Antibody-Drug Conjugate Overview: a State-of-the-art Manufacturing Process and Control Strategy.

Antibody-drug conjugates (ADCs) comprise an antibody, linker, and drug, which direct their highly potent small molecule drugs to target tumor cells via specific binding between the antibody and surface antigens. The antibody, linker, and drug should be properly designed or selected to achieve the desired efficacy while minimizing off-target toxicity. With a unique and complex structure, there is inherent heterogeneity introduced by product-related variations and the manufacturing process. Here this review primarily covers recent key advances in ADC history, clinical development status, molecule design, manufacturing processes, and quality control. The manufacturing process, especially the conjugation process, should be carefully developed, characterized, validated, and controlled throughout its lifecycle. Quality control is another key element to ensure product quality and patient safety. A patient-centric strategy has been well recognized and adopted by the pharmaceutical industry for therapeutic proteins, and has been successfully implemented for ADCs as well, to ensure that ADC products maintain their quality until the end of their shelf life. Deep product understanding and process knowledge defines attribute testing strategies (ATS). Quality by design (QbD) is a powerful approach for process and product development, and for defining an overall control strategy. Finally, we summarize the current challenges on ADC development and provide some perspectives that may help to give related directions and trigger more cross-functional research to surmount those challenges.

Pull me - push you? The disparate financing mechanisms of drug research in global health.

BACKGROUND: There is an inconsistency in the way pharmaceutical research is financed. While pull mechanisms are predominantly used to incentivize later-stage pharmaceutical research for products with demand in the Global North, so-called neglected diseases are chiefly financed by push funding. This discrepancy has so far been ignored in the academic debate, and any compelling explanation for why we draw the line between push and pull at poor people is lacking. MAIN BODY: Clinical development of new pharmaceuticals is chiefly financed by free market pull mechanisms. Even in cases where markets fail to deliver adequate incentives, demand enhancement mechanisms are used to replicate pull funding artificially, for example, with subscription models for antibiotics. Push funding in clinical research is almost always used when the poverty of patients means that markets fail to create sufficient demand. The general question of whether push or pull generally is the more efficient way to conduct pharmaceutical research arises. CONCLUSIONS: If the state is efficient in directing limited budgets for pharmaceutical research, push funding should be expanded to global diseases. If private industry is the more efficient actor, there would be enormous value in experimenting more aggressively with different approaches to enhance market demand artificially for neglected diseases.

Of rodents, research and relationships: a pharmacological odyssey.

This article is an autobiographical account of a research career in inflammatory diseases, mechanisms and pharmacotherapy, drug research and development, in academia and industry in various European countries spanning the last 55 years. The author describes how tenacity and independent thought, learned in formative years, and tempered later by the development of good relationships with colleagues have guided his career. This has spanned research, among other fields, on prostaglandins as pro-and anti-inflammatory mediators, oxidative stress and antioxidants, phospholipid mediators, cytokines, innate and adaptive immune responses and the establishment of various inflammatory and immunological models. The author has helped discover and develop novel therapeutic approaches to pain, arthritic, dermatological, respiratory, and autoimmune disorders and contributed to bringing eight drug candidates to clinical trials. He has helped establish new research labs in four different centres and been involved in teaching undergraduate and mature students in three different universities. With extensive experience in scientific publishing and several international awards, he emphasises that without good teamwork, little can be achieved in scientific research.

The Artificial Intelligence-Powered New Era in Pharmaceutical Research and Development: A Review.

Currently, artificial intelligence (AI), machine learning (ML), and deep learning (DL) are gaining increased interest in many fields, particularly in pharmaceutical research and development, where they assist in decision-making in complex situations. Numerous research studies and advancements have demonstrated how these computational technologies are used in various pharmaceutical research and development aspects, including drug discovery, personalized medicine, drug formulation, optimization, predictions, drug interactions, pharmacokinetics/ pharmacodynamics, quality control/quality assurance, and manufacturing processes. Using advanced modeling techniques, these computational technologies can enhance efficiency and accuracy, handle complex data, and facilitate novel discoveries within minutes. Furthermore, these technologies offer several advantages over conventional statistics. They allow for pattern recognition from complex datasets, and the models, typically developed from data-driven algorithms, can predict a given outcome (model output) from a set of features (model inputs). Additionally, this review discusses emerging trends and provides perspectives on the application of AI with quality by design (QbD) and the future role of AI in this field. Ethical and regulatory considerations associated with integrating AI into pharmaceutical technology were also examined. This review aims to offer insights to researchers, professionals, and others on the current state of AI applications in pharmaceutical research and development and their potential role in the future of research and the era of pharmaceutical Industry 4.0 and 5.0.

