Additional QTPP elements may exist depending on the indication, or other functional requirements, such as the size of the finished product, which may depend on the location on the body that the TDS product is to be applied.

Critical Quality Attributes

Early in product development, applicants should establish a list of critical quality attributes (CQAs). Using the QTPP as a guide, applicants should outline the CQAs that define the physical, chemical, biological or microbiological properties or characteristics that should be within an appropriate limit, range or distribution to ensure the desired product quality. This list of CQAs will likely evolve over the product development lifecycle, as additional information is obtained.

The FDA guidance summarizes typical CQAs for the drug substance, drug product and excipients for TDS. Notable for TDS are the qualification of adhesives; the guidance outlines parameters for evaluation of adhesive polymers as raw materials, adhesive as a laminate (in the absence of the Active Pharmaceutical Ingredient [API] and other excipients), and adhesive in the final product (along with drug substance and other excipients and components).

Another important attribute of the TDS is the identifying information printed on the product itself. This should be established early in development to ensure that the labeling process or inks used for printing do not interact with the TDS, and to assess inks in extractable/leachable studies. Applicants should be aware that products that are clear or colored to match human skin tone can make it difficult to find the TDS on the patient; this can lead to potential medication errors (for example, if the product becomes unknowingly detached or through the application of multiple products). Therefore, it is recommended that the backing membrane is printed with ink of adequate contrast for easy identification.

Information to be Submitted in an Application

The new guidance outlines the quality information to submit in a marketing application for a TDS product. The guidance describes information to include in the pharmaceutical development portion of the application, including expectations for registration and exhibit batches. For TDS, registration/exhibit batches should be manufactured from three distinct laminates, each made using different lots of API, adhesives, backing and/or other critical elements of the product. Release and stability sampling should be representative of the full length and width of the laminates to demonstrate robust manufacturing. Since TDS products are sensitive to small differences in the manufacturing process, a table comparing the clinical, BE, registration/exhibit and proposed commercial batches should be included in the application.  For each batch, the table should specify the manufacturing process used, results of critical in-process tests, yield and reconciliation data.

The guidance also describes the product characterization studies, manufacturing information and control evaluations to be completed for TDS products when preparing a marketing application. This includes evaluations of crystallization potential of the formulation, residual drug assessment, the effects of heat on drug delivery and adhesion testing. Both in vitro and in vivo adhesion testing should be performed, with in vivo assessments representative of real-world use.

Conclusions and Recommendations

The development of TDS is important, as there are many patients that benefit from these products. The new draft guidance provides a much-needed perspective on the FDA’s expectations for the development of these products, and how applicants should develop and properly characterize these products for a marketing application. In addition to the information provided in the new guidance, meeting with the FDA early in the development program is recommended and will help clarify the nonclinical, clinical, quality and regulatory requirements specific to a given program.

Is your company considering developing a TDS product? The experts at Regulatory Professionals (RPI), A Division of Premier Research, have assisted in the development of TDS products through all stages and can provide guidance and expertise for your program. For more information, contact us.