, Kanfer I, Sinner F (2016) Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. Clinical Pharmacokinetics. DOI 10.1007/s40262-016-0442-z.

Another research initiative evaluates the comparative bioavailability from topical dermatological drug products through epidermal PK sampling, using an in vivo technique known as skin stripping. This is an epidermal PK sampling technique performed by collecting the outermost layers of skin through sequential application and removal of tape strips, thereafter analyzing the samples for topically administered drug content at different sampling time points. This permits the in situ measurement of the rate and extent of drug delivery into the outermost layer of skin, the stratum corneum, which may be particularly relevant for certain topical products when this layer of skin is the site of drug action. The techniques being investigated also provide information about the rate and extent to which topically applied drugs clear or diffuse out of the stratum corneum and become available to the viable tissues in the deeper layers of the skin.

Such mechanistic information about the way that drugs partition into the skin from a topical product, and then permeate through the layers of the skin and eventually into the systemic absorption, can greatly enhance our understanding of how to evaluate and compare the bioavailability of generic drug products with their corresponding RLD products. Therefore, carefully designed studies are underway to monitor/measure the bioavailability of drug products in the stratum corneum as well as in the systemic circulation of the same population of human subjects.

Yet another research initiative evaluates the use of an in vitro permeation test (IVPT) with excised human skin mounted in a static Franz diffusion cell or a flow-through diffusion cell as part of a BE methodology. This in vitro approach permits direct collection of the drug permeating through the stratum corneum, epidermis, and/or dermis of human skin from a topical dermatological drug product. The merits of this approach are based upon the potential of the IVPT model to correlate with and be predictive of human in vivo bioavailability data, and upon the relative efficiency with which one can perform well-controlled studies of comparative bioavailability in vitro. As an in vitro methodology, this approach may support the determination of BE as part of a collective weight of evidence demonstrating that a generic product is equivalent in quality and performance to its corresponding RLD.

An essential element of such a collective weight of evidence approach may include comprehensive characterization of the physicochemical properties of complex topical semisolid dosage forms, to mitigate the risk that differences in physicochemical properties between the generic and RLD product may lead to differences in therapeutic performance via a variety of potential failure modes. Therefore, another research initiative evaluates ways to characterize the complexity of semisolid dosage forms, develops tools to measure novel product quality attributes that may have the potential to influence product performance, and seeks to correlate changes in critical quality attributes with corresponding changes topical bioavailability.

Figure 3: Physicochemical characterization of composition and microstructure of Acyclovir Cream 5% (marketed in the U.K.) when dispensed from a tube or from a pump: Two-Dimensional (2D) or three-dimensional (3D) confocal Raman microscopy (CRM) of acyclovir cream 5% UK-marketed products. A) 2D CRM of the cream dispensed from a tube, B) 3D CRM of the cream dispensed from a tube, C) 2D CRM of the cream dispensed from a pump, D) 3D CRM of the cream dispensed from a pump, E) 2D CRM of the cream prior to being dispensed, while still within the pump, F) Raman spectra corresponding to dimethicone globules (blue), acyclovir crystals (yellow) or the cream base (black). These results illustrate that the process of being dispensed through the pump appears to result in the formation of dimethicone globules in the cream. Adapted from Mohammed YH, Namjoshi SM, Jung N, Shewan HS, Stokes J, Benson HAE, Grice JE, Windbergs M, Raney SG and Roberts MS (2016) Are Topical Products Dispensed from Different Packaging Q3 Equivalent and Bioequivalent? Poster Presentation at the American Association of Pharmaceutical Scientists Annual Meeting (November 14, 2016).

Figure 4: Comparative bioavailability of acyclovir from Acyclovir Cream 5% (marketed in the U.K.) when dispensed from a tube or from a pump: Cumulative permeation profiles of acyclovir through excised human skin isolated epidermis mounted in Franz diffusion cells, using the same tube and pump products depicted in Figure 3. Source: Mohammed YH, Namjoshi SM, Jung N, Shewan HS, Stokes J, Benson HAE, Grice JE, Windbergs M, Raney SG and Roberts MS (2016) Are Topical Products Dispensed from Different Packaging Q3 Equivalent and Bioequivalent? Poster Presentation at the American Association of Pharmaceutical Scientists Annual Meeting (November 14, 2016).

