A comprehensive systematic review published in AAPS Open in August 2026 provides a detailed synthesis of how Quality by Design (QbD) principles are applied to the development of topical semisolid formulations. The study, authored by Yesuneh Tefera Mekasha, Melaku Getahun Feleke, and Yousuf Mohammed, critically evaluates the integration of Critical Quality Attributes (CQAs), Design of Experiments (DoE), and control strategies in creams, ointments, and gels. By analyzing 85 primary research articles, the review highlights how these scientific frameworks move pharmaceutical development away from traditional trial-and-error methods toward a more rigorous, risk-based approach that enhances product robustness and regulatory compliance.
The research team conducted the systematic search in PubMed and Google Scholar between June and August 2025, following the PRISMA 2020 guidelines to ensure transparency and reproducibility. From an initial pool of 5,692 records identified through Boolean queries, the authors screened titles and abstracts to remove 2,546 irrelevant entries. After a full-text review of 3,146 articles, 85 studies met the strict eligibility criteria for inclusion in the final qualitative synthesis. These included studies that provided detailed descriptions of QbD elements, specifically focusing on the identification of CQAs, the application of DoE methodologies, and the implementation of control strategies for topical semisolids.
Topical semisolid formulations present unique challenges in generic drug development due to their complex microstructures and local site of action. Unlike oral medicines, therapeutic equivalence for these products cannot be established solely through systemic bioavailability studies. Regulatory agencies such as the FDA and EMA require the demonstration of pharmaceutical equivalence, which includes Q1 (same ingredients) and Q2 (same concentrations). Additionally, microstructural equivalence (Q3) and performance equivalence (Q4) are critical for ensuring therapeutic interchangeability, as minor variations in excipients or processing can alter the arrangement of matter and drug release profiles.
The review categorized the 85 included studies into three primary thematic groups based on their methodological focus. Forty-six studies employed factorial or DoE methodologies to optimize formulation and process parameters. Twenty-six studies investigated bioequivalence and in vitro release or permeation, while twelve involved clinical or pharmacokinetic assessments in animal or human subjects. This distribution underscores the growing emphasis on statistical optimization in topical development, with DoE serving as a cornerstone for understanding the influence of Quality Target Product Profile (QTPP) components on final product quality.
Design of Experiments is identified as a central tool in the QbD framework for topical formulations. The review notes that DoE allows for the systematic exploration of multiple variables and their interactions, enabling efficient screening and robust optimization of formulation and process parameters. Commonly employed techniques include factorial designs, central composite designs, and mixture designs. These approaches help formulators define a design space that ensures reliable manufacturing and scalability. By optimizing parameters such as temperature, homogenization speed, and emulsifier concentration, researchers can significantly reduce the time and resources required to develop a robust formulation that achieves desired physicochemical characteristics.
Critical Quality Attributes such as viscosity, particle size, stability, and drug release are identified as key factors influencing the performance of topical semisolids. The review highlights that the identification of these CQAs is a critical step in QbD implementation, as they form the basis for establishing formulation design and process development strategies. For instance, particle size distribution of the active pharmaceutical ingredient directly affects drug bioavailability, with larger and irregularly shaped crystals linked to reduced skin permeation. Similarly, rheological behavior and physical stability are profoundly influenced by the choice of dosage form and excipient composition, necessitating tailored approaches for different therapeutic targets.
Control strategies represent the final tangible output of a QbD-based development program, ensuring that CQAs remain within acceptable ranges throughout the product lifecycle. The review emphasizes that a control strategy is not merely a list of tests but a holistic, scientifically justified system that manages sources of variability. It integrates risk management and analytical QbD principles to provide assurance of consistent quality. However, the evidence indicates that these strategies remain underutilized in topical semisolids, with persistent gaps in harmonized regulatory standards and the application of advanced tools like Process Analytical Technology (PAT).
Despite the benefits of QbD, the review identifies significant challenges in its application. Microstructural equivalence (Q3) remains a bottleneck due to the lack of standardized measurement techniques and acceptance criteria for complex microstructures. Performance equivalence (Q4) also presents difficulties, as in vitro release and permeation tests are not always predictive of in vivo performance. Furthermore, the absence of a universal regulatory standard for the bioequivalence assessment of topical products complicates global development and approval processes, with differences in requirements across regulatory authorities like the FDA and EMA.
The study also notes that scalability and reproducibility are major concerns in industrial manufacturing. Minor variations in process parameters such as temperature and mixing time can significantly affect product quality, and scaling up from laboratory to industry scale often introduces variability that is difficult to control. The substantial upfront costs of software, specialized equipment, and trained personnel further limit the widespread implementation of QbD, particularly among small-to-medium-sized enterprises and generic manufacturers. Many organizations incur these costs without realizing the full regulatory flexibility due to a lack of harmonized global standards.
Future directions for the field should emphasize the integration of advanced tools such as Process Analytical Technology (PAT) and patient-centric quality attributes to strengthen clinical relevance. The review suggests that linking patient-centric factors, such as sensory perception and adherence, to CQAs is essential for capturing the full clinical performance of topical products. Additionally, the integration of artificial intelligence and machine learning could enable real-time control and predictive modeling, addressing the current limitations in translating in vitro surrogates to in vivo clinical outcomes.
