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A Long and Winding Road for Transdermal Products – FDA Has It Covered

On November 22, 2019 the Food and Drug Administration (FDA) published a Level 1 draft guidance titled Transdermal and Topical Delivery Systems - Product Development and Quality Considerations.  The Federal Register notice discussing the guidance and the comment period can be found here and the draft guidance itself can be accessed here.

The publication of the draft guidance is a significant milestone that has been years – over a decade – in the making.  Transdermal products have had a rather vexing regulatory history at times and the FDA has devoted significant resources to providing industry with prior notice and guidance about both technical and policy issues.  Consider the cumulative effect of these various product quality and current good manufacturing practice (CGMP) related events that affected how FDA approached evaluating various transdermal products and developing regulatory policy and guidance that have taken place since 2006.

  • After the FDA received numerous reports of “adhesion lacking” for transdermal drug delivery systems, FDA authors published the paper Transdermal Drug Delivery System (TDDS) Adhesion as a Critical Safety, Efficacy and Quality Attribute in August 2006.  A copy of the paper can be accessed here.
  • In January 2008 Noven Pharmaceuticals, Inc. (now operating as a member of the Hisamitsu® Group) received a Warning Letter from FDA.  In a filing made to the Securities and Exchange Commission (SEC), Noven disclosed that the FDA cited CGMP deficiencies related to the peel force specifications for removal of Daytrana’s release liner, and data supporting the peel force characteristics of Daytrana’s enhanced release liner throughout the product’s shelf life.
  • Both brand name and generic manufacturers of fentanyl transdermal patches recalled some products in February 2008 due to the risk of potentially serious adverse events or lack of efficacy related to manufacturing defects.
  • In July 2010, FDA authors published the paper Release Liner Removal Method for Transdermal Drug Delivery Systems (TDDS) to improve the capability of manufacturers to measure release liner removal adhesion for TDDS. A copy of the paper can be found here.
  • Based on its earlier research involving release liner removal methods, FDA published the guidance Residual Drug in Transdermal and Related Drug Delivery Systems in August 2011.  A copy of the guidance can be found here.​​​​​​​
  • Also, during August 2011 Noven received a Warning Letter from FDA for process development and other CGMP deficiencies related to the manufacture of the firm’s fentanyl transdermal system at its facility in Carlsbad, California. An archived copy of the Warning Letter can be found here. ​​​​​
  • A consortium of authors from the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute (PQRI) published the whitepaper Passive Transdermal Systems Whitepaper Incorporating Current Chemistry, Manufacturing and Controls (CMC) Development Principles in March 2012. A copy of the article can be found here.​​​​​​​
  • FDA personnel once again published an article Navigating Sticky Areas in Transdermal Product Development in July 2016. The agency’s goal in publishing the article was to improve, advance and accelerate commercial development of this complex controlled release dosage form. A copy of the article can be accessed here.
  • The Miami, Florida manufacturing facility for Noven received another FDA Warning Letter in August 2016 which included CGMP violations related to two TDDS products – Minivelle® and Daytrana®. A copy of the Warning Letter can be found here.
  • Pocono Coated Products received a Warning Letter from FDA in October 2016 for various CGMP violations related to the manufacture of transdermal drug products for a customer at its facility in North Carolina. A copy of the Warning Letter can be located on the FDA website here
  • In April 2018 the FDA sent a Warning Letter to Phase 4 Pharmaceutical LLC. Rather than manufacturing transdermal drug products, the firm was functioning as a re-packager of over-the-counter (OTC) transdermal drug products and the FDA found several violations of CGMP that affected product quality. A copy of the Warning Letter can be found on the FDA website here.
  • The FDA published a summary report in May 2018 of its science and research efforts for transdermal drugs as part of fulfilling its Generic Drug User Fee Act (GDUFA) commitments. The report included a discussion of accomplishments, research and collaborations, key outcomes and future directions for regulatory science and policy. A copy of the report is published on the FDA website here.
  • To further meet GDUFA commitments, FDA published the guidance Assessing Adhesion with Transdermal Delivery Systems and Topical Patches for ANDAs Draft Guidance for Industry in October 2018. A copy of the guidance can be found on the FDA website here

There is a familiar pattern from FDA in these events.  It is time-consuming for FDA to draft and publish new Manuals of Policy and Procedure (MaPP) or guidance, much less rulemaking.  And given the recent executive orders from the president and policies from the Office of Information and Regulatory Affairs (OIRA) that mandate more extensive reviews of guidance documents, it is far easier and more effective for FDA to have its professional staff author publications that appear in peer reviewed journals and reputable trade publications.

