Leveraging Modeling and Simulation to Enhance the Efficiency of Bioequivalence Approaches for Generic Drugs: Highlights from the 2023 Generic Drug Science and Research Initiatives Public Workshop.

The 2023 Generic Drug Science and Research Initiative Public Workshop organized by the U.S. Food and Drug Administration (FDA) discussed the research needs to improve and enhance bioequivalence (BE) approaches for generic drug development. FDA takes such research needs and panel discussions into account to develop its Generic Drug User Fee Amendments III (GDUFA III) Science and Research Initiatives specific to generics. During the five workshop sessions, presentations and panel discussions focused on identifying and addressing scientific gaps and research needs related to nitrosamine impurity issues, BE assessment for oral products, innovative BE approaches for long-acting injectable products, alternative BE approaches for orally inhaled products, and advanced BE methods for topical products. Specifically, this report highlights the discussions on how to improve BE assessment for developing generic drug products based on research priorities for leveraging quantitative methods and modeling, as well as artificial intelligence/machine learning (AI/ML).

Determining bioequivalence possibilities of long acting injectables through population PK modelling.

Long acting injectables (LAI) products are a popular intervention for treating a number of chronic conditions, with their long drug release reducing the administration frequency and thus improving patient adherence. The extended release, however, can provide a major challenge to bioequivalence (BE) testing since the long absorption half-life results in a long washout period, meaning that a traditional BE study can be many months or years in length. The unique PK profile for LAI products also means that it is critical to have appropriate metrics to summarise the plasma concentration profile. In this work, we use paliperidone as a case study to demonstrate how Population PK modelling can be utilised to explore sensitivity of summary metrics to different products. We also determine a range of products that are bioequivalent after both multiple dosing and single dosing. Finally, we show how the modelling can be used in a (virtual) PK study as an alternative approach to determining bioequivalence. This work demonstrates the potential for Population PK modelling in bioequivalence assessment, opening doors to more streamlined product development.

Utilização do método alternativo in vitro em substituição ao método in vivo na detecção de pirogênio para produtos injetáveis

Pyrogens are substances capable of inducing mild reactions such as fever or severe systemic reactions that can lead to death. Injectable products need to be free of pyrogens when released by the quality control of the pharmaceutical industries, to meet good manufacturing practices. Currently there are 3 types of tests for pyrogen detection, the Monocyte Activation Test, the Bacterial Endotoxin Test and the Pyrogen Test in Rabbits, which is widely used in the release of injectable products. However, the pyrogen test in rabbits requires the use of many animals and cannot be used in certain substances such as anti-inflammatory drugs. The alternative method of bacterial endotoxin testing is not able to detect other pyrogens such as products of the metabolism of fungi, viruses and gram-positive bacteria. The Monocytes Activation Test is an alternative method that covers a wide range of pyrogens, can be used on a large scale for the release of injectable products and is more sensitive because it uses human blood as substrate. This study aimed to evaluate the applicability of the use of the monocytes activation test in place of the pyrogen test in rabbits used in biological quality control in the release of batches of injectable products produced by the Butantan Institute.

Pirogênios são substâncias capazes de induzir reações leves como febre ou reações sistêmicas severas que podem levar à morte. Os produtos injetáveis necessitam ser livres de pirogênios quando da sua liberação pelo controle de qualidade das indústrias farmacêuticas, para atender as Boas Práticas de Fabricação. Atualmente existem 3 tipos de testes para detecção de pirogênio, o teste de Ativação de Monócitos, o Teste de Endotoxina Bacteriana e o Teste de Pirogênio em Coelhos, sendo esse amplamente empregado na liberação dos produtos injetáveis. Porém, o teste de pirogênio em coelhos é um teste que demanda a utilização de muitos animais e não pode ser usado em determinadas substâncias como antinflamatórios. O método alternativo de teste de endotoxina bacteriana não é capaz de detectar outros pirogênios como os produtos do metabolismo de fungos, vírus e bactérias gram-positivas. Já o teste de Ativação de Monócitos é um método alternativo que abrange uma ampla gama de pirogênios, pode ser usado em grande escala para liberação dos produtos injetáveis e é mais sensível, pois utiliza como substrato sangue humano. Este trabalho teve como objetivo avaliar a aplicabilidade da utilização do teste de ativação de monócitos em substituição ao teste de pirogênio em coelhos empregado no Controle Qualidade Biológico na liberação dos lotes dos produtos injetáveis produzidos pelo Instituto Butantan.

Achieving "Zero" Defects for Visible Particles in Injectables.

The reduction of visible particles in injectable products is an important element in the consistent delivery of high-quality parenteral products. An important part of this effort is the control of particles that may emanate from the primary packaging materials. The Parenteral Drug Association (PDA), with the support of the Pharmaceutical Manufacturers Forum (PMF), has undertaken the task of developing test methods to assess the cleanliness of primary packaging components used in the manufacturing of sterile injectable products. Further work is focused on end-to-end analysis of the supply chain to identify additional points where particles may enter the finished product workflow. This includes shipment, receipt, transfer, and fill and finishing operations. This information and appropriate corrective actions and control methods, coupled with appropriate patient risk-based acceptance limits, are intended to provide better and more consistent supply of injectable products that meet current compendial and good manufacturing practice (GMP) expectations. Aligning control limits between supplier and pharmaceutical manufacturers will offer further improvement. This paper describes the formation of a task force to address these needs and current progress to date.LAY ABSTRACT: Visible particles must be controlled in parenteral products. Such particles come from many sources including the primary packaging materials. The Parenteral Drug Association (PDA), with the support of the Pharmaceutical Manufacturers Forum (PMF), has formed a task force to review and improve particle measurement methods and perform an end-to-end analysis of how particles may enter into parenteral products. These activities are intended to lead to more consistent control limits for visible particles and ultimately more consistent supply of high quality injectable products.