Hot-melt extrusion (HME) is a promising technology for the production of new chemical entities in the developmental pipeline and for improving products already on the market. In drug discovery and development, industry estimates that more than 50% of active pharmaceutical ingredients currently used belong to the biopharmaceutical classification system II (BCS class II), which are characterized as poorly water-soluble compounds and result in formulations with low bioavailability. Therefore, there is a critical need for the pharmaceutical industry to develop formulations that will enhance the solubility and ultimately the bioavailability of these compounds. HME technology also offers an opportunity to earn intellectual property, which is evident from an increasing number of patents and publications that have included it as a novel pharmaceutical formulation technology over the past decades. This review had a threefold objective. First, it sought to provide an overview of HME principles and present detailed engineered extrusion equipment designs. Second, it included a number of published reports on the application of HME techniques that covered the fields of solid dispersions, microencapsulation, taste masking, targeted drug delivery systems, sustained release, films, nanotechnology, floating drug delivery systems, implants, and continuous manufacturing using the wet granulation process. Lastly, this review discussed the importance of using the quality by design approach in drug development, evaluated the process analytical technology used in pharmaceutical HME monitoring and control, discussed techniques used in HME, and emphasized the potential for monitoring and controlling hot-melt technology.

/pdf/hot-melt-extrusion-from-theory-to-application-in-3lrysbwbms.pdf

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation

At the beginning of the twentieth century, Sir Ronald Fisher introduced the concept of applying statistical analysis during the planning stages of research rather than at the end of experimentation. When statistical thinking is applied from the design phase, it enables to build quality into the product, by adopting Deming's profound knowledge approach, comprising system thinking, variation understanding, theory of knowledge, and psychology. The pharmaceutical industry was late in adopting these paradigms, compared to other sectors. It heavily focused on blockbuster drugs, while formulation development was mainly performed by One Factor At a Time (OFAT) studies, rather than implementing Quality by Design (QbD) and modern engineering-based manufacturing methodologies. Among various mathematical modeling approaches, Design of Experiments (DoE) is extensively used for the implementation of QbD in both research and industrial settings. In QbD, product and process understanding is the key enabler of assuring quality in the final product. Knowledge is achieved by establishing models correlating the inputs with the outputs of the process. The mathematical relationships of the Critical Process Parameters (CPPs) and Material Attributes (CMAs) with the Critical Quality Attributes (CQAs) define the design space. Consequently, process understanding is well assured and rationally leads to a final product meeting the Quality Target Product Profile (QTPP). This review illustrates the principles of quality theory through the work of major contributors, the evolution of the QbD approach and the statistical toolset for its implementation. As such, DoE is presented in detail since it represents the first choice for rational pharmaceutical development.

Design of experiments (DoE) in pharmaceutical development.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jps.24594

The Future of Pharmaceutical Manufacturing Sciences.

Regulatory agencies have recently recommended a Quality by Design (QbD) approach for the manufacturing of therapeutic molecules. A QbD strategy requires deep understanding at the molecular level of the attributes that are crucial for safety and efficacy and for insuring that the desired quality of the purified protein drug product is met at the end of the manufacturing process. A mass spectrometry (MS)-based approach to simultaneously monitor the extensive array of product quality attributes (PQAs) present on therapeutic molecules has been developed. This multi-attribute method (MAM) uses a combination of high mass accuracy / high resolution MS data generated by Orbitrap technology and automated identification and relative quantification of PQAs with dedicated software (Pinpoint). The MAM has the potential to replace several conventional electrophoretic and chromatographic methods currently used in Quality Control to release therapeutic molecules. The MAM represents an optimized analytical solution to focus on the attributes of the therapeutic molecule essential for function and implement QbD principles across process development, manufacturing and drug disposition.

Development of a quantitative mass spectrometry multi-attribute method for characterization, quality control testing and disposition of biologics

Silica is one of the most abundant minerals in the Earth’s crust, and over time it has been introduced first into human life and later into engineering. Silica is present in the food chain and in the human body. As a biomaterial, silica is widely used in dentistry, orthopedics, and dermatology. Recently amorphous sol-gel SiO2 nanoparticles (NPs) have appeared as nanocarriers in a wide range of medical applications, namely in drug/gene target delivery and imaging diagnosis, where they stand out for their high biocompatibility, hydrophilicity, enormous flexibility for surface modification with a high payload capacity, and prolonged blood circulation time. The sol-gel process is an extremely versatile bottom-up methodology used in the synthesis of silica NPs, offering a great variety of chemical possibilities, such as high homogeneity and purity, along with full scale pH processing. By introducing organic functional groups or surfactants during the sol-gel process, ORMOSIL NPs or mesoporous NPs are produced. Colloidal route, biomimetic synthesis, solution route and template synthesis (the main sol-gel methods to produce monosized silica nanoparticles) are compared and discussed. This short review goes over some of the emerging approaches in the field of non-porous sol-gel silica NPs aiming at medical applications, centered on the syntheses processes used.

https://www.mdpi.com/1420-3049/23/8/2021/pdf

Sol-gel Silica Nanoparticles in Medicine: A Natural Choice. Design, Synthesis and Products.

Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT).

Strategic framework for education and training in Quality by Design (QbD) and process analytical technology (PAT).

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Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT).

Strategic framework for education and training in Quality by Design (QbD) and process analytical technology (PAT).