Transdermal drug delivery systems (TDDS) are combination products classified as such due to their dual function as medical devices and pharmaceuticals. For example, medical device characteristics of a TDDS include adherence to the user for the duration of the wear time, control of adhesive flow from the perimeter of the system while in use (cold flow), and occlusion of the drug-containing system to prevent unintended exposure. Pharmaceutical characteristics of a TDDS include product potency and drug delivery rate, for example. To maintain the integrity of these complex combination systems, the developers of the system must explicitly define what attributes are critical to the quality (i.e., blend uniformity, patch dimensions, or patch delivery rate). It is the responsibility of the manufacturer to ensure then they can control their process appropriately to maintain these product critical quality attributes (CQA). A Quality by Design (QbD) approach to TDDS development ensures that the critical process parameters (CPP’s) of each process are optimized and controlled as they will have a direct impact on the TDDS CQA’s.
There are several types of TDDS, such as water-based vs. organic solvent-based, rate-controlled membranes vs. drug-in-adhesive matrix, and even active vs. passive delivery systems. The focus of this article will be on drug-in-adhesive, passive delivery, organic solvent-based TDDS.
There are three typical major unit operations for TDDS manufacturing: blending, coating, and packaging. While the blending and packaging process is important to the quality of the TDDS, the coating process is arguably the most critical unit operation as it is responsible for maintaining control of the majority of the CQA’s. The coating process establishes the thickness of the TDDS, which, in combination with the TDDS area, defines the potency of the finished product. It also establishes the residual volatiles(organic solvents, monomers, and functional excipients), which should be optimized for patient safety as well as device functionality characteristics. The coating process can be broken down into subsections that include coating, drying, lamination, and finished roll winding. Coating techniques of TDDS manufacturing normally consist of either slot die or comma knife-over-roll systems. Knife-over-roll systems make use of a physical gap between a stainless-steel knife and anvil roll to set the coating thickness, whereas slot dies to use a die head and pump system. Knife over roll systems provides ease of set-up and cleaning, while slot die systems typically provide superior thickness control and stop and start coating options for an individual lane or patch coating. Each technique is affected by the viscosity of the blend being utilized. A QbD approach is necessary for successful optimization and control of CQA’s affected by the CPP’s of the coating process.
Pharmaceutical characteristics of a TDDS include product potency and drug delivery rate
The coating process consists of depositing a specified uniform amount of blend onto a film. When a comma knife-over-roll coating technique is utilized, the gap between the knife and transfer roll is critical for the coating thickness, whereas with a slot die coating technique, the pump speed and die gap is critical. The drying process consists of continuously moving the coated film throughout a convection oven. This process traditionally relies on temperature, airflow, and residence time parameters to maintain consistent drying conditions. Optimization of any CPP (with respect to product CQAs) throughout the coating/drying process is best done using statistical design of experiment (DOE). Optimization of these parameters takes into account any interactions between the parameters themselves, which is particularly useful if the oven utilizes multiple drying zones. For example, it is common in these systems that temperature and airflow have a combined effect on solvent removal (drying).
A successful QbD approach allows the construction of a design space through modeling the relationships between the process CPPs and the product CQAs. These statistical models will allow for a better understanding of the operating ranges of the process. Once the operating ranges have been defined as a control strategy that ensures the inputs are maintained within their ranges, and the outputs are within their specifications is necessary. One method of controlling outputs is statistical process control (SPC). SPC is an ideal control state for the critical process parameters as out of trend alerts can be sent real-time to alert operators or process engineers of potential effects on CQA’s.
Prior to commercialization, a process validation must take place to statistically prove your control strategy is capable of maintaining the desired quality product. Throughout the life of the product, continued process verification (CPV) seeks to continually prove the process maintains the same level of control as proved in the process validation.
In conclusion, a QbD approach to the coating process is necessary to ensure TDDS CQA’s are well controlled, providing consistent performance to patients.