Mastering Quality: Uniting Risk Assessment With Quality by Design (QbD) Principles for Pharmaceutical Excellence.

The aim of this article is to present ideas and tools of risk assessment that can be implemented to overcome various pharmaceutical quality challenges. These elements cover the development, production, distribution, inspection, and reporting of review procedures for drug substances, drug products, and biological products at every stage of their lifecycle. In light of the constant requirement to ensure the drug's efficacy, safety, and quality, the pharmaceutical sector is always evolving. A key strategy for attaining pharmaceutical excellence in this dynamic environment is incorporating novel methods like quality by design (QbD) and risk assessment. Risk assessment is a methodical strategy to locate, assess, and minimize any risks in the manufacturing and development of pharmaceuticals. On the other hand, QbD principles place more emphasis on end-product testing and place it in the context of designing quality into the product from the beginning. The major goal of this paper is to address and examine the integration of risk assessment approaches with the QbD principle workflow to ensure pharmaceutical quality. Recent articles on how risk assessment has been used in pharmaceuticals were evaluated. To provide a useful overview, the various assessment methodologies have been highlighted, emphasizing their benefits and drawbacks.

Impact of NaCl on Monoclonal Antibody Aggregation Induced by Agitation.

Monoclonal antibodies (mAbs) are a successful class of therapeutics, but their development can be challenging due to the risk of degradation that could happen during manufacturing, storage, and clinical use. One of the common causes of degradation is agitation stress from transportation and clinical handling, which increases interfacial stresses to mAbs. For example, the preparation of the dose solution prior to administration often requires diluting therapeutic mAbs in intravenous (IV) infusion bags containing normal saline, which can substantially reduce the level of protective surfactant and increase the level of salt in mAb solutions. Then the interfacial stress in the subsequent transportation of IV bags can cause mAb aggregation or even particle formation. To better understand the complex interplay between dilution, interfacial stress, and salt, we studied the impact of sodium chloride (NaCl) on the aggregation of two mAbs under agitation stress. We found that the presence of NaCl accelerates the aggregation of both mAbs, but the aggregation mechanism, morphology, and reversibility are very different. Our results clearly highlight the impact of salt on mAb stability at the clinical in-use condition. We believe this study further increases our understanding of protein aggregation mediated by interfacial stresses and brings valuable insights to support development of mAb formulations for patients.

Detection of Pharmaceutical Personal Protective Equipment in Video Stream.

Pharmaceutical manufacturing is a complex process, where each stage requires a high level of safety and sterility. Personal Protective Equipment (PPE) is used for this purpose. Despite all the measures of control, human factor (improper PPE wearing) causes numerous losses for human health and material property. This research proposes solid computer vision system for ensuring safety in pharmaceutical laboratories. For this we have tested wide range of state-of-the-art object detection methods. Composing previously obtained results in this sphere with our own approach to this problem, we have reached the high accuracy (mAP@0.5) ranging from 0.77 up to 0.98 in detecting all the elements of common set of PPE used in pharmaceutical laboratories. Our system is the step towards safe medicine producing.

The Effect of Formulation Variables on the Manufacturability of Clopidogrel Tablets via Fluidized Hot-Melt Granulation-From the Lab Scale to the Pilot Scale.

Solid pharmaceutical formulations with class II active pharmaceutical ingredients (APIs) face dissolution challenges due to limited solubility, affecting in vivo behavior. Robust computational tools, via data mining, offer valuable insights into product performance, complementing traditional methods and aiding in scale-up decisions. This study utilizes the design of experiments (DoE) to understand fluidized hot-melt granulation manufacturing technology. Exploratory data analysis (MVDA) highlights similarities and differences in tablet manufacturability and dissolution profiles at both the lab and pilot scales. The study sought to gain insights into the application of multivariate data analysis by identifying variations among batches produced at different manufacturing scales for this technology. DoE and MVDA findings show that the granulation temperature, time, and Macrogol type significantly impact product performance. These factors, by influencing particle size distribution, become key predictors of product quality attributes such as resistance to crushing, disintegration time, and early-stage API dissolution in the profile. Software-aided data mining, with its multivariate and versatile nature, complements the empirical approach, which is reliant on trial and error during product scale-up.

