Global outlook on affordability of biotherapeutic drugs.

Although biotherapeutic drugs have the potential of transforming the management of many life-threatening diseases, their affordability and accessibility remain an issue. This study offers an overview of the global affordability of biotherapeutic products. For this, prices for 10 representative biotherapeutic products were examined in 40 countries, including high-income countries (HICs), upper middle-income countries (UMICs), lower middle-income countries (LMICs), and low-income countries (LICs). The affordability of these biotherapeutics was calculated based on the World Health Organization/Health Action International (WHO/HAI) method. As expected, affordability was found to be better in HICs, followed by UMICs, LMICs, and finally, LICs. Furthermore, based on the trend of per capita income, we predict that in UMICs and LMICs, the affordability of high molecular weight biologics will worsen by 1.5× and 2× by 2030, respectively, and further by 4× and 6× by 2040. On the other hand, affordability will stay nearly the same for people living in HICs in the coming decades. Our analysis suggests that it is imperative that measures be taken to make this class of products more affordable and accessible. Governments can contribute by creating conducive policies. Global institutions like the WHO can play a significant role as well. Finally, manufacturers need to invest in and implement manufacturing innovations.

Soft sensor based rapid detection of trace chlorine dioxide (ClO2) concentration in water.

Chlorine dioxide (ClO2) is a widely used sterilizer and a disinfectant across a multitude of industries. When using ClO2, it is imperative to measure the ClO2 concentration to abide by the safety regulations. This study presents a novel, soft sensor method based on Fourier transform infrared spectroscopy (FTIR) spectroscopy for measurement of ClO2 concentration in different water samples varying from milli Q to wastewater. Six distinct artificial neural network models were constructed and evaluated based on three overarching statistical standards to select the optimal model. The OPLS-RF model outperformed all other models with R2, RMSE, and NRMSE values of 0.945, 0.24, and 0.063, respectively. The developed model demonstrated limit of detection and limit of quantification values of 0.1 and 0.25 ppm, respectively, for water. Furthermore, the model also exhibited good reproducibility and precision as measured by the BCMSEP (0.064). The soft sensor-based method presented in the study offers significant advantages in terms of simplicity and speedy detection. In summary, the study presents development of a soft sensor that is capable of predicting the trace content of chlorine dioxide ranging between 0.1 to 5 ppm in a water sample by connecting FTIR with an OPLS-RF model.

FDA Warning Letters: A Retrospective Analysis of Letters Issued to Pharmaceutical Companies from 2010-2020.

Purpose: To launch a pharmaceutical product in the US market, approval from the FDA is required. Pharmaceutical companies undergo FDA pre-approval inspection (PAI for small molecule products) or pre-license approval (PLI for biological products) at their manufacturing sites (including contract development and manufacturing organization, testing laboratories, and packaging labelling facilities) prior to approval. After the products are approved by the FDA, surveillance inspections are performed by the FDA which are risk based as which company and which site will be inspected. The present study examines the causes of warning letters issued by the Center for Drug Evaluation and Research (CDER), FDA to the pharmaceutical companies after post-approval inspections. Methods: Warning letters issued from the time period 2010 to 2020 were obtained from the FDA website, and information about date of issuance, company, and type of violations was extracted for the study. Results: Poor compliance to CGMP and misbranding were the most common reasons for the warning letters. Detailed analysis of CGMP warning letters elucidated three major types of violations, namely deficiencies in process validation, documentation practices (data integrity), and quality control corresponding to 26%, 21%, and 15% warning letters, respectively. Conclusion: Review of the analysed letters demonstrates that the FDA's major concern is over CGMP compliance. To avoid these warning letters, pharmaceutical manufacturers need to improve their quality compliance and focus on creating effective quality management systems that govern the entire manufacturing process, quality control, employee training, and documentation practice. Companies should develop an internal compliance check list and also be ready for corrective measures as and when required. Supplementary Information: The online version contains supplementary material available at 10.1007/s12247-022-09678-2.

Dynamics of biosimilar uptake in emerging markets.

INTRODUCTION: Globally, biosimilars are expected to play a key role in lowering healthcare costs and providing increased patient access to biological therapies. Given this, and in line with the European Union and World Health Organization, many emerging nations have adapted and established biosimilar regulatory guidelines. Emerging nations present a lucrative market for biosimilar development and commercialization, yet they also pose unique challenges. A thorough understanding of the unique attributes of emerging markets in relation to biosimilars is needed to promote their successful uptake in low- and middle-income countries. AREAS COVERED: This article highlights the opportunities and challenges that emerging markets represent in terms of biosimilar uptake. A comprehensive analysis of biosimilar uptake in European countries, where biosimilars have gained significant market share, was carried out to identify policies that can enhance market penetration in emerging nations. EXPERT OPINION: Implementation of pricing and procurement policies, as well as provider and patient confidence in biosimilar efficacy, are key factors in their uptake. Due to the high cost of biosimilar development, incentivizing domestic companies with the biosimilar manufacturing capability to produce these drugs will be helpful in ensuring a sustainable biosimilar market and a steady supply chain.

