Overcoming Development Challenges in Transdermal Patches: A QbD-Driven Approach
Transdermal drug development is a complex process involving multiple stages, including drug design, dosage form development, and clinical trials. This process presents numerous challenges and difficulties, the resolution of which requires interdisciplinary collaboration encompassing expertise in pharmaceutics, chemistry, biology, materials science, and clinical medicine. Meticulous drug design, excipient selection, process optimization, and clinical evaluation are key to overcoming these hurdles and developing safe and effective transdermal drug delivery systems.
Recently, at the China Pharmaceutical Full Industry Chain New Resources Conference held in Nanjing, the special session on Transdermal Technology R&D and Application Innovation Cooperation brought together numerous renowned industry experts to delve into the opportunities and challenges across the entire transdermal formulation industry chain. Dr. Li Feifei, founder of Beimei Pharmaceuticals, delivered a keynote speech titled “Common Defects in Transdermal Drug Delivery,” systematically outlining the current difficulties and shortcomings faced by transdermal drug delivery systems, thereby providing industry peers with more mature experience and effective countermeasures.
The journey of transdermal drug delivery systems from laboratory research to industrial-scale production is fraught with challenges, necessitating concerted efforts and sustained investment from both within and outside the industry. Over the past decade, although progress in transdermal formulations was slow, supply chain integration has been achieved for certain products. In recent years, heightened attention has spurred significant industry development, a scenario that was hardly imaginable just a few years ago.
In the development of transdermal drug delivery systems (TDDS), the selection of excipients and equipment is critical. In the past, pharmaceutical companies had to communicate with excipient manufacturers one by one to secure suitable materials, while equipment manufacturers primarily considered economic factors, such as purchase volume and excipient usage rates. These challenges made the industrialization of TDDS particularly difficult. However, with increased industry attention, acquiring the necessary resources has become less arduous. Nevertheless, many high-barrier excipients and equipment still require sustained effort and support from industry peers. The development of domestically produced excipients and equipment especially relies on widespread adoption and feedback to accelerate progress. Overall, the industrialization of transdermal drug delivery systems is a long-term process that demands patience, diligence, and industry collaboration.
Transdermal patches are categorized into locally acting patches and systemically acting patches. Hydrogel patches are predominantly used for local effects, whereas hot-melt adhesives and solvent-based adhesives can be formulated for either local or systemic drug delivery. Currently, transdermal drugs marketed in Europe and the United States are primarily designed for systemic delivery, while a greater number of locally acting transdermal patches are available in Japan and China.
In the past two to three years, transdermal formulations of chemical drugs in China have mainly been categorized into three types: cataplasm patches, locally acting patches, and systemically acting patches. Among these, domestic pharmaceutical companies have shown greater participation in the cataplasm patch segment. Loxoprofen and lidocaine have emerged as the two most popular products due to their excellent efficacy in pain management, with approximately 46 domestic manufacturers currently having filed applications or obtained market approval.
Currently, more than 20 pharmaceutical companies have filed applications or obtained approval for the marketing of systemically acting transdermal patches, including some products launched in previous years as well as originator drugs. However, due to limitations and barriers associated with excipients such as acrylic and silicone pressure-sensitive adhesives, the research and development progress of this drug class has been relatively slow, with manufacturers primarily focusing on categories such as granisetron and lisdeksamfetamine.
Currently, there are few manufacturers filing for market approval of locally acting patches. Compared with hydrogel patches, hot-melt adhesive patches have a less diverse range of excipients. In contrast to solvent-based adhesives, their production process is relatively complex, resulting in fewer current regulatory submissions, which are mainly concentrated on three active ingredients: flurbiprofen, loxoprofen, and eflufenamole.
Currently, the industry is focusing more on the excipient issues associated with hot-melt adhesives and solvent-based adhesives. Once the excipient challenges of solvent-based adhesives are resolved, their manufacturing formulation and process are relatively straightforward. However, hot-melt adhesives require additional consideration of equipment, and their production process is more complex, presenting difficulties in areas such as cleaning, production stability, formulation processing, and excipient screening.
In fact, there is substantial room for improvement in transdermal patches. Solvent-based adhesives can cover a wide range of indications, but the primary obstacle lies in excipients. For solvent-based adhesives, excipients exhibit high specificity and can determine the characteristics of the formulation. Therefore, excipients are indispensable for the development of systemic transdermal drug delivery. This has been a key focus for the transdermal formulation industry in recent years, with an emphasis on advancing the development and research of excipients.
Since the launch of the first transdermal patch in 1979, the number of recalls involving transdermal patches and similar dosage forms has been steadily increasing. The majority of these recalls are attributed to product quality issues, such as drug crystallization, reservoir leakage, and poor adhesion. These recall incidents have provided valuable insights and lessons for the development of the transdermal drug delivery industry.
Currently, there are relatively few reservoir-type drug products in China; greater attention should be paid to issues related to drug crystallization, adhesiveness, and irritation.
Dr. Li emphasized that particular attention to crystallization issues in solvent-based adhesives is critical, as even a 1% degree of crystallization can reduce transdermal drug delivery by 20–30%. The presence of crystallization compromises the drug’s steady state. Therefore, every aspect must be carefully considered during the initial phases of drug stability studies. Additionally, local irritation should be monitored. The FDA previously recalled the Zecuity patch for migraine treatment due to issues related to its specific iontophoresis mechanism. Consequently, pharmaceutical companies must conduct sensitization testing during clinical trials.