Forecasting the potential impact of cell and gene therapies in France: projecting product launches and patients treated.

Objective: To evaluate the potential impact of cell and gene therapies (CGTs) in France by forecasting the number of patients that will be treated with CGTs over the period 2023-2030 by therapeutic area and region. Methods: A review of CGTs in clinical development and related disease epidemiology was conducted to forecast the number of CGT launches and patient population between 2023 and 2030. The number of expected launches was identified by filtering the clinical development pipeline with estimated time to launch and probability of success values from Project ALPHA. Disease prevalence and incidence in France were combined with projected adoption rates derived from historical data to forecast the patient population to be treated. Results: Up to 44 new CGTs are forecasted to launch in France in the period 2023-2030, which translates into more than 69,400 newly treated patients in 2030. Leading indications in terms of newly treated patients per year include cardiovascular disease, hematological cancers and solid tumors with 27,300, 15,200 and 13,000 newly treated patients in 2030, respectively. Discussion: The forecast suggests that the future landscape of CGTs will undergo a shift, moving from CGTs targeting (ultra) rare diseases to more prevalent diseases. In France, this will likely pose organizational challenges hindering patient access to these transformative therapies. Further research and planning around network organization and patient distribution are needed to assess and improve the readiness of the French healthcare system for ensuring access for this growing number of patients to be treated with CGTs.

Analysis of the Physical Characteristics of an Anhydrous Vehicle for Compounded Pediatric Oral Liquids.

The paucity of suitable drug formulations for pediatric patients generates a need for customized, compounded medications. This research study was set out to comprehensively analyze the physical properties of the new, proprietary anhydrous oral vehicle SuspendIt® Anhydrous, which was designed for compounding pediatric oral liquids. A wide range of tests was used, including sedimentation volume, viscosity, droplet size after dispersion in simulated gastric fluid, microscopic examination and content uniformity measurements to evaluate the properties of the anhydrous vehicle. The results showed that the vehicle exhibited consistent physical properties under varying conditions and maintained stability over time. This can be attributed to the unique blend of excipients in its formulation, which not only maintain its viscosity but also confer thixotropic behavior. The unique combination of viscous, thixotropic and self-emulsifying properties allows for rapid redispersibility, sedimentation stability, accurate dosing, potential drug solubility, dispersion and promotion of enhanced gastrointestinal distribution and absorption. Furthermore, the vehicle demonstrated long-term sedimentation stability and content uniformity for a list of 13 anhydrous suspensions. These results suggest that the anhydrous oral vehicle could serve as a versatile base for pediatric formulation, potentially filling an important gap in pediatric drug delivery. Future studies can further investigate its compatibility, stability and performance with other drugs and in different clinical scenarios.

Common ground: the opportunity of male contraceptives as MPTs.

Multipurpose prevention technologies (MPTs) and male contraceptive methods are currently in development to address unique and critical needs facing the global reproductive health community. Currently, MPT products in development are exclusively female-focused due to the readily available nature and regulatory precedent offered by female contraceptive active pharmaceutical ingredients (APIs); however, the opportunity to explore codevelopment with male contraceptive methods, which are at a comparatively early stage of development, should not be overlooked. These fields face parallel challenges including research and development, commercialization, regulatory approval, and market uptake, and these parallels can inform strategic alignment between the fields. One challenge that precludes codevelopment, however, is the path to market and associated funding models for these innovative, yet underappreciated fields. Without candid review, reconsideration, prioritization, and innovation led by the donor and investment communities, product developers will have no compelling reason to consider accepting the added regulatory and fiscal burden associated with combining development streams.

Synthesis of tritium-labeled Lu-PSMA-617: Alternative tool for biological evaluation of radiometal-based pharmaceuticals.

