Quality Assessment of API in Semisolid Topical Drug Products

Ke, Wu; Yeoh, Thean; Hsieh, Yi‐Ling; Osborne, David W.

doi:10.1007/978-3-030-17355-5_4

Cited by 5 publications

(6 citation statements)

References 112 publications

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“…The QTPP and the CQAs of the LOR-L-G were identified based on the literature research on topical semisolid nanoformulations. The QTPP for nanosized topical formulations mainly includes dosage form, route of administration, physical form, drug release, therapeutic indication, site of activity and biological effects [17,[21][22][23]. Table I contains the QTPP related to LOR-L-G. [4,15,17,19,24].…”

Section: Methodsmentioning

confidence: 99%

DEVELOPMENT AND CHARACTERIZATION OF LORATADINE LIPOSOMAL GEL USING QbD APPROACH

TOMA¹

2022

FARMACIA

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This study aimed to formulate, prepare and characterize a loratadine liposomal gel (LOR-L-G) using the Quality by Design (QbD) approach. The formulation variables and process parameters that influence the Critical Quality Attributes (CQAs) were identified using risk assessment. Five dependent variables were considered relevant for this study: particle size before and after extrusion, polydispersity index (PDI) before extrusion, loratadine (LOR) concentration and encapsulation efficiency (EE). A two-level full factorial design was performed in order to develop loratadine-loaded liposomes (LOR-L) with the desired Quality Target Product Profile (QTPP). Based on the results, the design space was generated and the optimum formulation was prepared. The in vitro drug release study aimed at measuring drug availability and revealed a prolonged release profile of LOR with a maximum concentration at 48 hours. LOR-L were incorporated into a Carbopol 940 gel base in order to obtain the final pharmaceutical product. The liposomal gel was characterized by viscosity, texture, spreadability and it was compared with a commercial product. The results indicated the applicability of the QbD approach in the development of LOR-L, and the obtained gel characteristics were suitable for a product useful in skin allergies. RezumatObiectivele studiului au fost formularea, prepararea și caracterizarea unui gel lipozomal cu loratadină (G-L-LOR) utilizând conceptul de calitate prin design (QbD). S-au identificat variabilele de formulare și parametrii de proces responsabili de afectarea atributelor critice de calitate ale lipozomilor cu loratadină (L-LOR) prin efectuarea analizei de risc. Au fost luate în considerare 5 variabile dependente, anume mărimea particulelor înainte și după extrudare, indicele de polidispersie (PDI) înainte de extrudare, concentrația de loratadină (LOR) și eficiența încorporării (EE). S-a folosit un plan experimental cu două niveluri pentru dezvoltarea L-LOR care să dețină caracteristicile de calitate dorite. Pe baza rezultatelor obținute s-a determinat domeniul optim și a fost preparată formularea optimă. S-a efectuat studiul de cedare in vitro, care a demonstrat o cedare prelungită a LOR din formulările lipozomale, cu o concentrație maximă la 48 ore. În vederea obținerii produsului farmaceutic final, lipozomii au fost încorporați într-o bază de gel de Carbopol 940. Gelul lipozomal a fost caracterizat din punct de vedere al vâscozității, texturii, capacității de întindere și a fost comparat cu un gel existent pe piață. Rezultatele au demonstrat aplicabilitatea conceptului de calitate prin design în dezvoltarea L-LOR, iar caracteristicile gelului obținut au fost potrivite pentru aplicarea acestuia în alergiile cutanate.

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Section: Methodsmentioning

confidence: 99%

DEVELOPMENT AND CHARACTERIZATION OF LORATADINE LIPOSOMAL GEL USING QbD APPROACH

TOMA¹

2022

FARMACIA

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“…However, it should be noted that the reliable characterization of microstructure has sparked numerous discussions among different stakeholders (academia, industry and several regulatory agencies) during the last few years. Among other, they imposed the following two questions: (i) which quality attributes are truly critical to the therapeutic performance of topical semisolid dosage forms, as well as (ii) what are the appropriate methodologies for measuring each of these quality attributes without disturbing the original product microstructure [ 3 , 4 ]. Currently, both European and American regulatory authorities do not provide recommendations for the methods that should be utilized for measuring the mentioned CQAs.…”

Section: Demonstration Of Extended Pharmaceutical Equivalence Of Topical Semisolid Drug Productsmentioning

confidence: 99%

“…Many failure modes of generic semisolid drug products arise from the differences in the physical and structural properties of the drug compared to the reference product. Generally, the variations in drug particle size, morphology and polymorphic form may affect both bulk qualities (such as rheology, density, content uniformity, and other physical properties) and product performance (such as drug release and efficacy of drug delivery to the target site) [ 3 ]. Indeed, recently, it was observed that the size of drug particles was one of the main factors determining acyclovir release from cream formulations [ 33 ].…”

