The raw material is acknowledged to be a source of variability, however, the conventional, empirical development approach does not offer much information regarding its critical attributes and how processes can be modulated to remain in the constant quality region of the product. The study aimed to develop extended release hydrophilic matrix tablets with indapamide based on the Quality by Design (QbD) concept, evaluating the impact of interchanging different types and suppliers of raw material on the finished product quality profile. Results showed significant in vitro release test variability, with 16 -71% failure rates when compared to four different EMA and FDA dissolution specification recommendations. Design of experiments based impact assessment concluded that the active pharmaceutical ingredient, hydroxypropyl methylcellulose and compression force was accountable for the variation, while orthogonal partial least squares (O2PLS) based root cause analysis extension redefined results in term of critical material attributes. Findings suggest that a risk-based, multivariate analysis assisted control strategy for the incoming raw materials could prevent quality concerns within routine manufacturing.
RezumatMateria primă este recunoscută a fi o sursă de variabilitate, totuși abordarea de dezvoltare empirică, convențională nu oferă multe informații cu privire la atributele critice și modul în care procesele pot fi modulate pentru a rămâne în regiunea de calitate constantă a produsului. Studiul propune dezvoltarea de comprimate cu indapamidă de tip matrice hidrofilă cu eliberare prelungită pe baza conceptului de calitate prin design (Quality by Design -QbD), cu evaluare concomitentă a impactulului materiilor prime asupra calității finale. Rezultatele au evidențiat o variabilitate semnificativă în cadrul testului de eliberare in vitro, cu rate de eșec între 16 -71% în comparație cu patru recomandări diferite privind specificațiile de dizolvare EMA și FDA. Evaluarea impactului pe baza metodei planurilor experimentale a concluzionat că substanța activă, hidroxipropil metilceluloza și forța de comprimare ar fi responsabile pentru variație, în timp ce identificarea cauzei prin metoda celor mai mici pătrate ortogonale (O2PLS) a redefinit rezultele în termenii atributelor critice ale materialelor. Concluziile sugerează că o strategie de control, bazată pe analiza multivariată, ar putea preveni problemele de calitate din cadrul unei producții de rutină.
Three-dimensional printing (3DP) by fused deposition modeling (FDM) has gained momentum as a promising pharmaceutical manufacturing method due to encouraging forward-looking perspectives in personalized medicine preparation. The current challenges the technology has for applicability in the fabrication of solid dosage forms include the limited range of suitable pharmaceutical grade thermoplastic materials. Hence, it is important to investigate the implications of variable properties of the polymeric carrier on the preparation steps and the final output, as versatile products could be obtained by using the same material. In this study, we highlighted the influence of polyvinyl alcohol (PVA) particle size on the residence time of the mixtures in the extruder during the drug-loaded filament preparation step and the consequent impact on drug release from the 3D printed dosage form. We enhanced filament printability by exploiting the plasticizing potential of the active pharmaceutical ingredient (API) and we explored a channeled tablet model as a design strategy for dissolution facilitating purposes. Our findings disclosed a new perspective regarding material considerations for the preparation of PVA-based solid dosage forms by coupling hot melt extrusion (HME) and FDM-3DP.
The three-dimensional printing (3DP) of the plastic materials is considered as a modern alternative to pharmaceutical manufacturing. Fused deposition modelling (FDM) is a versatile 3DP technique that enables the simple production of complex pharmaceutical dosage forms with personalization potential. This application can be exploited for therapeutic purposes; however, it is important to understand the material and technological considerations, the advantages and disadvantages of the technology in order to produce pharmaceutical products of the required quality.
RezumatImprimarea tridimensională a materialelor plastice este considerată o alternativă modernă pentru fabricația medicamentelor. Modelarea prin depunerea filamentului topit este o tehnică versatilă de imprimare tridimensională care permite fabricarea simplă a unor forme farmaceutice complexe cu potențial de personalizare ridicat. Această caracteristică poate fi exploatată î n diverse scopuri terapeutice, însă este importantă înțelegerea considerentelor materiale și tehnologice, a avantajelor și dezavantajelor, pentru a putea fabrica produse farmaceutice de calitate.
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