This project focuses on the generation and evaluation of functional alternatives to radiometal-based pharmaceuticals supporting basic research and the in vitro developmental phase. Employing robust tritium chemistry and non-radioactive metal surrogates in two synthetic and labeling strategies resulted in ([ring-3H]Nal)PSMA-617 and ([α,ß-3H]Nal)PSMA-617. In particular, ([α,ß-3H]Nal)Lu-PSMA-617 exhibited high radiolytic as well as metal-complex stability and was compared to the clinically-established radiopharmaceutical [177Lu]Lu-PSMA-617. The cell-based assays confirmed the applicability of ([α,ß-3H]Nal)Lu-PSMA-617 as a substitute of [177Lu]Lu-PSMA-617 in pre-clinical biological settings.

Circadian rhythm of plasminogen activator inhibitor-1 and cardiovascular complications in type 2 diabetes.

Cardiovascular complications are a common death cause in type 2 diabetes patients, as they are often combined. Plasminogen-activator Inhibitor 1 (PAI-1) participates in the development and progression of cardiovascular complications in diabetes. Insulin resistance increases PAI-1 production, and high PAI-1 levels lead to an environment conducive to thrombosis and earlier and more severe vascular disease. Current evidence also suggests that PAI-1 has a rhythmic profile of circadian fluctuations and acrophase in the morning within a single day, which might explain the high morning incidence of cardiovascular events. Thus, PAI-1 is a possible drug target. Although several PAI-1 inhibitors have been developed, none have yet been allowed for clinical use. Research on rhythm has also led to the concept of "chronotherapy", a rhythm-based drug regimen expected to improve the treatment of cardiovascular complications in diabetic patients. Herein, we searched several databases and reviewed relevant articles to describe the circadian rhythm characteristics and endogenous molecular mechanisms of PAI-1, its relationship with insulin resistance, the causes of cardiovascular complications caused by PAI-1, and the current development of PAI-1 inhibitors. We also summarized the possibility of using the circadian rhythm of PAI-1 to treat cardiovascular complications in diabetic patients.

Therapeutic targeting of Huntington's disease: Molecular and clinical approaches.

Huntington's disease (HD) is an autosomal dominant ailment that affects a larger population. Due to its complex pathology operating at DNA, RNA, and protein levels, it is regarded as a protein-misfolding disease and an expansion repeat disorder. Despite the availability of early genetic diagnostics, disease-modifying treatments are still missing. Importantly, potential therapies are starting to make their way through clinical trials. Still, clinical trials are ongoing to discover potential drugs to relieve HD symptoms. However, now being aware of the root cause, the clinical studies are focused on molecular therapies to target it. The road to success has not been without bumps since a big phase III trial of tominersen was unexpectedly discontinued due to exceeding risks than drug's benefit to the patients. Although the trial's conclusion was disappointing, there is still cause to be optimistic about what this technique may achieve. We have reviewed the present disease-modifying therapies in clinical development for HD and examined the current landscape of developing clinical therapies. We further investigated the pharmaceutical development of Huntington's medicine in the pharma industries and addressed the existing challenges in their therapeutic success.

R Shiny App for the Automated Deconvolution of NMR Spectra to Quantify the Solid-State Forms of Pharmaceutical Mixtures.

Bioavailability and chemical stability are important characteristics of drug products that are strongly affected by the solid-state structure of the active pharmaceutical ingredient (API). In pharmaceutical development and quality control activities, solid-state NMR (ssNMR) has proved to be an excellent tool for the detection and accurate quantification of undesired solid-state forms. To obtain correct quantitative outcomes, the resulting spectrum of an analytical sample should be deconvoluted into the individual spectra of the pure components. However, the ssNMR deconvolution is particularly challenging due to the following: the relatively large line widths that may lead to severe peak overlap, multiple spinning sidebands as a result of applying Magic Angle Spinning (MAS), and highly irregular peak shapes commonly observed in mixture spectra. To address these challenges, we created a tailored and automated deconvolution approach of ssNMR mixture spectra that involves a linear combination modelling (LCM) of previously acquired reference spectra of pure solid-state components. For optimal model performance, the template and mixture spectra should be acquired under the same conditions and experimental settings. In addition to the parameters controlling the contributions of the components in the mixture, the proposed model includes terms for spectral processing such as phase correction and horizontal shifting that are all jointly estimated via a non-linear, constrained optimisation algorithm. Finally, our novel procedure has been implemented in a fully functional and user-friendly R Shiny webtool (hence no local R installation required) that offers interactive data visualisations, manual adjustments to the automated deconvolution results, and the traceability and reproducibility of analyses.