Section: Demonstration Of Extended Pharmaceutical Equivalence Of Topical Semisolid Drug Productsmentioning

confidence: 99%

“…Namely, the pharmaceutical industry is to invest significant resources to demonstrate the quality, efficacy, and safety of any product before the authorities grant its market authorization [ 2 ]. Semisolid formulations, such as ointments, creams, and gels, due to an extremely complex microstructure (i.e., the microscale arrangement of matter and state of aggregation), are accompanied by more complicated, interdependent relationships among the structure, properties, manufacturing process, and performance as compared to solid and injectable dosage forms, that increase the potential for variability and number of failure modes [ 3 , 4 ]. Furthermore, topical drug products face unique obstacles to the development of generics compared to other drug products for which the assessment of bioequivalence is amenable to traditional pharmacokinetic methods [ 1 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

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The Implications of Regulatory Framework for Topical Semisolid Drug Products: From Critical Quality and Performance Attributes towards Establishing Bioequivalence

2021

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Due to complex interdependent relationships affecting their microstructure, topical semisolid drug formulations face unique obstacles to the development of generics compared to other drug products. Traditionally, establishing bioequivalence is based on comparative clinical trials, which are expensive and often associated with high degrees of variability and low sensitivity in detecting formulation differences. To address this issue, leading regulatory agencies have aimed to advance guidelines relevant to topical generics, ultimately accepting different non-clinical, in vitro/in vivo surrogate methods for topical bioequivalence assessment. Unfortunately, according to both industry and academia stakeholders, these efforts are far from flawless, and often upsurge the potential for result variability and a number of other failure modes. This paper offers a comprehensive review of the literature focused on amending regulatory positions concerning the demonstration of (i) extended pharmaceutical equivalence and (ii) equivalence with respect to the efficacy of topical semisolids. The proposed corrective measures are disclosed and critically discussed, as they span from mere demands to widen the acceptance range (e.g., from ±10% to ±20%/±25% for rheology and in vitro release parameters highly prone to batch-to-batch variability) or reassess the optimal number of samples required to reach the desired statistical power, but also rely on specific data modeling or novel statistical approaches.

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“…The control strategy for a drug substance is composed of a combination of procedural, parametric, and attribute controls (e.g., starting material/intermediate and drug substance specifications and in-process tests). The specification of a drug substance is partly defined by impurity levels, which is impacted by the design of the required purification, crystallization, and isolation processes. − The levels of impurities that are known/suspected to be toxic or whose identity are not yet confirmed (e.g., observed by high-performance liquid chromatography (HPLC) without confirmation of the molecular structure) are generally the most important due to their potential impact on patient safety. , Unacceptable impurity levels in a product may lead to its recall . Impurity levels are often core QTPP components and can be critical quality attributes (CQAs) of a product …”

Section: Introductionmentioning

confidence: 99%

Mathematical Modeling and Optimization to Inform Impurity Control in an Industrial Active Pharmaceutical Ingredient Manufacturing Process

Diab

Christodoulou

Taylor

et al. 2022

Org. Process Res. Dev.

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Mathematical modeling of pharmaceutical manufacturing processes can provide insights and understanding regarding the key factors impacting product quality. In this study, we describe the development of a dynamic model for a stage in an active pharmaceutical ingredient (API) manufacturing process, its calibration and validation versus industrial experimental data, and its use to address three objectives: (1) assessment of process operating parameter criticality on key performance indicators (KPIs); (2) confirming whether the considered process operating space safely respected limits of critical quality attribute (CQA) impurities; and(3) finding process setpoints that can potentially improve the KPIs. Objective 1 used global sensitivity analysis (GSA) to find that only operating parameters associated with the reactor were significant. Objectives 2 and 3 used nonlinear optimization, confirming that impurity limits are respected at any point in the considered process operating space and suggesting a shifted process setpoint that could allow enhanced yield (∼4% absolute increase) and reduced impurity content (∼0.5 mol % absolute reduction).

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Quality Assessment of API in Semisolid Topical Drug Products

Cited by 5 publications

References 112 publications

DEVELOPMENT AND CHARACTERIZATION OF LORATADINE LIPOSOMAL GEL USING QbD APPROACH

DEVELOPMENT AND CHARACTERIZATION OF LORATADINE LIPOSOMAL GEL USING QbD APPROACH

The Implications of Regulatory Framework for Topical Semisolid Drug Products: From Critical Quality and Performance Attributes towards Establishing Bioequivalence

Mathematical Modeling and Optimization to Inform Impurity Control in an Industrial Active Pharmaceutical Ingredient Manufacturing Process

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