Trend of pharmaceuticals 3D printing in the Middle East and North Africa (MENA) region: An overview, regulatory perspective and future outlook.

The traditional method of producing medicine using the "one-size fits all" model is becoming a major issue for pharmaceutical manufacturers due to its inability to produce customizable medicines for individuals' needs. Three-dimensional (3D) printing is a new disruptive technology that offers many benefits to the pharmaceutical industry by revolutionizing the way pharmaceuticals are developed and manufactured. 3D printing technology enables the on-demand production of personalized medicine with tailored dosage, shape and release characteristics. Despite the lack of clear regulatory guidance, there is substantial interest in adopting 3D printing technology in the large-scale manufacturing of medicine. This review aims to evaluate the research efforts of 3D printing technology in the Middle East and North Africa (MENA) region, with a particular emphasis on pharmaceutical research and development. Our analysis indicates an upsurge in the overall research activity of 3D printing technology but there is limited progress in pharmaceuticals research and development. While the MENA region still lags, there is evidence of the regional interest in expanding the 3D printing technology applications in different sectors including pharmaceuticals. 3D printing holds great promise for pharmaceutical development within the MENA region and its advancement will require a strong collaboration between academic researchers and industry partners in parallel with drafting detailed guidelines from regulatory authorities.

Registering transparency: the making of the international clinical trial registry platform by the world health organization (2004-2006).

BACKGROUND: This paper examines the events and conditions that led to the creation of the International Clinical Trials Registry Platform (ICTRP) in 2006 by the World Health Organization (WHO), and how the WHO addressed the issue of transparency in global pharmaceutical research. Using historical textual analysis, I trace the scientific debates that advocated for the establishment of official clinical trial registries in medical journals, and the sequence of actions following the GSK Paxil scandal in 2004, identifying the major ethical and scientific arguments that led to the involvement of the WHO as a key actor in trial registration in the context of the Big Pharma business model. RESULTS: Through the questions "Why register?" and "Why registries?" as a roadmap, I examine the issues of publication bias and selective reporting by the industry, scrutinizing two ways in which the practice of publication bias damaged transparency in industry-sponsored research. The first involved ethical concerns regarding human subject exploitation and concealing of negative results. The second addresses the deterioration of the certainty of evidence due to incomplete access to trials results. By reviewing the series of events that occurred between 2004 and 2006 -between the Paxil scandal and the launch of the ICTRP-, I analyze the actions taken by the different actors involved: (1) the International Committee of Medical Journal Editors (ICMJE) and the creation of the Ottawa Group; (2) the WHO, beginning with the Ministerial Summit on Health Research held in November of 2004, and (3) the responses of the pharmaceutical industry and specifically GSK to the call for transparency and trial registration. CONCLUSIONS: The history of trial registration through the ICTRP as a dataveillance apparatus shows the difficulty of regulating a health enterprise turned into a global business. Moreover, it shows the challenges of globalization and how easier and faster it is to globalize business compared to good practices, raising the question of why it has been so hard to undo these trends. Indeed, the history of the movement for trial registration is not a history of regulation success, or at least not yet.

Three-Dimensional Cell Co-Culture Liver Models and Their Applications in Pharmaceutical Research.