ORS staff facilitating research in this area

• Sam Raney, PhD, Priyanka Gosh, PhD, Tannaz Ramezanli, PhD, Yi Zhang, PhD, Markham Luke, MD, PhD

Projects and Collaborators

• Novel Methodologies and IVIVC Approaches to Assess Bioequivalence of Topical Drugs
  • Site PI: Frank Sinner
  • Grant #: 1U01FD004946
• Bioequivalence of Topical Drug Products: In Vitro – In Vivo Correlations
  • Site PI: Audra Stinchcomb
  • Grant #: 1U01FD004947
• Characterization of Critical Quality Attributes for Semisolid Topical Drug Products
  • Site PI: Michael Roberts
  • Grant #: 1U01FD005226
• Topical Products and Critical Quality Attributes
  • Site PI: Sathyanarayana Murthy
  • Grant #: 1U01FD005233
• Development of a Universal Bioequivalence Test Method for Topical Drugs using dOFM
  • Site PI: Frank Sinner
  • Grant #: 1U01FD0045861
• Benchmark of Dermal Microdialysis to Assess Bioequivalence of Topical Dermatological Products
  • Site PI: Grazia Stagni
  • Grant #: 1U01FD005862
• Internal Project: Coupling Chemical Analysis to High Resolution Microscopy Methods for Enhanced Physicochemical Characterization of Drug Products Containing Nanomaterials and Other Complex Formulations
  • FDA Collaborator: Katherine Tyner
  • FDA Center/Office/Division: CDER/OPQ/SS

Publications

• Bodenlenz M, Tiffner K, Raml R, Augustin T, Dragatin C, Birngruber T, Schimek D, Schwagerle G, Pieber TR, Raney, SG, Kanfer I, Sinner F (2016) Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. Clinical Pharmacokinetics. DOI 10.1007/s40262-016-0442-z.
• Grosser S, Park M, Raney SG, Rantou E (2015) Determining Equivalence for Generic Locally Acting Drug Products. Statistics in Biopharmaceutical Research; 7(4), 337-345.

Oral presentations

• Kanfer I. (2016) The Development and Application of Surrogate Methods to Assess Bioequivalence of Topical Generic Products Intended for Local Action. Invited oral presentation at the 3rd Bioequivalence Summit: Ensure Regulatory Compliance When Demonstrating the Bioequivalence of New Dosage Forms, Delivery Methods and Biosimilars, Boston MA. (September 26, 2016).
• Murthy N. (2016) Topical Semisolid Drug Product Critical Quality Attributes (Q3 Characterization) with Relevance to Topical Bioequivalence. Invited oral presentation at the BASF-Center for Dermal Research Workshop: The Role of Topical Semi-solid Microstructure on Product Performance and Functionality, Piscataway, NJ. (May 24, 2016).
• Raney SG. (2016) The Matter of Medicine-Does Form Follow Function or Vice Versa? Invited oral presentation at the BASF-Center for Dermal Research Workshop: The Role of Topical Semi-solid Microstructure on Product Performance and Functionality, Piscataway, NJ (May 24, 2016)
• Raney SG (2016) The Impact of GDUFA Regulatory Science. Invited oral presentation at the Center for Drug Evaluation and Research (CDER) Scientific Rounds (April 27, 2016).
• Bunge AL and Guy RH. (2016) Evidence from In Vivo Skin Stripping Studies: Utility for Evaluating Topical Bioavailability. Invited oral presentation at the Fifteenth International Conference on Perspectives in Percutaneous Penetration, La Grande Motte, France (March 30, 2016).
• Murthy N. (2016) Characterizing Failure Modes and Critical Quality (Q3) Attributes of Semi-Solid Topical Drug Products. Invited oral presentation at the Fifteenth International Conference on Perspectives in Percutaneous Penetration, La Grande Motte, France (March 30, 2016).