This is particularly true when FDA begins to receive information that may signal product quality issues in the marketplace.  In this case, FDA began to notify industry of certain quality issues affecting transdermal drug products with the article in 2006, followed up with another article in 2010 after generating data in its own research laboratories at the Office of Testing and Research (OTR) and used the article published in 2016 as a prelude to the draft guidance issued in November.  There are also myriad other communications that FDA has generated between 2013-2017 that are summarized in the summary report for transdermal product regulatory research funded by GDUFA.

The newly published guidance also has a message to industry in the title – “…product development and quality considerations” (emphasis added).  Sustainable compliance with CGMP begins with a technically sound and fit for purpose development program and technology transfer hand-off from development to technical operations in an organization that has created a mature quality function that is aligned with both product development and technical operations.

As several of the Warning Letters for transdermal products point out, the FDA commonly encounters CGMP non-compliance with manufacturers whose product development program is inadequate – such as the issue of setting, reviewing and meeting appropriate product performance specifications. With that background in mind, here’s an overview of how FDA has organized the new draft guidance and highlights of the critical content.

Product Development Considerations

  • A description of the various types of transdermal products.
  • A reminder that transdermal products are classified as combination products and are subject to both drug CGMP regulations at 21 CFR §§ 210 & 211 as well as the medical device design control regulations at 21 § CFR 820.30.
  • Using ICH Q8(R2) as a template for developing a quality target product profile (QTPP) as a first step in product development.
  • Various critical quality attributes for transdermal products, such as drug substance crystal form and melting point and an emphasis on excipients such as adhesive polymers and membranes that have repeatedly been the focus of various quality issues FDA has confronted over the years.
  • A suggestion to minimize product complexity and reduce the number of potential failure modes.

Application Content Recommendations

  • Extensive recommendations for information provided in Section 3.2.P.2 of a new drug application. Notable items here include:
    • Batch formulae designed to tolerate variation in the solvent content of raw materials and the process conditions.
    • Data from primary stability batches manufactured from three distinct laminates, where each laminate is made using different lots of drug substance, adhesives, backing, and/or other critical elements in the product.
    • A battery of product characterization studies that include skin permeability, crystallization, thermodynamic stability of drug substance, strength, residual drug, in-vitro permeation testing, extractable and leachable testing, assessing the effects of heat, and microscopic matrix evaluation.


  • ​​​​​​​The description of the proposed in-process controls (IPC) in Section 3.2.P.3 should address the following:
    • At the mixing stage, IPCs can provide assurance of assay, viscosity, uniformity, and pH for aqueous mixtures.
    • IPCs for coating, drying, and lamination can provide assurance of uniformity across the laminate and throughout the run. Measurements for film appearance, coat weight, and/or a test for residual solvents may be applicable IPCs for coating and drying.
    • For films that are dispersions at the microscopic scale (e.g., acrylic adhesive dispersed in silicone, povidone dispersed in silicone, or solid drug substance dispersed in adhesive), applicants should describe the IPCs established to monitor uniformity throughout a coating run in the application.
    • In cases where the upstream controls can be used to confirm certain finished TDS specifications, such as residual solvents and residual adhesive impurities, IPC testing can be used in lieu of release testing for these attributes.
  • Section 3.2.P.5 of the application that would have information on control of the drug product, including the specification and an extensive list of the typical CQA included in the specification.
  • Discussion of analytical methods and criteria associated with typical CAQ for transdermal products such as adhesive impurities, uniformity of dosage units, permeation enhancer content, adhesion testing, cold flow, in-vitro drug release, crystal presence and pouch integrity.

This situation exemplifies the FDA at its zenith - using the combination of many its tools such as publications, participation in conferences and workshops, internal research that is made available to the public, compliance instruments such as Warning Letters and Form FDA 483 that can be requested through the Freedom of Information Act, and successive guidance on several specific topics affecting transdermal products. 

The FDA has clearly given industry prior notice of its policy position for these products and a profusion of recommendations to improve an applicant’s product development program and regulatory submissions.