Understanding Quality Paradigm Shifts in the Evolving Pharmaceutical Landscape: Perspectives from the USP Quality Advisory Group.

Recent changes in the pharmaceutical industry have led to significant paradigm shifts in the pharmaceutical quality environment. Globalization of the pharmaceutical industry, increasingly rapid development of novel therapies, and adoption of new manufacturing techniques have presented numerous challenges for the established regulatory framework and quality environment and are impacting the approaches utilized to ensure the quality of pharmaceutical products. Regulators, industry, and standards-setting organizations have begun to recognize the need to rely more on integrated risk-based approaches and to create more nimble and flexible standards to complement these efforts. They also increasingly have recognized that quality needs to be built into systems and processes throughout the lifecycle of the product. Moreover, the recent COVID-19 crisis has emphasized the need to adopt practices that better promote global supply chain resilience. In this paper, the USP Quality Advisory Group explores the various paradigm shifts currently impacting pharmaceutical quality and the approaches that are being taken to adapt to this new environment. Broad adoption of the Analytical Procedure Lifecycle approach, improved data management, and utilization of digital technologies are identified as potential solutions that can help meet the challenges of these quality paradigm shifts. Further discussion and collaboration among stakeholders are needed to pursue these and other solutions that can ensure a continued focus on quality while facilitating pharmaceutical innovation and development.

COVID-19 vaccine platforms: Delivering on a promise?

The emergence of the novel SARS-CoV-2 and COVID-19 has brought into sharp focus the need for a vaccine to prevent this disease. Vaccines have saved millions of lives since their introduction to the public over 200 years ago. The potential for vaccination reached new heights in the mid-20th century with the development of technologies that expanded the ability to create novel vaccines. Since then, there has been continued technological advancement in vaccine development. The resulting platforms provide the promise for solutions for many infectious diseases, including those that have been with us for decades as well as those just now emerging. Each vaccine platform represents a different technology with a unique set of advantages and challenges, especially when considering manufacturing. Therefore, it is essential to understand each platform as a separate product and process with its specific quality considerations. This review outlines the relevant platforms for developing a vaccine for SARS-CoV-2 and discusses the advantages and disadvantages of each.

Do Standards Matter? What is Their Value?

Standards allow us to manage expectations for a diverse range of goods and services across the globe. From coordinating international global telecommunications across 24 different time zones to ensuring access to safe drinking water, standards allow us to work, communicate, collaborate, and live with certain expectations about safety and efficacy. When standards are fit-for-purpose, they raise the quality of products and services without requiring us to think about how that quality is assured. The result is that the successful implementation of standards for certain products can counterintuitively make it easy to overlook their importance when creating policies and regulations for next-generation products, such as generic drugs vis-à-vis biosimilars. Here we review the value of public standards as applied to the pharmaceutical industry. Using case studies, we demonstrate how standards for complex products, such as biologics, can be created and managed to ensure their optimal value to society while minimizing the burden to the industry. We also discuss the sustainability of standard development and whether there is sufficient transparency to maintain their role in the public trust. Finally, we assess the ability of standards to promote access to reasonably priced and high-quality biosimilars while enabling efficient product development and review.

Dietary supplements quality analysis tools from the United States Pharmacopeia.

The United States Food and Drug Administration (FDA) issued the dietary supplement (DS) current good manufacturing practice (GMP) regulations in compliance with the mandate from the Dietary Supplements Health and Education Act (DSHEA), with the intention of protecting public health by ensuring the quality of DS. The GMP regulations require manufacturers to establish their own quality specifications for identity, purity, strength, composition, and absence of contaminants. Numerous FDA-conducted GMP inspections found that the private specifications set by these manufacturers are often insufficient to ensure adequate quality of dietary ingredients and DS. Wider use of the public standards developed by the United States Pharmacopeial Convention (USP), in conjunction with GMP compliance, can help ensure quality and consistency of DS as they do for medicines. Public health protection could be enhanced by strengthening the GMP provisions to require conformance with relevant United States Pharmacopeia-National Formulary (USP-NF) standards, or in the absence of USP standards, other public compendial standards. Another serious concern is the presence of synthetic drugs and drug analogues in products marketed as DS. Use of the new USP General Chapter Adulteration of Dietary Supplements with Drugs and Drug Analogs <2251> may reduce the exposure of consumers to dangerous drugs disguised as DS. Copyright © 2016 John Wiley & Sons, Ltd.

