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In a draft guidance published this week, the US Food and Drug Administration recommended that makers of transdermal and transmucosal drug-delivery systems use "an appropriate scientific approach" during product design, development, and manufacturing to minimize the amount of residual drug substance present at the end of the products' labeled use periods.
In a draft guidance published this week, the US Food and Drug Administration recommended that makers of transdermal and transmucosal drug-delivery systems use “an appropriate scientific approach” during product design, development, and manufacturing to minimize the amount of residual drug substance present at the end of the products’ labeled use periods. The draft guidance acknowledged that, to achieve the correct release rate and systemic drug levels, these systems now must contain “a surplus of drug substance.” But because the residual drug can affect the products’ quality, safety, and efficacy, FDA recommended minimizing the excess amount of drug, consistent with current technology.
The draft guidance, titled Residual Drug in Transdermal and Related Drug Delivery Systems, defined transdermal and transmucosal delivery systems as products that deliver at least one active pharmaceutical ingredient across the skin or mucosa for systemic or local effect. The products can be simple or complex in design and include passive systems (e.g., drug in patch, film, and foam) and active systems (e.g., iontophoresis and sonophoresis).
Currently marketed transdermal and transmucosal delivery systems may retain 10–95% of their initial total amounts of drug after the intended use periods, and the residual drug could pose hazards for patients, caregivers, family members such as children, and pets, according to the draft guidance. Failure to remove a transdermal delivery system could prolong the pharmacological effect of the drug and lead to adverse events. In the draft guidance, FDA noted that children had died after inadvertent exposure to discarded transdermal delivery systems.
To reduce the risks that residual drug presents, the draft guidance recommended that companies use a quality by design (QbD) approach to developing and manufacturing transdermal and transmucosal delivery systems. The draft guidance defined QbD as a scientific, risk-based approach to process and product development that can lead to continual improvement. QbD “can aid in developing a product to deliver the optimum amount of drug across the skin while minimizing the amount of excess drug, thus resulting in the least possible amount of residual drug,” according to the draft guidance. A QbD approach is appropriate for developing new products and reformulating existing products, and it can foster understanding of the effects of factors such as raw-material variation and the manufacturing process on product quality.
The draft guidance suggested reducing the amount of residual drug by modifying a product’s formulation, design, or system components (e.g., by using permeation enhancers, self-depleting solvent systems, and appropriate adhesives). FDA asked companies to include in their regulatory applications scientific justification for the amount of residual drug in a transermal or transmucosal delivery system. The level of information in the application should demonstrate product and process understanding and reflect a risk-based approach to minimizing the amount of residual drug, according to the draft guidance. The document also noted that the amount of residual drug in a new delivery system should not exceed that in similar FDA-approved products.