• Roberts MS. (2016) Topical Semisolid Drug Product Critical Quality Attributes (Q3 Characterization) With Relevance to Topical Bioequivalence. Invited oral presentation at the Fifteenth International Conference on Perspectives in Percutaneous Penetration, La Grande Motte, France (March 30, 2016).
• Sinner F. (2016) A Novel Approach to Assess Bioavailability of Topical Drugs directly in the Skin - Open Flow Microperfusion. Invited oral presentation at the Fifteenth International Conference on Perspectives in Percutaneous Penetration, La Grande Motte, France (March 30, 2016).
• Franz TJ. (2016) Evidence of IVIVC for In Vitro Permeation Test: Utility for Evaluating Topical Bioavailability and Bioequivalence. Invited oral presentation at the Fifteenth International Conference on Perspectives in Percutaneous Penetration, La Grande Motte, France (March 30, 2016).
• Delgado Charro MB. (2016) Recent Advances on Topical, Transdermal and Nail Drug Delivery. Invited oral presentation at the Spanish-Portuguese Conference on Controlled Drug Delivery “Revolutionary Approaches in Nanomedicine Development Granada, Spain (January 21st, 2016).
• Murthy N. (2015) Evaluating Quality (Q3) Attributes and Potential Failure Modes for Topical Semisolid Drug Products. Invited oral presentation at the AAPS Annual Meeting Symposium: Bio-Equivalence Standards for Topicals (BEST): Evidence for Integrating Multiple Quality (Q3) and Performance Tests to Evaluate the Best Generic Products (October 28, 2015)
• Stinchcomb A. (2015) Evaluating Topical Bioavailability In Vivo by Skin Stripping and In Vitro by IVPT. Invited oral presentation at the AAPS Annual Meeting Symposium: Bio-Equivalence Standards for Topicals (BEST): Evidence for Integrating Multiple Quality (Q3) and Performance Tests to Evaluate the Best Generic Products (October 28, 2015)
• Sinner F. Evaluating Topical Bioavailability In Vivo by Dermal Open Flow Microperfusion and Equivalence by IVRT. Invited oral presentation at the AAPS Annual Meeting Symposium: Bio-Equivalence Standards for Topicals (BEST): Evidence for Integrating Multiple Quality (Q3) and Performance Tests to Evaluate the Best Generic Products (October 28, 2015)
• Raney SG. (2015) Considerations Relating to Product Quality Characterization for Topical Semisolid Dosage Forms. Invited oral presentation at the AAPS Annual Meeting Exhibitor Seminar: The Role of Topical Semisolid Microstructure on Formulation Performance and Efficacy (October 27, 2015)
• Raney SG (2015) Characterizing Critical Quality Attributes for Topical Semisolid Dosage Forms. Invited oral presenation at the U.S. Pharmacopeia Workshop on Quality Attributes of Drug Products Applied to the Skin. Rockville, MD (September 22, 2015).
• Rantou E and Raney SG (2015) Special Cases for the Statistical Evaluation of Bioequivalence: An Example of In-Vitro Skin Permeation Test Data. Invited oral presenation at the Drug Industry Association (DIA) Annual Meeting, Washington, DC (June 15, 2015).
• Raney SG (2015) Evaluating Equivalence for Transdermal Systems: Unique Scientific and Regulatory Considerations Impacting CMC/Quality and Bioequivalence Assessments for Generics. Invited oral presenation at the CDER CASE Course on Product Quality of Transdermal Drug Delivery Systems. White Oak, Silver Spring, MD (May 7, 2015)