The authors acknowledge several limitations in their review, including the restriction to English-language publications and the reliance on publicly accessible databases, which may have excluded proprietary or industry-held data. Many included studies also exhibited methodological constraints, such as limited stability data and the absence of clinical validation. These factors collectively limit the depth and generalizability of the review’s conclusions concerning long-term product performance and large-scale applicability.
Overall, the systematic review demonstrates that QbD principles significantly improve the development of topical semisolid formulations by ensuring systematic control of formulation and process variability. While the framework enhances product quality, consistency, and regulatory alignment, persistent challenges in microstructural and performance equivalence, scalability, and regulatory harmonization must be addressed. By providing a clear roadmap for improving development efficiency, the review serves as a strategic reference for researchers, formulators, and regulators aiming to advance the commercialization of robust and therapeutically equivalent topical dosage forms.
The review synthesizes findings from publications spanning 1993 to 2025, offering a historical perspective on the evolution of QbD in topical pharmaceuticals. The included studies covered a diverse array of dosage forms, including gels, creams, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, emulgels, liposomes, and nanosponges. This breadth highlights the versatility of QbD principles across different semisolid systems. The authors note that the complexity of these systems, characterized by strong interactions between excipients, processing conditions, rheology, and drug release behavior, makes statistical optimization particularly valuable. By systematically exploring these multivariable relationships, researchers can better understand how specific formulation components influence final product performance, moving beyond empirical guesswork to a data-driven development process.
Specific examples from the included literature illustrate the practical application of these principles. One study applied a QbD framework to develop topical creams using hot-melt extrusion, identifying CQAs and linking them to critical process parameters. The researchers found that higher processing temperatures in specific zones enhanced cream adhesion by improving oil phase mixing, while all formulations exhibited desirable shear-thinning behavior. Drug release and permeation followed the Higuchi diffusion model and were largely unaffected by variations in process parameters, suggesting that formulation composition played a more dominant role in bioperformance than process conditions in that specific context. This finding underscores the importance of identifying which variables truly drive product quality, as not all CQAs are equally influenced by process changes, which can complicate risk assessment and design space justification.
Another area of focus was the optimization of papain- and bromelain-based topical gels, where the concentrations of chitosan and sodium carboxymethyl cellulose were critical for achieving desired CQAs such as viscosity, spreadability, and bioadhesive strength. The optimized formulation demonstrated superior wound-healing activity in rat excision and incision models compared to control and standard treatments. However, the authors noted limitations in this study, including the lack of long-term stability data beyond three months and the absence of clinical validation in higher animal models or humans. These gaps highlight the ongoing challenge of translating preclinical efficacy into clinically relevant outcomes, a hurdle that QbD aims to address through more rigorous early-stage optimization and control strategies.
The review also examined the role of excipient selection in dermal delivery, using acyclovir as a case study. An optimized aqueous gel formulation containing Transcutol® as a penetration enhancer demonstrated superior dermal penetration compared to a reference cream, despite having a lower drug load. This suggests that the choice of excipients can significantly impact drug solubility and skin permeability. However, a key bottleneck remained in translating in vitro permeation test results to in vivo performance, as the in vitro tests failed to predict the superior in vivo behavior of the test formulation. This discrepancy emphasizes the limitations of current surrogate models and the need for more predictive tools that can accurately bridge the gap between laboratory measurements and clinical efficacy.
Control strategies were further explored through the lens of analytical QbD, where multimodal techniques such as laser diffraction, automated microscopy, and MDRS were used for robust particle characterization. While these methods provide detailed insights into product attributes, discrepancies between different analytical techniques and the absence of harmonized guidance complicate regulatory acceptance. The review notes that while QbD and advanced analytical frameworks have strengthened the scientific foundation of topical drug development, the practical implementation of these strategies is often hindered by scalability issues and the lack of standardized methods for assessing microstructural equivalence. Addressing these technical and regulatory barriers is essential for realizing the full potential of QbD in ensuring consistent, high-quality topical products for patients.
Subject of Research: Application of quality by design principles in topical semisolid formulations development: a systematic review of CQA, DoE, and control strategies
Article Title: Application of quality by design principles in topical semisolid formulations development: a systematic review of CQA, DoE, and control strategies
Article References: Mekasha, Y. T., Feleke, M. G., & Mohammed, Y. (2026). Application of quality by design principles in topical semisolid formulations development: a systematic review of CQA, DoE, and control strategies. AAPS Open, 12(1), Article 39. https://doi.org/10.1186/s41120-026-00174-2
Image Credits: AI Generated
DOI: 10.1186/s41120-026-00174-2
Keywords: Application, quality, design, principles, topical, semisolid, formulations, development, systematic, review, control, strategies
News Source: Ophelia Keating. (November 13, 2026). Systematic Review Maps QbD Gaps in Topical Formulations. Scienmag.