Biosimilar monoclonal antibodies: the scientific basis for extrapolation.

INTRODUCTION: Biosimilars are biologic products that receive authorization based on an abbreviated regulatory application containing comparative quality and nonclinical and clinical data that demonstrate similarity to a licensed biologic product. Extrapolation of safety and efficacy has emerged as an important way to simplify biosimilar development. Regulatory authorities have generally reached the consensus that extrapolation of similarity from one indication to other approved indications of the reference product can be permitted if it is scientifically justified. AREAS COVERED: Recently, the first biosimilar, biosimilar infliximab (Remsima/Inflectra) to the innovator monoclonal antibody infliximab (Remicade), was approved in the European Union, Canada and South Korea; the USA subsequently approved its first biosimilar, a less complex molecule (filgrastim-sndz). Based on two clinical trials of biosimilar infliximab in patients with rheumatoid arthritis and ankylosing spondylitis, the European Medicines Agency allowed extrapolation to all eight approved indications for innovator infliximab, whereas Health Canada did not permit extrapolation to the indications for ulcerative colitis and Crohn's disease. These differing decisions on extrapolation of indications for biosimilar infliximab highlight important unanswered regulatory and scientific questions. Here, we propose substantive scientific considerations for indication extrapolation. EXPERT OPINION: The preclinical and clinical criteria that are currently required to merit indication extrapolation have not been rigorously evaluated.

Consistency of quality attributes for the glycosylated monoclonal antibody Humira® (adalimumab).

Humira® (adalimumab) is a recombinant human IgG1 monoclonal antibody (mAb) glycoprotein consisting of 1330 amino acids that is specific for human tumor necrosis factor (TNF). The biological activity and clinical profile of mAb therapeutics, including adalimumab, is influenced by their protein structure and glycosylation patterns, which can be affected by the expression system, cell culture conditions and purification process methodology. While clinical outcome cannot yet be attributed to many of the individual structural features that constitute a mAb, it is evident that detailed structural attribute analysis is necessary if structural contributions to function are to be comprehensively defined. Adalimumab product quality data generated from over a decade of manufacturing across multiple production sites and through a series of manufacturing scale changes are presented here. These data reveal a consistent and tightly controlled profile for the product.

Deletions in the S1 domain of Rrp5p cause processing at a novel site in ITS1 of yeast pre-rRNA that depends on Rex4p.

Rrp5p is the only protein so far known to be required for the processing of yeast pre-rRNA at both the early sites A0, A1 and A2 leading to 18S rRNA and at site A3, the first step specific for the pathway leading to 5.8S/25S rRNA. Previous in vivo mutational analysis of Rrp5p demonstrated that the first 8 of its 12 S1 RNA-binding motifs are involved in the formation of the 'short' form of 5.8S rRNA (5.8S(S)), which is the predominant species under normal conditions. We have constructed two strains in which the genomic RRP5 gene has been replaced by an rrp5 deletion mutant lacking either S1 motifs 3-5 (rrp5-Delta3) or 5-8 (rrp5-Delta4). The first mutant synthesizes almost exclusively 5.8S(L) rRNA, whereas the second one still produces a considerable amount of the 5.8S(S) species. Nevertheless, both mutations were found to block cleavage at site A3 completely. Instead, a novel processing event occurs at a site in a conserved stem-loop structure located between sites A2 and A3, which we have named A4. A synthetic lethality screen using the rrp5-Delta3 and rrp-Delta4 mutations identified the REX4 gene, which encodes a non-essential protein belonging to a class of related yeast proteins that includes several known 3'-->5' exonucleases. Inactivation of the REX4 gene in rrp5-Delta3 or rrp-Delta4 cells abolished cleavage at A4, restored cleavage at A3 and returned the 5.8S(S):5.8S(L) ratio to the wild-type value. The sl phenotype of the rrp5Delta/rex4(-) double mutants appears to be due to a severe disturbance in ribosomal subunit assembly, rather than pre-rRNA processing. The data provide direct evidence for a crucial role of the multiple S1 motifs of Rrp5p in ensuring the correct assembly and action of the processing complex responsible for cleavage at site A3. Furthermore, they clearly implicate Rex4p in both pre-rRNA processing and ribosome assembly, even though this protein is not essential for yeast.