In the United States, allergenicity testing for transdermal patches requires a 200-subject, two-cycle clinical trial. In China, however, allergenicity testing is considered a secondary endpoint, with primary emphasis placed on irritation studies. As the route of administration for transdermal patches, the skin provides a natural barrier; leveraging this characteristic enables stable and sustained drug release. The drug release profile of transdermal patches is controlled and extended-release, which is particularly important for long-term administration. Therefore, for transdermal patches intended for long-term use, evaluating their irritancy and allergenicity is critical.
Issues with transdermal patches in terms of crystallization, adhesion, and irritation are closely related to numerous aspects of the research and development process.
First, regarding the characteristics of active pharmaceutical ingredients (APIs), the characterization and control of key excipients are critical to the safety, efficacy, and quality controllability of pharmaceutical formulations. Topical formulations frequently utilize polymeric excipients. Although most of these are inert, monomers, adhesives, and other agents are used during the polymerization process. In this context, residual small molecules and changes in molecular weight can affect both the irritancy and transdermal properties of patches. Therefore, such high-performance products must be developed based on pharmaceutical principles, with safety and non-irritancy as primary objectives. The molecular weight distribution of excipients also warrants attention. A major issue with many polymeric excipients is their excessively broad molecular weight distribution, which can significantly impact the formulation when it fails to meet uniformity requirements.
From a manufacturing process perspective, achieving uniform drug mixing presents a significant challenge for equipment. Taking hydrogel patches as an example, there is a time limit for the storage of intermediates; the longer the mixing time, the less window remains for coating, thereby limiting batch sizes. Therefore, factors such as the flowability designed during initial drug development and stability during production must be taken into account. For transdermal patches, priority is given to ensuring therapeutic efficacy and skin comfort for users, which imposes higher requirements on equipment regarding mixing sequence and processing techniques.
For sampling and testing, the sampling process for semi-solid preparations is relatively complex due to their high viscosity, which makes them less easy to withdraw than liquids. Despite the challenges, sampling is necessary, and testing is best performed after sampling. The use of mirror infrared technology can improve testing efficiency and reduce the workload of quality control (QC). The post-sampling inspection process is similar to routine inspections and may include viscosity testing, with specific procedures depending on actual conditions.
For coating and drying processes, the coating methods vary depending on the formulation. The drying process of solvent-based adhesives involves solvent evaporation, and it is essential to consider how the drying method affects the morphology of the formulation and its transdermal absorption efficacy. The drying process can significantly influence formulation parameters, similar to the dissolution effect observed in formulations.
In terms of quality standards, transdermal drug delivery systems have some critical quality attributes (CQAs) that are often overlooked, such as crystallization, freezing, and adhesion. During the early-stage design of process formulations, the definition of CQAs is primarily based on changes in crystallization, adhesion, and morphological stability. This requires greater effort to consider how to conduct more experimental designs and simultaneous evaluations.
Whether for innovative drugs or improved new drugs, pharmaceutical companies should strive to achieve the desired drug characteristics from the outset, with stability being a critical factor. Dr. Li urges researchers to prioritize stability considerations during the early stages of drug development. Since stability studies are highly time-consuming, greater attention must be paid during the initial design phase. Furthermore, the product’s shelf life should be calculated from the time the adhesive is mixed with the drug, and the product description must be included on the backing membrane in stability studies.
In formulation development, a Quality by Design (QbD) approach should be adopted, with the design tailored to the clinical indications and therapeutic area.
The selection of topical formulations should be based on clinical needs and therapeutic goals. For instance, transdermal patches may be more suitable than semi-solid formulations for drugs requiring precise dose control. In pharmaceutical design, in addition to considering drug efficacy, emphasis should also be placed on the patient experience. As patients exhibit strong preferences in selecting topical medications, their acceptance and satisfaction with the product are crucial.
In quality control during the manufacturing process, particular attention must be paid to product quality controllability and the capability for continuous production. Simplifying formulation processes helps reduce development and manufacturing costs while ensuring product quality. Furthermore, real-time monitoring is critical to ensuring product quality during the mixing and synchronization stages of formulation. The use of online monitoring technologies, such as infrared or Raman spectroscopy, can enhance both production efficiency and product quality. Meanwhile, close attention should be given to changes in characteristic parameters of the formulation during storage, especially for dosage forms such as hydrogel patches, as these changes may significantly affect product quality and efficacy.
As a complex formulation, transdermal preparations are still in the early stages of development both domestically and internationally. In China, the field of transdermal preparations is currently at the stage of learning and generic imitation, with many technologies and equipment needing to be imported from abroad. This necessitates recognizing the numerous drawbacks inherent in the development of transdermal preparations, learning from these shortcomings to avoid repeating the same mistakes, and thereby enabling continuous improvement in technology and products.
Although there are currently few transdermal products available for generic replication, improvement and innovation remain key directions for the future development of transdermal formulations. These formulations hold significant potential for expansion across multiple indications, thereby creating opportunities for product enhancement. Nevertheless, it is imperative to remember that the industry must adhere to the principles of safety, efficacy, and quality control in the development of transdermal formulations, returning to the fundamental mission of pharmaceutical manufacturing.