The global landscape on interchangeability of biosimilars.

INTRODUCTION: Biosimilars hold the potential to be an integral healthcare component that can significantly improve affordability and thereby accessibility of the otherwise expensive biotherapeutic products. Regulators, payors, and policymakers, each have a major role to play in successful adoption of biosimilars. One of the issues that has been a point of frequent discussion is that of interchangeability of biosimilars. AREAS COVERED: This article aims to review the position that the major regulatory bodies have taken on interchangeability of biosimilars. Key issues that remain are also discussed. Adalimumab and etanercept have been chosen as real-world case studies to demonstrate interchangeability considerations. The need for gaining global harmonization on interchangeability is highlighted. EXPERT OPINION: A global harmonization on the interchangeability can likely accelerate biosimilar adoption and result in better accessibility to biologics. Experience gained with real-world studies supports switching to biosimilars from originators however post-marketing pharmacovigilance should be in place to assess the risk-benefit profile of biosimilars in the long run.

Raman spectroscopy for in situ, real time monitoring of protein aggregation in lyophilized biotherapeutic products.

Quality of biotherapeutic products is of paramount importance for ensuring patient safety. Analytical tools that can facilitate rapid quality assessment of the therapeutic product at the point of care are very much in demand. In this article, we apply chemometrics based analysis of Raman spectra towards quantitative prediction of protein aggregation in lyophilized biotherapeutic products. Two commercially available therapeutic proteins, erythropoietin (EPO) and human growth hormone (HGH), have been used to demonstrate the applicability of the proposed approach. Thermally induced protein aggregation was monitored by size exclusion chromatography as well as Raman spectroscopy with a 785 nm wavelength laser. Partial least square (PLS) regression was used to analyse the Raman spectra and create a model for quantitative determination of aggregate. Satisfactory performance was observed with both EPO and HGH with R2 of 0.91 and 0.94, cross-validation correlation coefficient of 0.85 and 0.89, and Root Mean Square Error computed from cross calibration (RMSEcv) of 5.25 and 1.92, respectively. The developed approach can enable rapid and accurate assessment of aggregation in lyophilized samples of biotherapeutic products. The study also demonstrates novel use of Raman spectroscopy for protein quantification through a vial.

Considerations related to comparative clinical studies for biosimilars.

Introduction: Biosimilar medicines have transformed the healthcare landscape by providing improved access to life-saving medicines at a lower cost. Biosimilars are a distinct category of biologic therapeutics that enter the market after patent expiration of a reference molecule. Regulatory bodies worldwide have developed guidance to expedite the approval and entry of these drugs to the market. Biosimilar approval is based on a totality of the evidence approach, demonstrating similarity between the biosimilar and the originator in terms of physicochemical properties, quality characteristics, biological activity, safety, and efficacy.Areas covered: This article provides an overview of the biosimilar regulatory guidelines and discusses the importance and considerations of comparative clinical studies that are performed during biosimilar development. Two review assessment reports, one each from the EMA and the FDA, are presented.Expert opinion: The discussed case studies illustrate the importance of pharmacokinetic and pharmacodynamic studies in the regulatory approval of biosimilars. It is crucial for biosimilar developers to judiciously determine clinical parameters including biomarkers, endpoints, and acceptance criteria before executing clinical studies.

Approval of biosimilars: a review of unsuccessful regulatory filings.

INTRODUCTION: Over the past three decades, biotherapeutics have transformed health care by offering effective treatments for complex diseases that were otherwise difficult to deal with via small molecule pharmaceuticals. Patents on several biotherapeutics have expired or are due to expire in recent times, and this has fueled the growth in biosimilars, products that are deemed to be similar to the already-approved innovator products in terms of safety and efficacy. Production of biosimilars is complicated by the fact that in biotech processes, the process is the product and there have been many instances where a small change in the manufacturing process results in significant undesirable clinical impact. This is why regulatory authorities around the world have formulated stringent guidelines for the approval of biosimilars. AREAS COVERED: This article aims to review unsuccessful regulatory filings for biosimilar approval. EXPERT OPINION: We have focused on regulatory submissions to EMA and FDA. Key shortcomings of the filings that failed to receive approval have been identified and discussed.

Matrix-entrapped cellular secretome rescues diabetes-induced EPC dysfunction and accelerates wound healing in diabetic mice.