Pharmacobezoar Formation From HPMC-AS-Containing Spray-Dried Formulations in Nonclinical Safety Studies in Rats.

Changing the physical state from crystalline to amorphous is an elegant method to increase the bioavailability of poorly soluble new chemical entity (NCE) drug candidates. Subsequently, we report findings from repeat-dose toxicity studies of an NCE formulated as a spray-dried amorphous solid dispersion (SD-ASD) based on hydroxypropyl methylcellulose acetate succinate (HPMC-AS) in rats. At necropsy, agglomerates of SD-ASD were found in the stomach and small intestine, which in reference to literature were termed pharmacobezoars. We interpreted the pH-dependent insolubility of HPMC-AS in the acidic gastric environment to be a precondition for pharmacobezoar formation. Gastric pharmacobezoars were not associated with clinical signs or alterations of clinical pathology parameters. Pharmacobezoar-correlated histopathological findings were limited to the stomach and consisted of atrophy, erosion, ulcer, and inflammation, predominantly of the nonglandular mucosa. Pharmacobezoars in the small intestines induced obstructive ileus with overt clinical signs which required unscheduled euthanasia, prominent alterations of clinical pathology parameters indicative of hypotonic dehydration, degenerative and inflammatory processes in the gastrointestinal tract, and secondary renal findings. The incidence of pharmacobezoars increased with dose and duration of dosing. Besides the relevance of pharmacobezoars to animal welfare, they limit the non-observed adverse effect level in nonclinical testing programs and conclusively their informative value.

Therapeutic Potential and Pharmaceutical Development of a Multitargeted Flavonoid Phloretin.

Phloretin is a flavonoid of the dihydrogen chalcone class, present abundantly in apples and strawberries. The beneficial effects of phloretin are mainly associated with its potent antioxidant properties. Phloretin modulates several signaling pathways and molecular mechanisms to exhibit therapeutic benefits against various diseases including cancers, diabetes, liver injury, kidney injury, encephalomyelitis, ulcerative colitis, asthma, arthritis, and cognitive impairment. It ameliorates the complications associated with diabetes such as cardiomyopathy, hypertension, depression, memory impairment, delayed wound healing, and peripheral neuropathy. It is effective against various microbial infections including Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Escherichia coli, Candida albicans and methicillin-resistant Staphylococcus aureus. Considering the therapeutic benefits, it generated interest for the pharmaceutical development. However, poor oral bioavailability is the major drawback. Therefore, efforts have been undertaken to enhance its bioavailability by modifying physicochemical properties and molecular structure, and developing nanoformulations. In the present review, we discussed the pharmacological actions, underlying mechanisms and molecular targets of phloretin. Moreover, the review provides insights into physicochemical and pharmacokinetic characteristics, and approaches to promote the pharmaceutical development of phloretin for its therapeutic applications in the future. Although convincing experimental data are reported, human studies are not available. In order to ascertain its safety, further preclinical studies are needed to encourage its pharmaceutical and clinical development.

Heterosynthons, Solid Form Design and Enhanced Drug Bioavailability.

Starting from a molecular pharmacophore, which is a marker of drug action in medicinal molecules, we propose that the heterosynthon, a supramolecular synthon between unlike functional groups, plays an analogous role in the design and discovery of high bioavailability drugs. The heterosynthon could provide a more efficient and economical route to novel drugs.

Emerging therapeutic developments in neurodegenerative diseases: A clinical investigation.