Poster presentations

• Jung N, Namjoshi SN, Mohammed YH, Grice JE, Raney SG, Roberts MS, Windbergs M (2016) Skin Penetration Kinetics of Different Acyclovir Formulations Analyzed by Confocal Raman Microscopy. Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Mohammed YH, Namjoshi SN, Jung N, Shewan H, Stokes J, Benson, HA, Grice JE, Windbergs M, Raney SG, Roberts MS (2016) 2. Are Topical Products Dispensed from Different Packaging Q3 Equivalent and Bioequivalent? Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Namjoshi SN, Mohammed YH, Benson, HA, Grice JE, Clegg J, Raney SG, Roberts MS (2016) Water Content and Product Drying Rate as Well as the Amount of Propylene Glycol May Impact the Topical Bioavailability of Acyclovir from Cream Products. Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Shewan HM, Boehm MW, Suvanmani V, Mohammed YH, Namjoshi SN, Raney SG, Roberts MS, Stokes J, (2016). Low Volume and High Shear Rheology on a Conventional Rheometer: A Tool for Characterizing Pharmaceutical Skin Creams. Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Sharma PK, Srinatha A, Muralikrishnan A, Raney SG, Ghosh P, S. Murthy SN, (2016). Determination of pH for an Oil-in-Water Based Semisolid Cream: Method Development and Standardization. Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Maurya A, Srinatha A, Raney SG, Ghosh P, S. Repka MA, Murthy SN, (2016). The pH of Topical Creams Can Change Rapidly following Application on the Skin In Vivo. Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Srinatha A, Maurya A, Ghosh P, S. Raney SG, Murthy SN, (2016). Influence of the Method of Dose Application on the In Vitro Permeation Profile of Acyclovir from Topical Creams. Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Srinatha A, Ghosh P, S. Raney SG, Maibach HI, Murthy SN, (2016). Is Water Activity the Primary Determinant of Metamorphosis for Topical Creams? Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Srinatha A, Hashemnejad SM, Kundu S, Ghosh P, S. Raney SG, Murthy SN, (2016). Clinical Relevance of Rheological Characteristics of Topical Creams: Relationship Between Yield Stress and Dose Spreading Area. Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Bodenlenz M, Tiffner KI, Raml R, Augustin T, Dragatin C, Birngruber T, Kainz S, Schwagerle G, Korsatko S, Raney SG, Kanfer I, Sinner F (2016). Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. Poster Presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Tiffner K, Kanfer I, Schimek D, Reisenegger P, Raml R, Augustin T, Raney SG, Sinner F (2016). Comparative In Vitro Release Tests (IVRT) of Seven Topical Acyclovir Products Using a Validated IVRT Method with a Vertical Diffusion Cell (VDC) Apparatus. Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Shukla S, Ghosh P, Raney SG, Hassan HE, Bunge A, Stinchcomb AL (2016) Evaluation of Two Lidocaine Topical Patch 5% Products by Cutaneous Pharmacokinetic Methods: In Vitro Tape Stripping and In Vitro Permeation Testing. Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) Conference, Denver, Colorado (November, 2016).
• Shewan HM, Suvanmani V, Mohammed YH, Namjoshi SN, Raney SG, Roberts MS, Stokes JR, (2016). Low volume and high shear rheology on a conventional rheometer: a tool for characterising pharmaceutical skin creams. Poster presentation at the XVIIth International Congress on Rheology (ICR2016), Kyoto, Japan. (August 2016).
• Pensado A, Chiu WS, Cordery SF, Bunge AL, Delgado-Charro MB, and Guy RH. Dermatopharmacokinetics as a tool for bioequivalence testing: a case study comparing acyclovir creams from the US and UK. Poster Presentation at 15th Annual Meeting of Skin Forum, London, UK (June 21st 2016).
• Cordery SF, Chiu WS, Shehab MZ, Bunge AL, Delgado-Charro MB, and Guy RH. In Vitro – In Vivo Correlation (IVIVC) of Diclofenac Bioavailability from Three Topical Drug Products. Poster Presentation at 15th Annual Meeting of Skin Forum, London, UK (June 21st 2016).
• Tiffner K, Kanfer I, Schimek D, Reisenegger P, Raml R, Raney SG, Sinner F (2016) Comparative In Vitro Release of Six Different Topical Acyclovir Products Using a Vertical Diffusion Cell (VDC) Apparatus. Poster presentation at the American Association of Pharmaceutical Scientists (AAPS) National Biotechnology Conference (May 16, 2016).
• Tiffner K, Kanfer I, Schimek D, Reisenegger P, Raml R, Augustin T, Raney SG, Sinner F (2016) Comparative In Vitro Release Tests (IVRT) of Seven Topical Acyclovir Products Using a Validated IVRT Method with a Vertical Diffusion Cell (VDC) Apparatus. Poster presentation at the Fifteenth International Conference on Perspectives in Percutaneous Penetration, La Grande Motte, France (March 30, 2016)
• Bodenlenz M, Tiffner K, Raml R, Tschapeller B, Augustin T, Dragatin C, Birngruber T, Kainz S, Schimek D, Schwagerle G, Pieber TR, Raney SG, Kanfer I, Sinner F (2016) Clinical Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence in the Dermis In Vivo. Poster presentation at the Fifteenth International Conference on Perspectives in Percutaneous Penetration, La Grande Motte, France (March 30, 2016)
• Namjoshi SN, Mohammed YH, Grice JE, Clegg J, Raney SG, Roberts MS (2016) Water Content and Product Drying Rate as Well as the Amount of Propylene Glycol May Impact the Topical Bioavailability of Acyclovir from Cream Products. Poster presentation at the Fifteenth International Conference on Perspectives in Percutaneous Penetration, La Grande Motte, France (March 30, 2016)
• Mohammed YH, Namjoshi SN, Grice JE, Jung N, Shewan H, Stokes J, Windbergs M, Raney SG, Roberts MS (2016) Influence of Product Dispensers on the Microstructure of Acyclovir Creams. Poster presentation at the Fifteenth International Conference on Perspectives in Percutaneous Penetration, La Grande Motte, France (March 30, 2016).
• Tiffner K, Bodenlenz M, Schwingenschuh S, Hajnsek M, Reisenegger P, Kainz S, Augustin T, Baumann P, Tschapeller B, Schwagerle G, Raml R, Kanfer I, Sinner F. Can we predict skin penetration by using TEWL or skin impedance? Poster presentation at the 13th Meeting of the European Epidermal Barrier Research Network (September 9, 2015).
• Jung N, Namjoshi SN, Mohammed YH, Grice JE, Raney SG, Roberts MS, Windbergs M (2016) Skin Penetration Kinetics of Different Acyclovir Formulations Analyzed by Confocal Raman Microscopy. Poster presentation at the Fifteenth International Conference on Perspectives in Percutaneous Penetration, La Grande Motte, France (March 30, 2016).

Outcomes

• Revision of Product-specific recommendations for Acyclovir cream (December 2016)
  

ResourcesForYou

• Office of Generic Drugs FY 2016 Regulatory Science Research Report