As the primary site for the biotransformation of drugs, the liver is the most focused on organ type in pharmaceutical research. However, despite being widely used in pharmaceutical research, animal models have inherent species differences, while two-dimensional (2D) liver cell monocultures or co-cultures and three-dimensional (3D) liver cell monoculture in vitro liver models do not sufficiently represent the complexity of the human liver's structure and function, making the evaluation results from these tools less reliable. Therefore, there is a pressing need to develop more representative in vitro liver models for pharmaceutical research. Fortunately, an exciting new development in recent years has been the emergence of 3D liver cell co-culture models. These models hold great promise as in vitro pharmaceutical research tools, because they can reproduce liver structure and function more practically. This review begins by explaining the structure and main cell composition of the liver, before introducing the potential advantages of 3D cell co-culture liver models for pharmaceutical research. We also discuss the main sources of hepatocytes and the 3D cell co-culture methods used in constructing these models. In addition, we explore the applications of 3D cell co-culture liver models with different functional states and suggest prospects for their further development.

Challenges and Opportunities to Updating Prescribing Information for Longstanding Oncology Drugs.

A number of important drugs used to treat cancer-many of which serve as the backbone of modern chemotherapy regimens-have outdated prescribing information in their drug labeling. The Food and Drug Administration is undertaking a pilot project to develop a process and criteria for updating prescribing information for longstanding oncology drugs, based on the breadth of knowledge the cancer community has accumulated with the use of these drugs over time. This article highlights a number of considerations for labeling updates, including selecting priorities for updating; data sources and evidentiary criteria; as well as the risks, challenges, and opportunities for iterative review to ensure prescribing information for oncology drugs remains relevant to current clinical practice.

Assessing the quality of meta-analyses in systematic reviews in pharmaceutical research in Iran by 2016: A systematic review.

Background: Meta-analyses, like all other studies, may be poorly designed and implemented. This study was designed to determine the quality of meta-analyses in systematic reviews in the field of pharmaceutical research in Iran. Methods: Web of Science Core Collection, EMBASE, Ovid Medline, CINAHL, Scopus, and PubMed were systematically searched on June 4, 2017. The search was limited to the researches in the field of pharmaceutical studies. Based on inclusion criteria, 104 systematic reviews with meta-analysis (SRMA) were selected and assessed using quality assessment tools introduced by Higgins. Results: Participants, experimental interventions, and outcomes were reported in all the articles. Comparator intervention and study design were correctly reported in 103 (99.04%) and 101 (97.12%) articles, respectively. The comprehensive search strategy was available only in 48 articles (46.16%), and there was no evidence of a comprehensive search in 56 articles (53.84%). Risk of bias was investigated in 78 articles (75%). Also, funnel plots were the most commonly used method for reporting the bias in 64 articles (46.42%). Conclusion: In many of the meta-analyses, several items of the tool that represented a high-quality meta-analysis were absent. According to the findings, the comprehensive search and quality assessment were not at an appropriate level. Thus, the importance of reproducibility of information and quality assessment of included studies should be emphasized.

Development of immediate release Rupatadine fumarate 10 mg tablets: A Quality by Design (QbD) approach.

Objective: The main objective of this research is to develop an immediate release Rupatadine fumarate 10 mg tablets formulation by direct compression, through a Quality by Design approach in Costa Rica. Methods: According to a Quality by Design approach; Target Product Profile, Quality Target Product Profile, and the Critical Quality Attributes were defined. In the preformulation study, compatibility tests were carried out between the raw materials. The Critical Material Attributes were established using Quality Risk Management. Three formulation prototypes were prepared by direct compression and its Critical Process Parameters were defined. The analysis of the prototypes was realized in terms of organoleptic properties, identification, potency, content uniformity, dissolution, disintegration, friability and loss by drying. Results: All the prototypes showed a white or slightly pink surface, potency between 90.0 -110.0 % of the labeling, an acceptance value for the content uniformity lower than the specification (AV < 15), the dissolved amount of active pharmaceutical ingredient was greater than 85.0 % at 30 minutes, friability less than 1.0 %, a disintegration time less than 15 minutes and moisture content less than 2.0 %. Conclusions: The approaching of a Quality by Design model to the current development allowed to obtain satisfactory results in the three formulation prototypes. The excipients to be used can be lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, pregelatinized starch, magnesium stearate, stearic acid, and PVP K-30.