Despite a century of intensive research, there is still a lack of disease-modifying treatments for neurodegenerative diseases that pose a threat to human society. A well-documented knowledge and resource gap has impeded the translation of fundamental research into promising therapies. In addition, the analysis of extensive preclinical data to allow the improved selection of therapeutic technologies and clinical candidates for further development is challenging. To address this need, we describe technologies that have emerged over the past decade that have enabled the development of novel, high-quality, cost-effective treatments for major neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Moreover, we benchmark emerging technologies that have been adopted by top pharmaceutical companies looking to bridge the gap between drug discovery and drug development in neurodegenerative disease.

Deep learning-based image-analysis algorithm for classification and quantification of multiple histopathological lesions in rat liver.

Artificial intelligence (AI)-based image analysis is increasingly being used for preclinical safety-assessment studies in the pharmaceutical industry. In this paper, we present an AI-based solution for preclinical toxicology studies. We trained a set of algorithms to learn and quantify multiple typical histopathological findings in whole slide images (WSIs) of the livers of young Sprague Dawley rats by using a U-Net-based deep learning network. The trained algorithms were validated using 255 liver WSIs to detect, classify, and quantify seven types of histopathological findings (including vacuolation, bile duct hyperplasia, and single-cell necrosis) in the liver. The algorithms showed consistently good performance in detecting abnormal areas. Approximately 75% of all specimens could be classified as true positive or true negative. In general, findings with clear boundaries with the surrounding normal structures, such as vacuolation and single-cell necrosis, were accurately detected with high statistical scores. The results of quantitative analyses and classification of the diagnosis based on the threshold values between "no findings" and "abnormal findings" correlated well with diagnoses made by professional pathologists. However, the scores for findings ambiguous boundaries, such as hepatocellular hypertrophy, were poor. These results suggest that deep learning-based algorithms can detect, classify, and quantify multiple findings simultaneously on rat liver WSIs. Thus, it can be a useful supportive tool for a histopathological evaluation, especially for primary screening in rat toxicity studies.

A review on the modernization of pharmaceutical development and manufacturing - Trends, perspectives, and the role of mathematical modeling.

Recently, the pharmaceutical industry has been facing several challenges associated to the use of outdated development and manufacturing technologies. The return on investment on research and development has been shrinking, and, at the same time, an alarming number of shortages and recalls for quality concerns has been registered. The pharmaceutical industry has been responding to these issues through a technological modernization of development and manufacturing, under the support of initiatives and activities such as quality-by-design (QbD), process analytical technology, and pharmaceutical emerging technology. In this review, we analyze this modernization trend, with emphasis on the role that mathematical modeling plays within it. We begin by outlining the main socio-economic trends of the pharmaceutical industry, and by highlighting the life-cycle stages of a pharmaceutical product in which technological modernization can help both achieve consistently high product quality and increase return on investment. Then, we review the historical evolution of the pharmaceutical regulatory framework, and we discuss the current state of implementation and future trends of QbD. The pharmaceutical emerging technology is reviewed afterwards, and a discussion on the evolution of QbD into the more effective quality-by-control (QbC) paradigm is presented. Further, we illustrate how mathematical modeling can support the implementation of QbD and QbC across all stages of the pharmaceutical life-cycle. In this respect, we review academic and industrial applications demonstrating the impact of mathematical modeling on three key activities within pharmaceutical development and manufacturing, namely design space description, process monitoring, and active process control. Finally, we discuss some future research opportunities on the use of mathematical modeling in industrial pharmaceutical environments.

QbD-guided pharmaceutical development of Pembrolizumab biosimilar candidate PSG-024 propelled to industry meeting primary requirements of comparability to Keytruda®.