Cellular secretory products have infinite potential, which is only recently explored for research and therapeutic applications. The present study elaborated on the formation of a unique matrix-entrapped cellular secretome (MCS), a hydrogel-like secretome produced by bone marrow-derived mononuclear cells when cultured on a three-dimensional electrospun nanofiber matrix under specific conditions. These culture conditions support the growth of a mixed population predominantly comprising of endothelial precursor cells (EPCs), along with mesenchymal stromal cells and pericytes. Interestingly, such secretome is not formed in a pure culture of EPCs on the similarly formulated matrix, suggesting that a heterotypic cell-cell interaction is essential for the formation of MCS. In addition, the specific composition of the matrix was found to be a critical necessity for the formation of MCS. Furthermore, the application of the MCS as a substrate promotes the growth of EPCs in culture. It also rescues the diabetes-induced EPC dysfunction as assessed based on the parameters, such as viability, proliferation, colony formation, cellular adhesion, chemotactic migration, and tubule formation. MCS augments the levels of eNOS-specific mRNA (Nos3) and also promotes the restoration of the SDF1/CXCR4 axis in diabetic EPCs. Notably, a topical application of MCS on diabetic wounds leads to an accelerated wound closure. Thus, the current data showed that MCS forms an excellent cell-free biomaterial in the treatment of diabetic wounds and non-healing ulcers.

Hemostatic Efficacy of Nanofibrous Matrix in Rat Liver Injury Model.

This present study examined the hemostatic efficacy of nanofibrous matrix in a rat liver model. The nanofibrous matrix comprising gelatin and polycaprolactone was prepared by electrospinning method. Twelve animals underwent surgery and were followed-up for a month. Time taken to cease bleeding, activated partial thromboplastin time, prothrombin time, and fibrinogen concentration were measured. Histopathological examination of liver was also done of treated and control animals. All test animals showed very rapid hemostasis after application of electrospun sheet. Histopathological study showed quick recovery of liver wound in the test group as compared to the control group. The nanofibrous matrix has proven to be not only safe and effective as hemostat but has also shown its potential for liver regeneration.

Gelatin-PMVE/MA composite scaffold promotes expansion of embryonic stem cells.

We introduce a new composite scaffold of gelatin and polymethyl vinyl ether-alt-maleic anhydride (PMVE/MA) for expansion of embryonic stem cells (ESCs) in an in vitro environment. To optimize the scaffold, we prepared a gelatin scaffold (G) and three composite scaffolds namely GP-1, GP-2, and GP-3 with varying PMVE/MA concentrations (0.2-1%) and characterized them by scanning electron microscopy (SEM), swelling study, compression testing and FTIR. SEM micrographs revealed interconnected porous structure in all the scaffolds. The permissible hemolysis ratio and activation of platelets by scaffolds confirmed the hemocompatibility of scaffolds. Initial biocompatibility assessment of scaffolds was conducted using hepatocarcinoma (Hep G2) cells and adhesion, proliferation and infiltration of Hep G2 cells in depth of scaffolds were observed, proving the scaffold's biocompatibility. Further Oct4B2 mouse embryonic stem cells (mESCs), which harbor a green fluorescence protein transgene under regulatory control of the Oct4 promotor, were examined for expansion on scaffolds with MTT assay. The GP-2 scaffold demonstrated the best cell proliferation and was further explored for ESC adherence and infiltration in depth (SEM and confocal), and pluripotent state of mESCs was assessed with the expression of Oct4-GFP and stage-specific embryonic antigen-1 (SSEA-1). This study reports the first demonstration of biocompatibility of gelatin-PMVE/MA composite scaffold and presents this scaffold as a promising candidate for embryonic stem cell based tissue engineering.

Hardystonite improves biocompatibility and strength of electrospun polycaprolactone nanofibers over hydroxyapatite: a comparative study.

The aim of this study was to compare physico-chemical and biological properties of hydroxyapatite (HA) and hardystonite (HS) based composite scaffolds. Hardystonite (Ca2ZnSi2O7) powders were synthesized by a sol-gel method while polycaprolactone-hardystonite (PCL-HS) and polycaprolactone-hydroxyapatite (PCL-HA) were fabricated in nanofibrous form by electrospinning. The physico-chemical and biological properties such as tensile strength, cell proliferation, cell infiltration and alkaline phosphatase activity were determined on both kinds of scaffolds. We found that PCL-HS scaffolds had better mechanical strength compared to PCL-HA scaffolds. Addition of HA and HS particles to PCL did not show any inhibitory effect on blood biocompatibility of scaffolds when assessed by hemolysis assay. The in vitro cellular behavior was evaluated by growing murine adipose-tissue-derived stem cells (mE-ASCs) over the scaffolds. Enhanced cell proliferation and improved cellular infiltrations on PCL-HS scaffolds were observed when compared to HA containing scaffolds. PCL-HS scaffolds exhibited a significant increase in alkaline phosphatase (ALP) activity and better mineralization of the matrix in comparison to PCL-HA scaffolds. These results clearly demonstrate the stimulatory role of Zn and Si present in HS based composite scaffolds, suggesting their potential application for bone tissue engineering.