The Quality by Design (QbD) concept applied to medicated plaster (patch) development gives us the certainty to obtain safe and reliable products with verifiable efficacy long before they enter the commercial production stage. It is not a bureaucratic requirement added at the end of development — it is the structure that defines how quality is designed in from the start.
From GMP to QbD: A Necessary Evolution
When medicated plaster development is considered, attention usually focuses on the clinical or pharmacological advantages of this pharmaceutical form: sustained release of the drug substance for several days, support for patient compliance in prolonged treatments, or the ability to avoid the first-pass hepatic metabolism effect suffered by orally administered drugs. But we could ask ourselves: what place do we assign to quality in the development of these products?
The concept of quality management in pharmaceutical production emerged in the 1980s, with the first publications of Good Manufacturing Practice (GMP) guidance, first in the United States and later in Europe. The objective in this first stage was to ensure that products were manufactured in such a way that they met the specifications and requirements for their intended use — known today as the Quality Target Product Profile (QTPP) — using manufacturing step monitoring and manufactured product attribute analysis as tools.
In the 1990s, the International Conference on Harmonization (ICH) was established to define common rules among the good manufacturing practices developed by different countries. This institution published the ICH Guidelines, addressing different aspects of quality management. Three of these guides — ICH Q8, Q9 and Q10 — refer to good practices for new product development, generating the term Quality by Design.
The concept of designing with quality refers to the fact that it is no longer sufficient to control the manufacture of products to avoid errors that harm the product or patient safety. It becomes necessary that development focuses on reducing the possibility of such errors emerging, by studying and defining the attributes of the materials used and the manufacturing parameters as starting points, and using risk analysis as a fundamental tool.
At the beginning of the 2000s, this development strategy began to be considered and required by regulatory agencies for the registration of new products, with the U.S. Food and Drug Administration (FDA) as a pioneer.
QbD Framework Elements Applied to TDS
The following table summarizes the central components of the QbD framework and their specific application to transdermal system development:
QbD Element | Definition | TDS Application |
|---|---|---|
QTPP(Quality Target Product Profile) | Set of quality characteristics the final product must meet to ensure efficacy and safety. | Dose per patch area, API release rate, wear period (24h / 72h / 7 days), target ICH climatic zone, required adhesive properties. |
CQAs(Critical Quality Attributes) | Product properties or characteristics whose variation has a direct impact on quality, efficacy, or safety. | API content, dose uniformity, crystallization in matrix, adhesive properties (peel, tack, cold flow), in vitro release (IVRT). |
CMAs(Critical Material Attributes) | Physical or chemical attributes of raw materials that significantly impact the product’s CQAs. | Viscosity and Tg of the adhesive polymer, API particle size, permeation enhancer purity, API-excipient compatibility. |
CPPs(Critical Process Parameters) | Process parameters whose variation affects the CQAs and therefore must be controlled or monitored. | Mixing speed and coating temperature, lamination speed, drying conditions (temperature / time / relative humidity), lamination pressure. |
Design Space | Multidimensional combination of CMAs and CPPs that ensures the product meets the QTPP. Variations within the design space do not require additional regulatory approval. | Definition of the acceptable range of process variables and material attributes that ensure CQAs within specification. |
Control Strategy | Planned set of controls (specifications, analytical methods, in-process controls) to ensure product consistency. | Raw material specifications, in-process controls (IPC), release testing, stability monitoring, process validation. |
Attributes, Parameters and Risk Analysis: How the Design Space Is Built
The Role of Material Attributes
An experienced pharmaceutical developer can define a set of raw materials that could be used in the development of a new product, based on previous experience and market availability. These materials consist of a drug substance, responsible for the therapeutic action, and a set of excipients that accompany it in the formula.
Both drug substance and excipients have physical and chemical characteristics that we call attributes. Those attributes that produce a significant impact on the product properties must be identified and studied to define an acceptable value or range of variation — what we call a specification. Once the specification is defined, only raw materials that comply with it may be used in manufacturing, mitigating the risk of a negative impact on product properties or on the manufacturing process.
The Role of Process Parameters
The same concept is applied to manufacturing process development. The speed, time, temperature, or any other variable that can be modified during the process are called parameters. As with attributes, parameters that can have a significant impact on product properties are identified and studied to define an acceptable value or range of variation, thus reducing the risk of a negative impact on the final product properties.
Risk Analysis as a Design Tool
Risk analyses are normally carried out by experts in the different development aspects, who seek to identify and evaluate the factors that could have a negative effect on the product — both in its composition and in the processes to which it is subjected during manufacturing. Once identified and evaluated, actions can be taken to control, mitigate, or eliminate them.
With the definition of process parameters and raw material attributes, we can generate what we call a design space: a safe variation margin that guarantees the product meets the requirements for which it was designed, providing quality and safety to the patient.
QbD in Transdermal Patch Development: Why It Matters More Here
Transdermal patches are one of the pharmaceutical forms where the QbD framework has the greatest practical impact. The reason is system complexity: the product must not only contain the correct dose of the active ingredient, but guarantee its release through the skin at a controlled rate throughout the entire use period — 24 hours, 72 hours, or up to 7 days depending on the product.
This means that the interactions between the active ingredient, the adhesive system, the backing, the release liner, and the patient’s skin must be fully understood and controlled. A QbD approach applied from the beginning of development allows identification of which variables are truly critical and which have acceptable variation ranges without compromising product performance.
Currently, this development concept has become a working standard for the global pharmaceutical industry and is applied by the most recognized pharmaceutical companies. Developing medicinal patches under this concept guarantees the ability to provide patients with safe and reliable products with verifiable efficacy throughout their useful life.
References
ICH Q8(R2). Pharmaceutical Development. August 2009. https://database.ich.org/sites/default/files/Q8%28R2%29%20Guideline.pdf
ICH Q9. Quality Risk Management. November 2005. https://database.ich.org/sites/default/files/Q9%20Guideline.pdf
ICH Q10. Pharmaceutical Quality System. April 2008. https://database.ich.org/sites/default/files/Q10%20Guideline.pdf
FDA. Pharmaceutical Quality for the 21st Century: A Risk-Based Approach. https://www.fda.gov/about-fda/reports/pharmaceutical-quality-21st-century-risk-based-approach-progress-report