Pharmaceutical development of biosimilars is primarily focused on meeting the regulatory requirements for analytical comparability of the product's critical quality attributes (CQAs), concerning safety and efficacy, to those of the originator drug of interest. To this end, the early adoption of a systematic science-based approach, as guided by quality-by-design (QbD) principles, is crucial due to the blind starting point where the same insights of an originator developer into the challenges of a given biopharmaceutical and its manufacturing process are lacking. In this study, we devised a pharmaceutical QbD-guided approach to undertake the biosimilar development of Pembrolizumab (Keytruda®), the ace of therapeutic monoclonal antibodies (mAbs) in terms of approved indications and market sales, and its manufacturing process development. Quality target product profile (QTPP) for Pembrolizumab biosimilar product was assembled using publicly available information on Keytruda®. Upon preliminary analyses of four different lots of Keytruda®, the product CQAs and their acceptable ranges of specification were determined via risk assessment based on the relevant pharmaceutical development quality guidelines, particularly those of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). The development and clone selection of Chinese Hamster Ovary (CHO) DG44 cell line was performed using DHFR expression vectors and Methotrexate (MTX) selective pressure. The CHO clone stably expressing relatively higher mAb titer (∼1200 mg/l) in small-scale shake-flask cultures, with the highest similarity of the CQAs charge variants contents (CVCs), N-glycan profile, and biological potency to those of Keytruda® reference standard was selected as the lead clone and the produced Pembrolizumab candidate was named PSG-024. The upstream process (USP) and downstream process (DSP) developments for production were started with the process evaluation screening experiments for the identification of critical process parameters (CPPs) founded upon the prior knowledge on different process stages, input process parameters (iPPs), output process parameters (oPPs), and their impacts on product CQAs. Thereby, screening experiments of USP fed-batch cell culture in 5-liter bioreactor resulted in improvement of PSG-024 expression titer to 2060 ± 70 mg/l and selection of the iPPs feed amount (A), glucose setpoint (B), culture temperature (C), and agitation rate (D) for the optimization design of experiments (DoEs) mainly focused on the CQA acidic CVC and the oPPs mAb expression yield. The USP optimization DoEs using response surface methodology (RSM) yielded valid prediction models and optimal conditions of A = 35%, B = 4.5 g/l, C = 37 °C, and D = 160-220 rpm, which resulted in the final PSG-024 expression titer of 3170 ± 40 mg/l without an excessive rise in acidic CVC. The DSP screening experiments led to achieving the mAb recovery rates of 94% ± 3% and 71.5% ± 3.5% for affinity (capture) and cation-exchange (polishing) chromatography stages, respectively. The capture eluate buffer and viral inactivation conditions were optimized to prevent mAb eluate turbidity and protein aggregation. Moreover, the polishing stage optimization DoEs via one-factor-at-a-time method focused on wash and elution steps for control of the acidic CVC CQA and achieving >80% mAb recovery rate. By shifting to Step elution from the primary salt gradient method and considering an additional intermediate wash step, the maximum mAb recovery of 87% ± 1.5% was achievable while maintaining the CQA acidic CVC within the acceptable range. The consistency of final analytical comparability of PSG-024 demonstrated the effectiveness of the adopted pharmaceutical QbD approach for Pembrolizumab biosimilar development, paving the way for the technology transfer to the client to proceed further development.

Practical use of primary drying models in an industrial environment with limited availability of equipment sensors.

In the pharmaceutical industry, lyophilization is typically adopted to extend long-time stability of valuable thermolabile medicines and vaccines. Primary drying is the most time-consuming and energy-intensive step of the entire process; thus, accelerating and optimizing the primary drying recipe is a key process development goal. To that purpose, mathematical models have been proposed and successfully validated. However, models typically require invasive experiments and/or sensors (e.g. product temperatures) for parameter estimation, which are rarely available in good manufacturing practice (GMP) environment. This represents a severe limitation when leveraging the model to transfer operation recipes across different facilities and for scale-up. In this study, we assess the possibility to exploit limited industrial data for model parameter estimation, namely pressure measurements and gravimetric tests, by defining a calibration protocol that is tested on two different pieces of equipment. Results are verified on a recently proposed model, and show that statistically meaningful estimates can be obtained without the need of product temperature measurements. Model predictions and optimal inputs trajectories are comparable to those obtained from the model calibrated using the full set of temperature and pressure data.